Effects of Sphingosine 1-phosphate Modulators on Central Remyelination: A Systematic Review of Animal Models

Effects of Sphingosine 1-phosphate Modulators on Central Remyelination: A Systematic Review of Animal Models | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Sphingosine 1-phosphate Modulators on Central Remyelination: A Systematic Review of Animal Models Harley Vu, Nelson George, Junhua Xiao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8856008/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Promoting remyelination is a key therapeutic goal in demyelinating diseases such as multiple sclerosis (MS), yet effective strategies remain limited. Sphingosine-1-phosphate (S1P), a ubiquitous bioactive lipid, has emerged as a key therapeutic target in MS due to its dual roles in immune regulation and neuroprotection; however, the therapeutic efficacy of current S1P-based therapies in remyelination remains unclear. This systematic review evaluated in vivo studies up to July 2025, in accordance with PRISMA guidelines, to assess the efficacy of S1P modulators on remyelination in mammalian models of demyelination. A comprehensive search across three databases identified 24 eligible studies that investigated S1P receptor (S1PR) modulation in both acute and chronic models of demyelination, with or without immune-mediated components. Fingolimod was the most extensively studied compound (16 studies). Of the 18 studies assessing demyelination outcomes, S1P modulation consistently attenuated myelin loss and oligodendrocyte depletion. In contrast, remyelination outcomes were inconsistent: among 15 studies assessing repair, most reported no significant enhancement. While fingolimod showed limited evidence on remyelination, more promising effects were observed with selective S1PR1/5 modulators such as siponimod and ponesimod. Overall, current evidence supports a model in which S1P modulators act primarily through S1PR1-mediated immunomodulation and S1PR5-associated oligodendroglial protection, preserving oligodendrocyte lineage cells rather than driving terminal differentiation or de novo remyelination. Several compounds displayed bell-shaped dose-response patterns, highlighting the importance of dosing and treatment paradigms. Collectively, these findings indicate S1PR-based therapies primarily limit demyelination, with limited evidence of remyelination, emphasising the need for more efficacious S1P modulators to improve MS outcomes. S1P remyelination demyelination oligodendrocyte multiple sclerosis in vivo Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Myelin is a specialised, lipid-rich membrane that ensheathes many axons in the nervous system (Kister and Kister 2023 ; Stadelmann et al. 2019 ; Nave and Werner 2014 ), enabling rapid saltatory conduction and providing essential trophic support to neurons (Roggeri et al. 2020 ). Approximately 70–85% of myelin content is comprised of lipids, including cholesterol, phospholipids, and glycolipids, contributing to the structural stability and compaction of the myelin sheath (Poitelon et al. 2020 ). Demyelination, defined as the loss or damage of myelin, occurs in both genetic and acquired neurological diseases, disrupting axonal conduction and ultimately leading to progressive neurological disability (Coutinho Costa et al. 2023 ). Indeed, demyelination is a pathological hallmark of a plethora of central nervous system (CNS) disorders, particularly inflammatory demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM) (Coutinho Costa et al. 2023 ; Pirko and Noseworthy 2007 ). In MS, persistent neuroinflammation eventually leads to irreversible axonal damage and neurodegeneration, emphasising that the prevention of demyelination alone is insufficient to maintain long-term neurological function (Dighriri et al. 2023 ; Haki et al. 2024 ). Although MS lesions possess an intrinsic capacity for remyelination early in the disease course, many lesions remain chronically demyelinated, leading to irreversible axonal degeneration that drives clinical deficits in later stages. Indeed, incomplete or failure of remyelination remains an obstacle to functional recovery in MS. Remyelination is a complex, multicellular process influenced by axon-glia interactions, innate and systemic immune responses, and the extracellular milieu (Franklin and Simons 2022 ; Bourdette and Wooliscroft 2024 ). It begins with the clearance of myelin debris, followed by the activation of oligodendrocyte precursor cells (OPCs), which migrate to demyelinated regions and differentiate into myelinating oligodendrocytes (OLGs) (Leo and Kipp 2022 ; Kotter et al. 2006 ; Keirstead and Blakemore 1999 ). This lineage progression is accompanied by stage-specific molecular changes, with markers such as NG2 and PDGFRα identifying OPCs, O1, O4 and protein proteolipid (PLP) marking pre-oligodendrocytes, and CC1, CNPase, myelin-associated glycoprotein (MAG), or myelin basic protein (MBP) characterising mature myelinating cells, enabling the detailed assessment of remyelination dynamics in experimental models (Leo and Kipp 2022 ; Roggeri et al. 2020 ). Due to the complexity of these coordinated processes and the inflammatory microenvironment in myelin lesions, remyelination cannot be fully recapitulated in vitro . Therefore, in vivo mammalian models play a central role in remyelination research by enabling the assessment of efficacy within an intact CNS environment, where factors such as blood-brain barrier (BBB) permeability and cellular interactions can influence therapeutic outcomes (Lubetzki et al. 2020 ). Commonly used models such as cuprizone (CPZ), lysolecithin (LPC), and experimental autoimmune encephalomyelitis (EAE) mimic various pathophysiological aspects of MS and provide complementary information on toxin-induced demyelination, focal lesions, and autoimmune-driven neuropathology, respectively (Procaccini et al. 2015 ; Ransohoff 2012 ; Dedoni et al. 2023 ). Over the past decade, significant progress has been made in the landscape of MS therapy with the emergence of novel disease-modifying therapies (DMTs). These therapies primarily act by modulating immune responses, either by controlling immune cells overactivity or by preventing their infiltration into the CNS, subsequently reducing the frequency of relapse and disease severity (Filippi et al. 2022 ; Noyes and Weinstock-Guttman 2013 ). However, they display limited efficacy in progressive forms of MS driven by inflammatory demyelination and incomplete repair, presenting an unmet therapeutic gap (Harlow et al. 2015 ; Nyamoya et al. 2017 ). With the exception of ocrelizumab, which has shown only a modest effect on slowing disease progression, all 16 United States Food and Drug Administration (FDA)-approved MS therapies fail to halt or substantially delay the progressive accumulation of disability, particularly in progressive forms of MS (Hooijmans et al. 2019 ). Indeed, failure of remyelination represents a clear obstacle in the recovery of MS, arguing the urgent need for strategies that extend beyond immunosuppression to preserve axonal integrity and restore myelin. Among emerging therapeutic targets, sphingosine 1-phosphate (S1P) has gained substantial attention due to its dual role in immunomodulation and oligodendrocyte lineage biology. S1P exerts its cellular effects through sphingosine 1-phosphate receptors (S1PRs) – a family of five G protein-coupled receptors (S1PR1-S1PR5) (Spiegel and Milstien 2003 ; Binish and Xiao 2025 ; Cartier and Hla 2019 ). Among them, S1PR1 is ubiquitously expressed across multiple cell types, including lymphocytes, where it plays a central role in immunomodulation and therefore represents a key therapeutic target in MS (McGinley and Cohen 2021 ; Chen et al. 2022 ). Within the CNS, S1PR1 is expressed by neurons, astrocytes, and microglia, whereas S1PR5 is abundantly and selectively expressed by oligodendrocyte lineage cells, particularly within cortical white matter tracts (Coelho et al. 2010 ; Bravo et al. 2022 ). Fingolimod, the first S1PR modulator and oral therapeutic approved for MS (Fig. 1 ), demonstrated substantial clinical benefit through immunomodulatory mechanisms, but its direct effect on oligodendrocyte lineage cells in vivo remains uncertain. More recently, selective S1PR1/5 modulators such as siponimod, ozanimod, and ponesimod have been developed, raising the possibility that receptor-specific signalling may differentially influence remyelination (Coyle et al. 2024 ; Roggeri et al. 2020 ). Since the approval of fingolimod for relapsing-remitting MS (RRMS) in 2010 (Fig. 3 A), increasing preclinical studies have investigated the potential of S1P-based therapeutics not only in preventing demyelination but also influencing olidogdendroglial dynamics and remyelination in vivo . Despite these findings, however, the distinction between preventing demyelination, preserving OLGs, and actively promoting new myelin formation remains unclear. Furthermore, despite extensive clinical use and a growing body of preclinical literature, the extent to which S1P-based therapies promote myelin repair remains unclear and has not been systematically synthesised across mammalian models of demyelination. This systematic review, therefore, aims to evaluate the evidence of remyelination concerning S1P-based therapeutics in in vivo mammalian models of CNS demyelination. Specifically, it examines (i) the efficacy of these treatments in limiting demyelination, (ii) their effects on oligodendroglial dynamics within demyelinated lesions and (iii) their capacity to enhance remyelination as assessed through biochemical, histological, or ultrastructural outcomes. This systematic review provides a comprehensive evaluation, determining the status of current S1P-based therapeutics in regulating myelin repair and identifying key gaps for further research. 2. Methods 2.1 Study design This systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al. 2021 ). 2.2 Search strategy and study selection A systematic literature search was performed on three databases: Web of Science, PubMed, and Scopus to identify all studies that have been published up to the research date (2 July 2025), focusing on the following areas of interest: “remyelination” and “sphingosine-1-phosphate” and “ in vivo ”. After the selection of appropriate keywords, the search was performed within the “Title and Abstract” in PubMed, “Title, Abstract, and Keyword” in Scopus, and within “Topic” in Web of Science. The publication language was limited to English, and the following advanced searches for each database are reported: Web of Science search : TS = ("remyelination" OR "myelin repair" OR "myelin" OR "oligodendrocyte") AND TS = (“Sphingosine-1-phosphate" OR "S1P receptor" OR "S1PR" OR "fingolimod" OR "siponimod" OR "ozanimod" OR "ponesimod" OR "etrasimod”) AND TS = ("animal model" OR "mouse model" OR "rodent" OR " in vivo " OR "EAE" OR "cuprizone" OR "lysolecithin" OR "LPS") Pubmed search : ("remyelination" OR "myelin repair" OR "myelin" OR "oligodendrocyte" ) AND ( "Sphingosine-1-phosphate" OR "S1P receptor" OR "S1PR" OR "fingolimod" OR "siponimod" OR "ozanimod" OR "ponesimod" OR "etrasimod") AND ("animal model" OR "mouse model" OR "rodent" OR " in vivo " OR "EAE" OR "cuprizone" OR "lysolecithin" OR “LPS”) NOT "review" NOT “comment” NOT “editorial” Scopus search : TITLE-ABS-KEY ("remyelination" OR "myelin repair" OR "myelin" OR "oligodendrocyte" ) AND TITLE-ABS-KEY ( "Sphingosine-1-phosphate" OR "S1P receptor" OR "S1PR" OR "fingolimod" OR "siponimod" OR "ozanimod" OR "ponesimod" OR "etrasimod" ) AND TITLE-ABS-KEY ( "animal model" OR "mouse model" OR "rodent" OR " in vivo " OR "EAE" OR "cuprizone" OR "lysolecithin" OR "LPS" ) AND NOT "review" AND NOT "comment" AND NOT "editorial" 2.3 Inclusion and exclusion criteria The search strategy was structured using the PICOS (population, intervention, comparator, outcome, study) model, which guided the inclusion criteria. Population : Animals subjected to CNS demyelination via established experimental models (e.g. cuprizone, lysolecithin, EAE, LPS). Intervention : Treatment with S1P-based therapeutics (e.g., fingolimod, siponimod, ozanimod, ponesimod, estrasimod). Comparator : Demyelinated animals receiving no treatment, vehicle, or placebo treatment. Outcome : Quantitative or qualitative measures of CNS remyelination (e.g., histological assessment of myelin density, oligodendrocyte maturation, myelin protein expression). Study : In vivo preclinical studies using mammalian models (mouse, rat, etc.) Only articles that report the effects of S1P-based therapeutics on myelin or oligodendrocyte lineage cells (OLGs/OPCs) were included. This included studies in which S1P-based therapeutics were used to validate a novel compound or drug delivery model, provided that the effects of the S1P-based therapeutic alone were reported and could be extracted for this systematic review. All human studies or in vitro , ex vivo , and in silico studies were excluded. Studies that used a PNS demyelination model were also excluded. Additionally, studies that do not report the dosage of the S1P-based therapeutic were excluded. Finally, articles examining S1P-based therapeutics in in vivo CNS demyelination models were excluded if they did not assess at least one of the following outcomes: On preventing myelin damage/demyelination On promoting myelin repair/remyelination On OLG or OPC survival, differentiation, and maturation Using the Covidence software (available at www.covidence.org ), two reviewers independently assessed the titles and abstracts of the identified studies to determine their relevance. Studies that passed the initial screening underwent full-text review using the same process. Any conflicts arising during the screening process were resolved by a third reviewer. This approach allowed enabled the systematic exclusion of studies that did not meet the inclusion criteria and ensured the comprehensive evaluation of study eligibilities for this systematic review. The outcomes of the study selection process are reported in Fig. 2 . 2.4 Data extraction A standardised data extraction form was developed and pilot-tested to enable any minor adjustments to be made to the template if required. The primary data were extracted by a single reviewer using a custom-designed template to capture all relevant and necessary information from the included studies, which was subsequently reviewed by an independent reviewer. Extracted data were summarised in the tables and included the following information: Characteristics of the S1P-based therapeutics, including molecular weight, receptor target(s), evidence of molecular binding to S1PRs, and BBB permeability (Table 1 ). Description of the animal models used in each study, including their characteristics, method of induction, strengths, and limitations (Table 2 ). Efficacy of S1P-based therapeutics in preventing demyelination (Table 3 ). Efficacy of S1P-based therapeutics in promoting remyelination (Table 4 ). Table 1 Compound (S1PR modulator) characteristics Name of modulator Molecular weight Targeted S1PR Molecular binding evidence BBB permeability FTY720 (Fingolimod/Gilenya) 307.5 g/mol CID: 107970 S1PR1, S1PR3, S1PR4, S1PR5 S1PR1 (EC 50 = 0.3 nM) S1PR3 (EC 50 = 0.9 nM) S1PR4 (EC 50 = 345 nM) S1PR5 (EC 50 = 0.50 nM) (Scott et al. 2016) Brain:blood ratio of 14:1 in Lewis rats after 13 days treatment and 27:1 in Dark Agouti (DA) rats after 23-days treatment of 0.3 mg/kg FTY720. Blood and brain samples taken 24 hours after injection. Autoradiography have shown that [ 14 C]FTY720 is lipophilic and distributes into the parenchyma of rat CNS following a single oral dose (Foster et al. 2007). Siponimod (Mayzent) 516.6 g/mol CID: 44599207 S1PR1, S1PR5 S1PR1 (EC 50 = 0.39 nM) S1PR5 (EC 50 = 0.38 nM) (Scott et al. 2016) Brain:blood ratio approaching 6:1 in C57BL/6 mice at various doses ranging from 0.1 to 30 mg/kg of food. Autoradiography showed that [¹⁴C]siponimod readily penetrated rat CNS, with particularly high uptake in white matter regions (cerebellum, corpus callosum, medulla oblongata) and lower levels in areas such as the olfactory bulb (Bigaud et al. 2021). Ozanimod (Zeposia) 404.5 g/mol CID: 52938427 S1PR1, S1PR5 S1PR1 (EC 50 = 0.41 nM) S1PR5 (EC 50 = 11 nM) (Scott et al. 2016) Brain:blood ratio of 10:1 in C57BL/6 mice at 1 mg/kg dose, and brain:blood ratio of 16:1 in Sprague-Dawley rats at 0.5 mg/kg (Scott et al. 2016). RP-101074 * 360.4 g/mol (MW referenced from RP-101075; CID: 52938426) S1PR1, S1PR5 S1PR1 (EC 50 = 0.35 nM) S1PR5 (EC 50 = 4.5 nM) RP-101074 data not available, data shown are for RP-101075 (Surapaneni et al. 2021) RP-101074 BBB permeability data not reported. RP-101075 has a brain:blood ratio of 31:1 (species and dose not specified) (Scott et al. 2013). Ponesimod (Ponvory) 461.0 g/mol CID: 11363176 S1PR1, S1PR5 S1PR1 (EC 50 = 5.7 nM) S1PR5 (EC 50 = 11 nM) (Scott et al. 2016) According to preclinical and clinical studies, ponesimod does cross the BBB or at least exerts effects within the CNS. However, no quantitative brain:blood ratio or neuroimaging evidence has been disclosed. CYM5442 409.5 g/mol CID: 25110406 S1PR1 S1PR1 (EC 50 = 1.4 nM) (Gonzalez-Cabrera et al. 2008) Brain:plasma ratio of 35:1 in C57BL/6J mice 24 hours after 10mg/kg CYM5442 injection (Gonzalez-Cabrera et al. 2012). JTE-013 408.3 g/mol CID: 10223146 S1PR2 S1PR2 (IC 50 = 17 nM) (Osada et al. 2002) Similar to ponesimod, no quantitative brain:blood ratio or neuroimaging evidence for JTE-013 has been disclosed. Note . Summary of the characteristics of identified S1P-based therapeutics. Columns include the following: modulator name, molecular weight – data retrieved from the PubChem Compound Database, National Library of Medicine, Maryland, USA (Kim et al. 2025), targeted S1PR, molecular binding evidence to human S1PRs, and evidence of BBB permeability via brain:blood ratio and imaging evidence. *: RP-101074 molecular weight, molecular binding evidence, and BBB permeability data not available, therefore, the data shown are for RP-101075, another ozanimod metabolite. RP-101074 is the R-isomer of this metabolite. Abbreviations: CID – PubChem Compound Identifier; EC 50 – half-maximal effective concentration; IC 50 – half-maximal inhibitory concentration. Table 2 Animal models used to study de- and remyelination Animal model Characteristics and induction Strengths Limitations EAE Autoimmune-driven demyelination induced by immunisation with myelin antigens in complete Freund’s adjuvant containing pertussis toxin (Constantinescu et al. 2011) Mimics the pathological features and disease course of MS Robust immune-driven demyelination Well-established model (Constantinescu et al. 2011) Does not represent progressive MS No clear remyelination/recovery phase (Ransohoff 2012 ) Demyelination mostly confined to the spinal cord with few brain lesions Pathological characteristics dependent on species and myelin epitope (Palumbo and Pellegrini 2017) CPZ Toxin model causing oligodendrocyte apoptosis and demyelination by dietary administration of CPZ (0.2–0.3%) in chow (Ransohoff 2012 ) Well-established model with clear demyelination-remyelination timeline (Praet et al. 2014) Minimal peripheral immune involvement (Zhan et al. 2020) Does not fully recapitulate MS autoimmune pathology Mechanism behind OLG degeneration still poorly understood (Kipp 2024) Region-specific demyelination (Zhan et al. 2020) CPZ + EAE A combination of toxin-induced oligodendrocyte loss with autoimmune infiltration by feeding mice with CPZ chow for 3 weeks, followed by normal chow for 2 weeks, and EAE induction (Rüther et al. 2017) Better reflects MS pathology by combining neurodegeneration and inflammation, allowing the study of remyelination under active inflammatory conditions (Scheld et al. 2016) Technically demanding Animal welfare concern Not a well-established model yet EAEON Autoimmune-driven demyelination of the optic nerve, causing optic neuritis and visual deficits. Mode of induction is similar to EAE (Kezuka et al. 2011) Useful for studying optic neuritis and visual pathways Limited to optic nerve If not isolated, can occur with systemic EAE Twitcher mice (Krabbe’s disease model) Transgenic mouse model with mutation in the galactocerebrosidase (GALC) gene, leading to psychosine accumulation and demyelination (Suzuki and Suzuki 1995) Strong model for congenital demyelination with progressive and severe myelin loss (Suzuki and Taniike 1995) Rapid disease progression – mice have short lifespan (Suzuki and Suzuki 1995) LPC Focal injection of lysolecithin (LPC) into regions of the CNS such as the spinal cord, optic nerve, corpus callosum, causing localised demyelination (Plemel et al. 2018) Fast, localised, and reproducible demyelination Spontaneous remyelination one week after injection (Blakemore and Franklin 2008) Can target specific locations of the CNS Does not represent widespread demyelination like in MS Invasive injection (Hooijmans et al. 2019 ) Light-induced photoreceptor loss (LI-PRL) Retinal and optic nerve degeneration is induced by exposure to high-intensity light (Dietrich et al. 2020) Useful to study retinal and optic nerve degeneration independent of peripheral immune infiltration Non-invasive method of induction (Sindi et al. 2023 ) Does not represent widespread demyelination and lacks systematic immune involvements No direct link to MS (Dietrich et al. 2020) Cuprizone/rapamycin demyelination A combination of CPZ treatment and rapamycin, an inhibitor of the mTOR pathway, providing a more complete demyelination by inhibiting spontaneous remyelination (Yamate-Morgan et al. 2019) Enhances the severity and completeness of demyelination (Sachs et al. 2014) Inhibition of mTOR pathways affect other glia and neurons, making interpretation difficult (Yamate-Morgan et al. 2019) Note. Summary of the characteristics of animal models to study de- and remyelination. Columns include the following: name of animal model, characteristics of the model and mode of induction, strengths, and limitations. Table 3 Efficacy of S1PR modulators in preventing demyelination Author Model & species Treatment paradigm Dosage Sex & sample size Demyelination Outcomes Fingolimod (FTY720) Al-Izki et al. ( 2011 ) EAE. Biozzi antibody-high mice. Fingolimod started from EAE induction (day 0), at first relapse (day 10), or 1-month post-immunological tolerance (secondary progressive phase) until endpoint at 89 dpi. 1mg/kg or 3 mg/kg. Daily oral gavage. Both male and female mice included n = 8–9 per treatment group. No significant difference in toluidine blue staining between FTY720-treated and vehicle groups. Balatoni et al. ( 2007 ) EAE. Dark agouti (DA) rats. Prophylactic treatment: FTY720 treatment started at time of EAE induction and continued for 2 to 3 weeks. Therapeutic treatment: FTY720 treatment initiated on day 25 after EAE induction and continued for 3 weeks. 0.4 mg/kg. Daily oral gavage. Female. Sample size not explicitly stated, n = 12 per treatment group. Prophylactic treatment: FTY720 prevented detectable demyelination or lesions in the brain & limited SC demyelination Therapeutic treatment: FTY720 significantly reduced SC demyelination (p < 0.05) & eliminated detectable lesions vs controls. No differences in LFB staining at day 53 (no statistical analysis performed). Hashemian et al. ( 2019 ) LPC. Wistar rats. LPC injection followed by FTY720 treatment started on the same day and continued for 7 or 14 days. 0.3 mg/kg. Daily oral gavage. Male, n = 72. Reduced demyelination at d7 and d14 with FTY720 vs vehicle (quantitative fluoromyelin staining). PLP+ cells increased with FTY720 (no statistical analysis reported). Hu et al. ( 2011 ) LPC. Sprague-Dawley rats. LPC injection followed by FTY720 treatment started on 2 or 3 dpi and continued for 7 days. Either daily 1 mg/kg oral gavage starting 2 days after induction, or daily 2 µL (2 mg/mL) FTY720 injection into LPC lesion starting 3 days after induction. Sex not mentioned. For LFB staining, control n = 5, FTY720 n = 7. TEM n = 3. Local FTY720 injection of LPC rats doubled demyelinated lesion size compared to vehicle (p < 0.05) and induced demyelination in non-LPC rats. Oral FTY720 did not increase lesion volume. Kim et al. ( 2011 ) CPZ (demyelination phase only). C57BL/6 mice. 6 weeks of 0.2% CPZ feeding, FTY720 treatment started on day 1 and continued for 6 weeks. 1 mg/kg. Daily oral gavage. Male, n = 5–15 per treatment group. FTY720 attenuated demyelination, increased MBP intensity (p < 0.002) and proportion of myelinated fibers compared to vehicle (p < 0.002). FTY720 increased CC1+, Nkx2.2+, and NG2+/PCNA+ cell numbers (p < 0.013, p < 0.04, p < 0.0003). Kim et al. ( 2018 ) CPZ (demyelination phase only). C57BL/6 mice. 3 weeks of 0.2% CPZ feeding, treatment started on day 3 or day 10 until the end of week 3. 1 mg/kg. Daily intraperitoneal (IP) injection. Male, = 3–11 per analysis per group. Early FTY720 treatment at d3 reduced demyelination and prevented OLG death (fewer TUNEL+ cells, p < 0.05). CNPase and MAG WB/PCR confirmed OLG protection (p < 0.01 WB, p < 0.001 PCR). Delayed FTY720 treatment at d10 showed no OLG protection (no change in Mag/Mbp gene expression vs vehicle). Moradi et al. ( 2023 ) CPZ (demyelination phase only). Wistar rats. Treatment with fingolimod initiated 1 week before the induction of CPZ (0.3%) for 4 weeks. Treatment continued until endpoint. 0.5 mg/kg. Daily oral gavage. Male, n = 49. FTY720 increased toluidine blue staining, axon diameter, and myelin thickness in CC (TEM, p < 0.05). MBP and Olig2 levels were elevated vs CPZ/vehicle (PCR, p < 0.05) and approached normal controls (ELISA, p < 0.05). Nascimento Pires et al. ( 2025 ) CPZ (demyelination phase only). Swiss mice. 5 weeks of 0.2% CPZ feeding, treatment started on day 1 until the end of week 5. 1 mg/kg. Daily IP injection. Sex not mentioned, n = 6 per group. FTY720 partially restored lipid density in the CC vs CPZ (Sudan black, p < 0.05). CC cytoarchitecture remained disrupted, with reduced chain-like organisation vs control (H&E, p < 0.005). FTY720 preserved myelinated fibers in the 0.75–0.81 g-ratio range, but mean g-ratio, axon area, and fiber area were unchanged vs CPZ. FTY720 did not increase CC1 + cells but statistically decreased NG2 + cells vs CPZ (p < 0.01). Nystad et al. ( 2020 ) CPZ (demyelination phase). C57BL/6 mice. 6 weeks of 0.2% CPZ feeding. Treatment administered from the beginning of week 5 for 2 weeks. 1 mg/kg. Daily oral gavage. Female, n = 48. FTY720 did not ameliorate myelin loss vs vehicle during demyelination (p = 0.38). No differences observed in LFB or PLP scores in SMC or in myelin levels at any time point. FTY720 did not alter NOGO-A+ mature OLG density in the CC during demyelination (p = 0.58). In the SMC, mature OLGs did not increase during demyelination (p = 0.23). Robichon et al. ( 2023 ) EAE. C57BL/6 mice. EAE induction on day 0, daily treatment started at disease onset (score ≥ 1; 13–18 dpi) until day 40–55. 1 mg/kg. Daily oral gavage. Female, n = 18–20 per treatment group. No significant increase in myelination % with FTY720 vs vehicle (Black-Gold II staining). However, FTY720 significantly reduced lesion percentage vs vehicle (p < 0.05). Yazdi et al. ( 2015 ) LPC. C57BL/6 mice. Mice were treated with FTY720 for 8 or 12 days, and LPC was injected from day 6 of the treatment period. 0.3 or 1 mg/kg. Daily oral gavage. Male, n = 3 per condition (n = 21 total). At 6 dpi, LFB staining showed a significant reduction in demyelination in animals treated with FTY720 (0.3 or 1 mg/kg; both p < 0.001) compared to the LPC group. Zhang et al. ( 2015 ) EAE. SJL/J mice. EAE induction on day 0, daily treatment started on the day of EAE onset until day 7 or day 30 post onset. 0.15 or 0.3 mg/kg. Daily oral gavage. Female, n = 36. Western blotting of MBP is not significant between FTY720 and vehicle-treated mice at d7. NG2 + OPCs and BrdU+-NG2 + cells increased in CNS and SVZ at d7 (p < 0.01). FTY720 restored myelination after EAE (LFB, d30 p.o., p < 0.05). At d30, MBP protein for FTY720 significantly higher vs controls (p < 0.05). NG2 + OPCs and BrdU + -NG2 + cells increased in CNS and SVZ (p < 0.05). CNPase + mature OLGs increased across regions of ST/CC/SC (p < 0.01/0.05/0.01). BrdU + -CNPase + cells appeared by d30 (p < 0.05). Siponimod Behrangi et al. ( 2022 ) CPZ (demyelination phase only) and CPZ + EAE model. C57BL/6 mice. Treatment started on the same day of 0.25% CPZ feeding and continued for 1–3 weeks. Treatment was then discontinued, and CPZ + EAE mice were returned to normal chow for 2 weeks and received MOG immunisation at week 6. 0.315 mg/kg, 3.125 mg/kg, or 15.5 mg/kg. Daily oral gavage. Female, n = 10 per treatment group. Siponimod increased LFB grading (p < 0.01) and CC1 + mature OLGs (p < 0.05) vs vehicle. This effect was dose-dependent, 0.315mg/kg showed greater demyelination (LFB/PLP) than other doses. Siponimod reduced CPZ-induced increase in Olig2+/PCNA+ OPCs in WT but not S1PR5-KO mice, suggesting OLG protection rather than myelin regeneration. Dietrich et al. ( 2022 ) EAEON. C57BL/6 mice. EAEON was inducted and treatment started on the same day (prophylactic), or at 14 or 30 dpi (therapeutic). Treatment continued until either 21, 35, or 90 dpi. 2 or 6 mg/kg daily Siponimod intake via chow. Female, n = 48 (n = 6 per group) Prophylactic siponimod reduced optic nerve MBP loss vs vehicle (2 mg/kg p < 0.001; 6 mg/kg p < 0.01). Late treatment (d14) was beneficial at 2 mg/kg (p < 0.05), while d30 showed no effect on myelin loss. Therapeutic siponimod (d14) improved Olig2 + cell survival (2 mg/kg p < 0.01; 6 mg/kg p < 0.05), with no change in PDGFRα + cells. Krueger et al. ( 2025 ) CPZ (demyelination phase only). C57BL/6 mice. 4 or 7 weeks of 0.2–0.55% CPZ feeding. 4-week CPZ group received treatment from day 1, and 7-week CPZ group received treatment from week 5 to endpoint. 6.25 mg/kg BW. Daily oral gavage. Male, n = 5–8 per group. Siponimod partially reduced demyelination (LFB/PAS, anti-MAG, p < 0.05). Siponimod treatment from week 5 increased MBP and MAG staining (p = 0.0059, p = 0.0093) and raised Olig2 + cell density (p = 0.0869). Treatment from day 1 reduced Olig2+/Ki67 + OPCs (p = 0.02) but did not significantly increase Olig2 + cell density (p = 0.0869). CYM5442 Kim et al. ( 2018 ) CPZ (demyelination phase only). C57BL6 mice. 5 weeks of 0.2% CPZ feeding, treatment started from 3rd day of CPZ to endpoint. 10 mg/kg, daily IP injection. Male, n = 3–8 per analysis per group. CYM5442 reduced demyelination vs vehicle (Sudan Black, p < 0.05). Western blotting for CNPase and MAG at 3 weeks confirmed OLG protection and reduced demyelination (p < 0.05). Ozanimod Selkirk et al. ( 2021 ) EAE. C57BL/6 mice. EAE was induced and treatment started on the same day and continued for 14 days. 0.05, 0.2, or 1 mg/kg. Daily oral gavage. Female, n = 36 (n = 12 per group) All ozanimod doses have significantly lower demyelination score vs vehicle (H&E, p < 0.001). JTE-013 Seyedsadr et al. ( 2019 ) EAE and LPC models. C57BL/6 mice. EAE was induced and treatment started on day 1 p.o. and continued until endpoint (d18). LPC injection followed by treatment initiated on the same day and continued until day of sacrifice at 3, 7, 14 or 16 dpi. EAE: 30 mg/kg. Daily IP injection. LPC: 15 mg/kg. Twice daily IP injection. EAE: Male, n = 3–4 per group. LPC: Male, n = 13 per group. EAE: JTE-013 reduced demyelinated lesion areas in SC vs vehicle (MBP staining, p < 0.05). EdU+/CC1 + newly differentiated OLGs were higher in JTE-013 mice, but not significantly. LPC: At 3 dpi, MBP staining showed no significant difference in demyelination between vehicle and JTE-013, in either the spinal lesion or optic chiasm. RP-101074 Sindi et al. ( 2023 ) LI-PRL. C57BL/6 mice. LI-PRL induction followed by RP-101074 treatment initiated on the same day and continued for 5 weeks. 1 mg/kg. Daily oral gavage. Female, n = 5–6 per treatment group. Prophylactic RP-101074 significantly protected myelin (p < 0.0018), increased Sox2⁺ cells (p < 0.0001), and upregulated NG2 (p = 0.0005) and PDGFRα (p = 0.0001) vs vehicle, indicating enhanced OPC activation and myelin preservation. Note. Summary of the efficacy of S1PR modulators on demyelination in mammalian in vivo models. Columns include the following: modulator type; author and year of publication; in vivo model and species; treatment window; dosage; sex and sample size; and demyelination outcome. Abbreviations: CC – corpus callosum; dpi – days post-induction; H&E – hematoxylin and eosin; KO – knock-out; MAG – myelin-associated glycoprotein; MBP – myelin basic protein; PAS – Periodic acid–Schiff; PLP – proteolipid protein; p.o. – post-onset; SC – spinal cord; SMC – secondary motor cortex; ST – striatum; SVZ – subventricular zone; WT – wild-type Table 4 Efficacy of S1PR modulators on promoting remyelination Author Model & species Treatment paradigm Dosage and delivery Sex & sample size Remyelination Outcomes Fingolimod (FTY720) Alme et al. ( 2015 ) CPZ with remyelination phase. C57BL/6 mice 6 weeks of 0.2% CPZ feeding followed by normal chow. Treatment started from week 5 and continued for 4 weeks. 1 mg/kg. Daily oral gavage. Female, n = 32. No significant differences in remyelination (MBP and PLP staining) and mature OLGs (NOGO-A⁺) compared to vehicle control. Béchet et al. ( 2020 ) Twitcher mice FTY720 treatment started on postnatal day 21 and continued until animal endpoint (postnatal day 40–45). 1 mg/kg. Fingolimod reconstituted in drinking water daily. Male and female, n = 20–33. FTY720 increased MBP expression significantly (IHC, p = 0.04) but did not alter MOG expression (IHC, p = 0.248) or myelin debris levels in wild-type or twitcher mice (p > 0.999). FTY720 significantly increased Olig2 protein expression vs vehicle in cerebellum (p < 0.05). Hashemian et al. ( 2019 ) LPC. Wistar rats LPC injection followed by treatment on the same day. Treatment continued for 7 or 14 days. 0.3 mg/kg. Daily oral gavage Male, n = 72 FTY720 significantly increased MBP gene levels on d7 and d14 post-lesion vs vehicle. Olig2 gene expression increased on d7 (p < 0.05), but not on d14. Remyelination outcome was not available at protein or structural level. Hu et al. ( 2011 ) CPZ + rapamycin with remyelination phase. C57BL/6 mice. 4 weeks of 0.3% CPZ + 10 mg/kg rapamycin 5 days/week, followed by normal chow for 2 weeks. Treatment initiated during normal chow phase and continued for 2 weeks. 1 mg/kg. Daily oral gavage. Sex not mentioned. n = 4 each group (IHC, 12 total). n values unclear for TEM. No significant differences in remyelination between FTY720- and control-treated animals via IHC (MBP) and TEM in either model, although FTY720 increased NG2⁺ cells (p < 0.001) in the CPZ model. Kim et al. ( 2011 ) CPZ with remyelination phase. C57BL/6 mice. 6 weeks of 0.2% CPZ feeding followed by normal chow; treatment started from week 4–6 of CPZ diet for 4 weeks. 0.3-1 mg/kg. Daily oral gavage. Male, n = 5–15 per group. No significant differences in remyelination by LFB and IHC (MBP) staining as well as OLG/OPC numbers between FTY720 and vehicle. Kim et al. ( 2018 ) CPZ with remyelination phase. C57BL/6 mice. 5 weeks of 0.2% CPZ feeding followed by normal chow. Treatment administered from the start of week 5 for 2 weeks. 10 mg/kg, daily intraperitoneal (IP) injection. Male, n = 3–5 per group per analysis. No significant differences in myelin intensity (Oil Red staining), Olig2⁺ cells, or Olig2⁺/CC1⁺ cells in the corpus callosum of FTY720 vs vehicle-treated mice. Similarly, PLP⁻ area, lesion area, and Olig2 cellularity in the cerebellum did not differ between groups. Mitra et al. ( 2022 ) CPZ with remyelination phase. Sprague-Dawley rats 5 weeks of 0.2% CPZ feeding followed by normal chow. Treatment administered from the start of week 6 for 2 weeks. 3 mg/kg, daily IP injection. Female, n = 10 for each treatment group. No significant differences in remyelination by LFB following FTY720 treatment, although it partially restored demyelinated area of the median CC. Nystad et al. ( 2020 ) CPZ with remyelination phase. C57BL/6 mice. 6 weeks of 0.2% CPZ feeding followed by normal chow. Treatment administered from week 5 to week 9. 1 mg/kg. Daily oral gavage. Female, n = 48. No significant differences in remyelination via LFB or IHC (PLP) after 1 (p = 1.0; p = 0.96), or 3 weeks (p = 0.40; p = 0.28) of FTY720 vs vehicle. FTY720 exerted no effects on NOGO-A+ mature OLG at 1 week or 3 weeks of remyelination in the CC, although increased mature OLGs after 3 weeks of remyelination (p = 0.032) in the SMC, but not after 1 week (p = 0.66). Slowik et al. ( 2015 ) CPZ (both acute and chronic) with remyelination phase. C57BL/6 mice. Mice received 0.2% CPZ for 5 weeks (acute) or 12 weeks (chronic), followed by 11 or 28 days of recovery on normal chow. Treatment administered during the recovery phase for 11 or 28 days. 0.3 mg/kg. Daily oral gavage. Male, n = 72. No significant differences in remyelination (PLP, LFB staining) and Olig2 + cells following FTY720 administration in acute and chronic CPZ models. Yazdi et al. ( 2015 ) LPC. C57BL/6 mice. Mice were treated with FTY720 for 8 or 12 days, and LPC was injected from day 6 of the treatment period. 0.3 or 1 mg/kg. Male, n = 3 per condition (n = 21 total). 0.3 mg/kg FTY720 increased PLP myelination (p < 0.05) and myelinated axons. Both doses reduced g-ratio (p < 0.001), with 0.3 mg/kg more effective. 0.3 mg/kg increased OLG lineage cells vs vehicle control (p < 0.01) and 1 mg/kg (p < 0.05). BrdU⁺/Olig2⁺ increased with FTY720 treatment (p < 0.001). Siponimod Al-Otaibi et al. ( 2022 ) CPZ with remyelination phase. Swiss mice (SWR/J). 6 weeks of 0.3% CPZ feeding followed by normal chow. Treatment started from week 5 and continued for 4 weeks (until the end of week 9). 1.5 mg/kg. Daily oral gavage. Male, n = 85. Siponimod significantly increased the percentage of myelinated areas in the CC at early (p < 0.0001) and late (p = 0.0026) remyelination stages vs CPZ (LFB staining). Dietrich et al. ( 2022 ) CPZ with remyelination phase. C57BL/6 mice. 5 weeks of 0.2% CPZ feeding followed by Siponimod or drug-free chow (vehicle) for 2 additional weeks. 2 mg/kg. Daily intake via chow. Female, n = 21. Siponimod exerted a significant effect on remyelination in the CC compared to vehicle control, as assessed via MRI. No significant on remyelination (via LFB myelin staining) and mature oligodendrocytes (GSTπ⁺). Ozanimod Selkirk et al. ( 2021 ) CPZ + rapamycin with remyelination phase. C57BL/6 mice. 6 weeks of 0.3% CPZ feeding with daily treatment and rapamycin injection. Treatment started from day 1 and continued for 18 weeks. 5 mg/kg. Daily oral gavage. Male, n = 6–12 per group. No significant differences in remyelination in the cortex, CC, or hippocampus by IHC (PLP staining) and MRI compared to vehicle control. JTE-013 Seyedsadr et al. ( 2019 ) LPC. C57BL/6 mice. LPC induction and treatment were initiated on the same day. Treatment continued until endpoints at 3, 7, 14 or 16 dpi. 15 mg/kg. Twice daily IP injection. Male, n = 13 per treatment group. At 16 dpi, JTE-013 showed a 2.09-fold increase in remyelinated axons vs vehicle (Sudan black staining), confirmed by semithin sections (p < 0.05). No effect on myelin thickness (via TEM). JTE-013 exerted no significant effect on OLG proliferation at 7 dpi, but increased the number of newly differentiated oligodendrocytes at 14 dpi and 16 dpi (p < 0.05), indicating potentiated differentiation. Ponesimod Willems et al. ( 2024 ) CPZ with remyelination phase. C57BL/6 mice. 6 weeks of 0.3% CPZ feeding followed by normal chow. Treatment initiated 3 days prior to CPZ withdrawal and continued for 10 days. 1, 3, or 10 mg/kg. Daily oral gavage. Male, n = 9–11 per treatment group. Ponesimod increased remyelination in the medial CC at all three doses, assessed via IHC (MBP) and TEM (g-ratios). Cortical myelination increased only at 3 mg/kg (p = 0.0232). Note. Summary of the efficacy of S1PR modulators on remyelination in mammalian in vivo models. Columns include the following: modulator type; author and year of publication; in vivo model and species; treatment window; dosage; sex and sample size; and remyelination outcome. Abbreviations: CC – corpus callosum; dpi – days post-induction; SC – spinal cord; SMC – secondary motor cortex 2.5 Risk of bias assessment To assess the risk of bias and methodological quality of the included studies, the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool was used. This tool is adapted from the Cochrane risk of bias framework and has been specifically designed to address sources of bias that can be present in animal studies (Hooijmans et al. 2014 ). The SYRCLE assessment contains ten domains: random sequence generation, baseline characteristics, allocation concealment, random housing, blinding for caregivers and/or investigators, random outcome assessment, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. The results of the risk of bias assessment are presented in Fig. 3 . 3. Results 3.1 Study selection A total of 237 studies were initially identified through database searches. After removing 97 duplicates, 140 studies progressed to title and abstract screening. Following the screen, 114 studies were excluded, leaving 26 studies for full-text assessment. Of these, two additional studies were excluded, resulting in a final inclusion of 24 studies in this systematic review. Any conflicts that arose between the two primary reviewers during the screening process were resolved by the third reviewer, ensuring a consistent and thorough selection process. 3.2 Risk of bias and quality assessment All 24 included studies were critically appraised using the SYRCLE risk of bias assessment tool. Most studies were judged to have an unclear risk of bias across several criteria, such as random sequence generation, baseline characteristics, allocation concealment, random housing, blinding for caregivers and/or investigators, random outcome assessment, and incomplete outcome data. In contrast, most studies demonstrated a low risk of bias for blinding of outcome assessment and selective reporting. 3.3 Characteristics of S1P modulators and experimental models All 24 studies investigated S1PR modulators; however, no studies identified in the screening process examined the modulation of S1P metabolic pathways, such as inhibition of sphingosine kinases (SphK1/2) or sphingosine-1-phosphate lyase (SPL). The characteristics of the S1P-based modulators, and the number of studies investigating each compound are summarised in Table 1 and Fig. 4 . Out of the seven compounds identified through the systematic screening, four have been approved by the FDA for the treatment of relapsing forms of MS, including clinically isolated syndrome (CIS), RRMS, and active secondary progressive MS (SPMS). These compounds are fingolimod (approved in 2010), siponimod (approved in 2019), ozanimod (approved in 2020), and ponesimod (approved in 2021) (Table 1 and Fig. 1 ) (Coyle et al. 2024 ). The remaining three compounds, RP-101074, CYM5442, and JTE-013 are research tools used in preclinical studies and have not yet progressed to clinical trial stages (Table 1 ). While all other modulators are S1PR agonists, JTE-013 is unique as a functional antagonist of S1PR2 (Table 1 ) (Seyedsadr et al. 2019 ). 3.4 Efficacy of S1P modulator on myelination and oligodendrocytes The studies employed a wide range of methodological approaches to assess demyelination and remyelination. These included myelin-specific histological stains such as Luxol Fast Blue (LFB), Black-Gold II, toluidine blue, and Sudan Black, as well as immunohistochemistry (IHC), transmission electron microscopy (TEM), Western blotting (WB), polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and magnetic resonance imaging (MRI). However, not all studies incorporated a clearly defined remyelination phase in their experimental design. In particular, several studies reported changes in myelin-associated or oligodendrocyte lineage markers during demyelination-focused phases (e.g., CPZ exposure without a subsequent recovery period or progressive EAE models), making it difficult to distinguish myelin preservation from true remyelination. To address this heterogeneity, studies lacking a distinct remyelination phase were grouped in Table 3 , which summarises the efficacy of S1P-based modulators in preventing demyelination or preserving myelin during active injury. In contrast, studies that included an explicit remyelination phase, such as CPZ withdrawal paradigms or lysolecithin-induced focal demyelination with tissue collection at defined recovery time points, were grouped in Table 4 , which summarises evidence for the effects of S1P-based modulators on promoting. The systematic review synthesised 24 mammalian in vivo studies investigating the effects of S1P-based therapeutics on demyelination and remyelination in mammalian models of CNS injury. Of these, 18 studies evaluated the effects of S1PR modulation on the prevention of demyelination, including 12 studies on fingolimod (Kim et al. 2018 ; Al-Izki et al. 2011 ; Balatoni et al. 2007 ; Hashemian et al. 2019 ; Hu et al. 2011 ; Kim et al. 2011 ; Moradi et al. 2023 ; Nascimento Pires et al. 2025 ; Nystad et al. 2020 ; Robichon et al. 2023 ; Yazdi et al. 2015 ; Zhang et al. 2015 ), three on siponimod (Behrangi et al. 2022 ; Dietrich et al. 2022 ; Krueger et al. 2025 ), and one study each on CY5442 (Kim et al. 2018 ), ozanimod (Selkirk et al. 2021 ), JTE-013 (Seyedsadr et al. 2019 ), and RP-101074 (Sindi et al. 2023 ). Among these studies, 15 reported a reduction in demyelination (Seyedsadr et al. 2019 ; Kim et al. 2018 ; Sindi et al. 2023 ; Balatoni et al. 2007 ; Hashemian et al. 2019 ; Kim et al. 2011 ; Moradi et al. 2023 ; Nascimento Pires et al. 2025 ; Robichon et al. 2023 ; Yazdi et al. 2015 ; Zhang et al. 2015 ; Behrangi et al. 2022 ; Dietrich et al. 2022 ; Krueger et al. 2025 ; Selkirk et al. 2021 ), two reported no significant effect of fingolimod (Al-Izki et al. 2011 ; Nystad et al. 2020 ), and one reported increased demyelination following local delivery of fingolimod into LPC lesions (Hu et al. 2011 ). Across the demyelination-prevention studies, outcomes were assessed using a variety of readouts. Four studies quantified changes in demyelinated lesion number and/or size (Seyedsadr et al. 2019 ; Balatoni et al. 2007 ; Hu et al. 2011 ; Robichon et al. 2023 ), 16 reported changes in myelin staining intensity (Seyedsadr et al. 2019 ; Kim et al. 2018 ; Sindi et al. 2023 ; Al-Izki et al. 2011 ; Hashemian et al. 2019 ; Kim et al. 2011 ; Moradi et al. 2023 ; Nascimento Pires et al. 2025 ; Nystad et al. 2020 ; Robichon et al. 2023 ; Yazdi et al. 2015 ; Zhang et al. 2015 ; Behrangi et al. 2022 ; Dietrich et al. 2022 ; Krueger et al. 2025 ; Selkirk et al. 2021 ), and 11 quantified oligodendrocyte lineage cell numbers (Seyedsadr et al. 2019 ; Kim et al. 2018 ; Sindi et al. 2023 ; Hashemian et al. 2019 ; Kim et al. 2011 ; Nascimento Pires et al. 2025 ; Nystad et al. 2020 ; Zhang et al. 2015 ; Behrangi et al. 2022 ; Dietrich et al. 2022 ; Krueger et al. 2025 ). Fewer studies assessed biochemical or ultrastructural outcomes, with three reporting change in myelin-associated gene or protein expression (e.g., MBP, MAG, PLP) (Kim et al. 2018 ; Moradi et al. 2023 ; Zhang et al. 2015 ), and only two using TEM analyses (g-ratio, proportion of myelinated axons) (Moradi et al. 2023 ; Nascimento Pires et al. 2025 ). During active demyelination, S1PR modulation consistently altered oligodendrocyte lineage cell dynamics in a manner indicative of enhanced cell preservation and survival. Across models, treatment was associated with increased numbers of mature oligodendrocytes marked by CC1⁺, Nkx2.2⁺ (Kim et al. 2011 ), and NOGO-A⁺ (Nystad et al. 2020 ), alongside reductions in TUNEL⁺ apoptotic oligodendrocytes (Kim et al. 2018 ), suggesting protection from injury-induced cell death. Concurrent expansion of oligodendrocyte precursor populations, reflected by increases in Olig2⁺/PCNA⁺ (Behrangi et al. 2022 ), Olig2⁺/Ki67⁺ (Krueger et al. 2025 ), NG2⁺ and BrdU⁺/NG2⁺ cells (Zhang et al. 2015 ), further indicates an enhancement in the proliferative capacity following demyelination. A total of 15 studies examined the effects of S1PR modulation on enhancing remyelination, including 10 studies on fingolimod (Kim et al. 2018 ; Hashemian et al. 2019 ; Hu et al. 2011 ; Kim et al. 2011 ; Nystad et al. 2020 ; Yazdi et al. 2015 ; Alme et al. 2015 ; Béchet et al. 2020 ; Mitra et al. 2022 ; Slowik et al. 2015 ), two on siponimod (Dietrich et al. 2022 ; Al-Otaibi et al. 2022 ), and one study each on ozanimod (Selkirk et al. 2021 ), JTE-013 (Seyedsadr et al. 2019 ), and ponesimod (Willems et al. 2024 ). Remyelination outcomes were most commonly assessed using immunohistological myelin staining (14/15 studies) (Seyedsadr et al. 2019 ; Kim et al. 2018 ; Hu et al. 2011 ; Kim et al. 2011 ; Nystad et al. 2020 ; Yazdi et al. 2015 ; Dietrich et al. 2022 ; Selkirk et al. 2021 ; Alme et al. 2015 ; Béchet et al. 2020 ; Mitra et al. 2022 ; Slowik et al. 2015 ; Al-Otaibi et al. 2022 ; Willems et al. 2024 ), followed by oligodendrocyte lineage cell quantification (9/15 studies) (Seyedsadr et al. 2019 ; Kim et al. 2018 ; Hu et al. 2011 ; Kim et al. 2011 ; Nystad et al. 2020 ; Yazdi et al. 2015 ; Dietrich et al. 2022 ; Alme et al. 2015 ; Slowik et al. 2015 ). Only two studies reported gene or protein expression analyses (Hashemian et al. 2019 ; Béchet et al. 2020 ), four reported TEM assessments (Seyedsadr et al. 2019 ; Hu et al. 2011 ; Yazdi et al. 2015 ; Willems et al. 2024 ), and two utilised MRI-based measures (Dietrich et al. 2022 ; Selkirk et al. 2021 ). Overall, the remyelination outcomes were variable. Among fingolimod studies, only one reported significant remyelination (Yazdi et al. 2015 ), while eight studies reported no significant enhancement compared to controls or no evidence of remyelination at the structural level (Kim et al. 2018 ; Hashemian et al. 2019 ; Hu et al. 2011 ; Kim et al. 2011 ; Nystad et al. 2020 ; Alme et al. 2015 ; Mitra et al. 2022 ; Slowik et al. 2015 ). One study reported mixed findings, with no change in MOG immunostaining but significant in MBP immunostaining and Olig2 protein expression (Béchet et al. 2020 ). Siponimod showed mixed effects in one study (Dietrich et al. 2022 ) and a significant remyelinating effect in another (Al-Otaibi et al. 2022 ). Ozanimod did not significantly enhance remyelination (Selkirk et al. 2021 ), while JTE-013 increased myelin staining without corresponding improvements in g-ratio measurements (Seyedsadr et al. 2019 ). Ponesimod demonstrated a significant remyelinating effect; however, this finding was based on a single study (Willems et al. 2024 ), a limitation shared by several other S1PR modulators in this review. The heterogeneity of remyelination findings is further corroborated by the changes in oligodendrocyte lineage markers following S1P-based therapeutics. Several studies reported no significant changes in mature OLG markers, including NOGO-A⁺, CC1⁺, or Olig2⁺ cells (Kim et al. 2018 ; Hu et al. 2011 ; Alme et al. 2015 ), following fingolimod treatment, despite preserved lineage populations during earlier demyelinating phases. Nevertheless, some studies have reported the engagement of reparative pathways by promoting OPC differentiation. Increases in NG2⁺ OPCs and BrdU⁺/Olig2⁺ populations were observed following fingolimod treatment (Hu et al. 2011 ; Yazdi et al. 2015 ) indicating lineage activation at early and intermediate stages of repair. Modest increases in GST-π⁺ mature oligodendrocytes were also reported following siponimod treatment, although not significant (Dietrich et al. 2022 ). A pronounced lineage progression was observed following treatment JTE-013, which increased both EdU⁺/PDGFRα⁺ and EdU⁺/CC1⁺ populations (Seyedsadr et al. 2019 ), and RP-101074, which expanded Sox2⁺ progenitor pools (Sindi et al. 2023 ). Fingolimod was the most extensively studied compound (16/24 studies) and consistently prevented and reduced demyelination across EAE, LPC, and CPZ models based on histological evidence. However, in studies explicitly designed to assess remyelination, fingolimod generally failed to enhance myelin thickness, g-ratio, or the degree of myelin staining. The two studies reporting significant remyelination following fingolimod treatment utilised the LPC and EAE models (Yazdi et al. 2015 ; Zhang et al. 2015 ), which differ fundamentally from the CPZ model and do not always include a clearly defined remyelination phase. In contrast, newer S1PR1/5-selective modulators such as siponimod and ponesimod demonstrated more consistent evidence of remyelination, reflected by increased myelin staining intensity, enhanced oligodendrocyte lineage marker expression, reduced g-ratio values, and a higher proportion of remyelinated axons (Al-Otaibi et al. 2022 ; Willems et al. 2024 ). Analysis of publication numbers (Fig. 5 ) reveals that publication activity within this research topic was initially limited, with a single study published in 2007 (Balatoni et al. 2007 ). Research output increased gradually over the following years, reaching an initial peak of four publications in 2015 (Yazdi et al. 2015 ; Zhang et al. 2015 ; Alme et al. 2015 ; Slowik et al. 2015 ). This was followed by a decline in activity, with only one study published in 2018 (Kim et al. 2018 ). A second peak of four publications was observed in 2022 (Behrangi et al. 2022 ; Dietrich et al. 2022 ; Mitra et al. 2022 ; Al-Otaibi et al. 2022 ), after which output decreased again, although at least one study has been published each year from 2022 onwards. Between 2007 and 2015, all eight published studies focused exclusively on fingolimod (Balatoni et al. 2007 ; Hashemian et al. 2019 ; Hu et al. 2011 ; Kim et al. 2011 ; Zhang et al. 2015 ; Al-Izki et al. 2011 ; Alme et al. 2015 ; Slowik et al. 2015 ). The scope of investigated compounds began to expand afterwards, with CYM5442 studied in 2018 alongside fingolimod (Kim et al. 2018 ), followed by the investigation of the S1PR2 antagonist JTE-013 in 2019 (Seyedsadr et al. 2019 ). More selective and newer S1PR1/5 dual modulators were introduced in subsequent years, including ozanimod in 2021 (Selkirk et al. 2021 ), RP-101074 in 2023 (Sindi et al. 2023 ), and ponesimod in 2024 (Willems et al. 2024 ). Siponimod was examined in three studies published in 2022 (Behrangi et al. 2022 ; Dietrich et al. 2022 ; Al-Otaibi et al. 2022 ) and in another study in 2025 (Krueger et al. 2025 ). Fingolimod remained the most extensively studied compound throughout the entire publication period, with additional studies reported in 2019 (Hashemian et al. 2019 ), 2020 (Nystad et al. 2020 ; Béchet et al. 2020 ), 2022 (Mitra et al. 2022 ), 2023 (Moradi et al. 2023 ; Robichon et al. 2023 ), and 2025 (Nascimento Pires et al. 2025 ). Overall, these results suggest that research on S1P modulators focusing on understanding remyelination still remains limited. 4. Discussion Overall, the findings of this review reveal a clear distinction between the capacity of S1P-based modulators in preventing demyelination and actively promoting remyelination. Across in vivo models, modulation of S1P signalling consistently limits myelin loss and preserves oligodendroglial populations following demyelination; however, these protective effects do not uniformly translate into enhanced myelin repair. This observation suggests that myelin protection and remyelination represent biologically distinctive processes rather than sequential outcomes of the same therapeutic effect. Consequently, the efficacy of S1P receptor modulation appears to be highly dependent on the disease stage and lesion environment, highlighting the importance of treatment timing, dosage, and model selection when evaluating a compound’s therapeutic potential. 4.1 Trends in S1P modulator development As shown in Fig. 5 , the initial peak in publications in 2015 likely reflects increased research interest following the approval of fingolimod as the first oral therapy for multiple sclerosis in 2010. During this period, preclinical studies primarily focused on characterising fingolimod’s effects on demyelination, oligodendrocyte lineage dynamics, and early remyelination across toxin-induced and autoimmune models. The second peak observed in 2022 coincided with the emergence of more selective S1PR modulators, including siponimod and ozanimod, within the clinical development pipeline. This shift was accompanied by an expansion in research focus from validating fingolimod to investigating subtype-specific S1PR modulation. These newer compounds preferentially target S1PR1 and S1PR5, receptors implicated in neuroinflammation and oligodendrocyte lineage cell survival, potentially reducing the cardiovascular adverse effects associated with S1PR3 signalling seen with fingolimod’s non-specific receptor modulation (Calabresi et al. 2014 ; Khatri et al. 2011 ; Forrest et al. 2004 ). Together, current research investigating S1P modulators in remyelination heavily focuses on targeting individual S1PRs. 4.2 Efficacy of S1P modulators on myelin protection and repair Across in vivo models of demyelination, S1P modulators consistently demonstrate efficacy in preserving myelin integrity during active demyelination, with more than 80% (15/18) of studies reporting a reduction in myelin loss following treatment. These protective effects are most evident in immune-mediated models such as EAE, where modulation of neuroinflammatory processes limits oligodendrocyte injury and subsequent myelin loss. In toxin-based models, including CPZ and LPC, treatment during the demyelination phase frequently reduces lesion severity and preserves myelin-associated markers. However, distinguishing true myelin repair from protection of existing myelin remains challenging, as evidence for effective remyelination was considerably heterogeneous. In many cases, remyelination did not exceed the level of spontaneous repair observed following toxin withdrawal or resolution of inflammation, particularly in fingolimod, where only 1/10 study showed significant enhancement following fingolimod treatment (Yazdi et al. 2015 ). Interpretation of remyelination outcomes is further constrained by the limited number of studies available for several compounds, including ozanimod, JTE-013, and ponesimod, which prevents definitive conclusions regarding their therapeutic potential. The interpretation of remyelination outcomes in vivo is complicated due to a range of methodological and biological factors. A major source of variability arises from differences in drug dosage, treatment timing, and therapeutic strategy across studies. In this systematic review, S1P-based therapeutics were administered using both prophylactic and therapeutic paradigms, with some studies initiating treatment before (Moradi et al. 2023 ; Yazdi et al. 2015 ) or at the onset of demyelination (Sindi et al. 2023 ; Nascimento Pires et al. 2025 ), while others commenced treatment during defined recovery phases to initiate remyelination, most commonly following CPZ withdrawal (Kim et al. 2011 ; Alme et al. 2015 ). Although prophylactic paradigms are valuable for studying drug mechanisms, they do not fully reflect the clinical context of demyelinating diseases such as MS, where treatment is typically initiated following diagnosis. This distinction is especially important, as early intervention in patients with undiagnosed or alternative inflammatory CNS conditions may carry an increased risk of adverse effects, further limiting the translational relevance of prophylactic treatment strategies (Ford 2020 ). Across the remyelination studies included in this review, enhanced remyelination was often inferred from increases in myelin protein expression or histological staining alone, without concurrent assessment of axonal ensheathment, internode length, or myelin thickness. This limitation was evident in studies such as JTE-013 treatment, where increased myelin staining was not supported by corresponding ultrastructural changes in myelin thickness (Seyedsadr et al. 2019 ). While these measures can reflect enhanced myelination at different levels, their interpretation is limited when demyelination and recovery phases are not clearly separated and when ultrastructural or complementary analyses are lacking. Ultrastructural assessment using TEM therefore remains the gold standard for evaluating remyelination, as it enables the direct assessment of compact, functionally relevant myelin wrapping around axons (Franklin and Ffrench-Constant 2017 ; Keough and Yong 2013 ). However, relatively few studies incorporated such analyses, with only four remyelination studies reporting ultrastructural evaluation, contributing to uncertainty in the interpretation of remyelination outcomes. Substantial heterogeneity is also introduced by differences in the models of CNS demyelination, animal species and strain, age, and sex. Different in vivo models exhibit markedly different intrinsic remyelination efficiencies. Toxin-induced models such as LPC or CPZ often display robust and rapid remyelination, whereas immune-mediated models such as EAE exhibit incomplete or delayed repair due to persistent inflammation and an unfavourable lesion microenvironment that limits reliable assessment of remyelination. Consequently, therapeutic efficacy observed in one model may not translate directly to another. Several studies also reported remyelination-related outcomes without incorporating a defined remyelination phase from CPZ withdrawal, making it difficult to distinguish enhanced myelin repair from myelin preservation. Additional challenges also involve pharmacokinetics, as many studies did not report the receptor engagement or BBB permeability of S1PR modulators such as ponesimod, RP-101074, and JTE-013, making it difficult to link observed biological effects to specific pharmacological mechanisms. Differences in BBB permeability across models, species, and disease stages can further complicate interpretation (O'Brown et al. 2018 ). Together, these limitations hinder cross-study comparison and make it difficult to distinguish true pro-remyelinating effects from myelin protection, underscoring the need for more rigorous and standardised experimental designs when evaluating S1PR-targeting therapeutics (Moradi et al. 2023 ; Krueger et al. 2025 ). Despite the study heterogeneities, our systematic analysis indicates that current S1P modulators possess efficacy in protecting myelin against a demyelinating insult, but their roles in potentiating myelin formation after injury remain to be determined. 4.3 Efficacy of S1P modulators on oligodendroglial dynamics in demyelinated lesions Across demyelination models, S1P-based therapeutics exert a consistent effect on oligodendroglial lineage preservation and early lineage activation during active demyelination but display limited capacity to drive full lineage progression during recovery. Increases in markers of mature OLG such as CC1, NOGO-A, and Nkx2.2, together with reduced apoptotic TUNEL labelling (Kim et al. 2018 ; Kim et al. 2011 ), indicate that S1PR modulation primarily enhances OLG survival and resistance to injury rather than replacement of lost cells during demyelination. The concurrent expansion of OPC populations, reflected by increased Olig2⁺/Ki67⁺, Olig2⁺/PCNA⁺, NG2⁺, and BrdU⁺/NG2⁺ cells, further suggests that S1PR modulation maintains OPC pools during demyelinating phases, which may preserve the cellular substrate required for subsequent myelin repair (Zhang et al. 2015 ; Behrangi et al. 2022 ; Krueger et al. 2025 ). However, preservation of oligodendroglial lineage cells does not uniformly translate into increased numbers of mature, myelinating OLG during the remyelination phase. The absence of significant changes in CC1⁺, NOGO-A⁺, or Olig2⁺ oligodendroglial lineage populations following fingolimod treatment across several studies suggests that OLG survival alone is insufficient to overcome barriers to differentiation and myelin formation once demyelination is established, particularly in the context of persistent neuroinflammation within lesions (Kim et al. 2018 ; Hu et al. 2011 ; Alme et al. 2015 ). This dissociation between oligodendroglial lineage preservation and differentiation highlights a key limitation of S1PR modulators in promoting de novo remyelination, particularly in environments where inflammatory signalling, myelin debris, or axonal damage persists. Nevertheless, a subset of studies reported engagement of reparative lineage dynamics, characterised by expansion of OPCs and intermediate-stage lineage populations, including BrdU⁺/Olig2⁺ proliferating oligodendroglial cells and modest increases in GST-π⁺ post-mitotic oligodendrocytes (Yazdi et al. 2015 ). More pronounced lineage progression was observed following treatment with JTE-013 and RP-101074, which increased both early progenitor pools (EdU⁺/PDGFRα⁺, Sox2⁺) and differentiated oligodendrocytes (EdU⁺/CC1⁺) (Seyedsadr et al. 2019 ; Sindi et al. 2023 ), suggesting that certain S1P-targeting strategies may more effectively support coordinated lineage progression. These findings align with evidence from progressive MS indicating that remyelination failure reflects not only impaired OPC recruitment, but also deficits in oligodendrocyte differentiation and survival, all governed by disease stage and lesion microenvironment (Kuhlmann et al. 2023 ). Together, our evaluations indicate that while S1P modulators consistently support oligodendroglial survival within myelin lesions, their role in promoting the differentiation of newly formed or existing OLG, a key remyelinating process, remains inconclusive. 4.4 Mechanism of S1P modulators: how do they work? A key question is what mechanism underpins the effects of S1P modulators in myelin lesions. Currently available S1P modulators were originally designed as receptor-selective ligands to modulate S1PR signalling, most notably S1PR1, by inducing receptor internalisation and degradation, thereby preventing the lymphocyte egress from secondary lymphoid organs (Aoki et al. 2016 ; Brinkmann et al. 2010 ). This mechanism effectively reduces immune cell infiltration into the CNS and limits inflammatory demyelination. Preclinical studies suggest they may also affect oligodendrocyte lineage cells via S1PR5, but these mechanisms remain incompletely defined. Fingolimod shows strong evidence supporting an S1PR1-mediated immune mechanism, where conditional deletion of S1PR1 in glial fibrillary acidic protein (GFAP)-expressing astrocytes or a phosphorylation defect in the S1PR1 gene abolishes fingolimod’s efficacy, confirming its dependence on S1PR1 (Choi et al. 2011 ; Tsai et al. 2016 ). Although fingolimod has been proposed to exert direct CNS effects, including oligodendrocyte support and modulation of myelin membrane dynamics, these findings are largely restricted to in vitro or ex vivo systems (Miron et al. 2010 ), while in vivo remyelination outcomes remain inconsistent across models. Kim et al. demonstrated that fingolimod selectively downregulates S1PR1 but not S1PR5, providing a mechanistic explanation for its robust effect on preventing immune-mediated demyelination but comparatively weak effect on OPC-driven remyelination, which appears to depend on S1PR5 signalling (Kim et al. 2018 ). Therefore, the comparatively stronger remyelination outcomes reported for siponimod, ponesimod, and RP-101074 are consistent with direct engagement of oligodendrocyte lineage signalling via S1PR5, rather than indirect immunosuppressive effects from S1PR1 signalling alone. Siponimod, a selective S1PR1/5 modulator, was developed to enhance CNS-specific actions while retaining immunomodulatory efficacy. Studies included in this review demonstrate preservation of OLGs and reduced demyelination, with some evidence of improved remyelination compared to fingolimod (Al-Otaibi et al. 2022 ). Siponimod-mediated OLG protection occurs without activation of classical remyelination pathways or direct suppression of glial inflammatory signalling in vitro , indicating that its effects may reflect S1PR5-dependent OLG survival rather than induction of OPC differentiation. Supporting this mechanism, Behrangi et al. showed that S1PR5 genetic deletion abolishes siponimod’s protective effects, while in vitro it does not suppress cytokine production in glia, indicating in vivo anti-inflammatory effects are indirect (Behrangi et al. 2022 ). Despite also targeting S1PR1 and S1PR5, the mechanistic profile of ozanimod appears to be dominated by S1PR1 engagement. Selkirk et al. found that unbound plasma and brain concentrations sufficient for ozanimod’s therapeutic efficacy in the EAE model exceed the EC 50 for S1PR1 but remain below that required for S1PR5 activation, indicating that its effects are mediated by peripheral immune modulation and possibly oligodendrocyte survival, but unlikely direct remyelination (Selkirk et al. 2021 ). These findings provide a mechanistic explanation for the modest and inconsistent remyelination observed with ozanimod and support the conclusion that S1PR1 activation alone is insufficient to drive effective remyelination. Across the included studies, dose dependency emerged as an important determinant of therapeutic outcome, with higher doses generally associated with stronger protection against demyelination, whereas intermediate or lower doses more consistently supported remyelination. For example, 0.3 mg/kg fingolimod enhanced PLP⁺ myelination and oligodendrocyte differentiation more effectively than 1 mg/kg in the LPC model (Yazdi et al. 2015 ), and a lower dose of 2 mg/kg of siponimod was more protective than 6 mg/kg (Dietrich et al. 2022 ), although very low doses of 0.3 mg/kg were insufficient (Behrangi et al. 2022 ). Clear evidence for a bell-shaped dose-response relationship was provided by Sindi et al., who demonstrated that a 1 mg/kg dose of RP-101074 was more effective than 5 mg/kg at preventing visual function loss (Sindi et al. 2023 ). This pattern likely reflects dose-dependent differences in S1PR engagement and internalisation, where higher doses promote more extensive downregulation and bias signalling towards S1PR1-mediated immunomodulation, which may limit optimal engagement of S1PR5-dependent remyelination pathways. Moderate levels of receptor engagement may better support S1PR5-associated signalling within the oligodendrocyte lineage, whereas insufficient dosing might fail to activate either pathways (Behrangi et al. 2022 ). This interpretation is consistent with in vitro studies demonstrating dose-dependent effects between S1P-mediated OLG survival and OPC differentiation (Miron et al. 2008 ; Zhang et al. 2017 ). Overall, pharmacological and genetic evidence support that S1P modulators such fingolimod and ozanimod primarily target S1PR1 for immune modulation, subsequent oligodendrocyte survival, whilst others such as siponimod primarily target S1PR5 for oligodendrocyte protection, although their capacity to drive remyelination remains largely unknown. Except for fingolimod and siponimod, other modulators reported in the selected articles lack sufficient pharmacokinetic or genetic validation, highlighting a key gap in understanding their mechanism of action. 4.5 Future research perspectives Despite significant effort in understanding S1P modulators using in vivo models of central demyelination, their efficacy in remyelination is lacking, highlighting a clear gap for future research. An appropriate experimental paradigm and treatment window in a combination with molecular, histological, and ultrastructural approaches, will enable more complete understanding as to whether S1P-based therapeutics promote de novo myelin formation or merely preserve existing myelin. While prophylactic modulation of S1PR often yields more pronounced protective effects on myelin compared to therapeutic treatments (Kim et al. 2018 ; Dietrich et al. 2022 ), such designs are predominantly used investigate mechanisms of demyelination prevention rather than remyelination. Future studies should therefore emphasise therapeutic treatment paradigms initiated after demyelination, to better model clinical scenarios and directly examine repair processes. Notably, no studies identified in this review investigated modulation of S1P metabolism, such as targeting its synthesis through sphingosine kinases 1 and 2 (Sphk1/2) or its degradation through sphingosine 1-phosphate lyase (SPL). The level of bioactive S1P is tightly regulated through an equilibrium between its synthesis, mediated by SphK1/2, and its degradation by SPL, within a complex sphingolipid metabolic network (George and Xiao 2024 ; Xiao 2023 ; van Echten-Deckert 2023 ). As the terminal enzyme in the catabolic pathway of sphingolipids, SPL also regulates the degradation of sphingosines, sphingomyelins, and ceramides – all of which contribute to myelin synthesis and neural repair (Giussani et al. 2021 ). Despite their therapeutic potential, approaches that selectively modulate endogenous S1P levels remain limited due to the complexity of the sphingolipid metabolic network. Nonetheless, manipulating endogenous S1P synthesis or degradation represents a promising alternative strategy that may mitigate adverse effects associated with disease-modifying therapies such as lymphopenia, myocardial infarction, atrioventricular block, and bradycardia (Coyle et al. 2024 ). Unlike S1PR modulators, which induce irreversible receptor internalisation and degradation, endogenous S1P signalling involves receptor recycling, potentially allowing more physiologically regulated signalling (Xiao 2023 ). Exploration of these metabolic pathways may therefore offer a novel direction for promoting CNS repair. Finally, future research can prioritise in vivo mapping of receptor-specific downstream signalling pathways, particularly those linked to oligodendrocyte differentiation and myelin formation. Improved understanding of how different S1PR subtypes engage intracellular pathways in different lesion environments will be critical for developing more selective and effective strategies to enhance remyelination. 5. Conclusion This review for the first time systematically evaluated the effects of S1P-based therapeutics on in vivo remyelination in the mammalian CNS, with particular emphasis on myelin protection and oligodendrocyte lineage dynamics. Across all selected studies, S1P receptor modulators consistently limited demyelination; however, their capacity to promote remyelination and oligodendrocyte lineage progression was variable and somewhat inconclusive. Collectively, these findings support a hypothesis that therapeutics focusing on targeting individual S1PRs may possess limited capacity to enable oligodendrocyte survival and differentiation and ultimately myelin repair in myelin lesions where there is ongoing and often aggressive inflammation. While future research should continue to optimise siponimod and ponesimod for remyelination, this review argues the need to develop new S1P-based therapeutics, such as modulating S1P levels via its metabolic pathways, which could circumvent non-specific effects associated with non-selective receptor modulation (e.g. incomplete S1PRs internalisation). In addition, the heterogeneity of reported outcomes and remyelination phases further underscores the influence of experimental model and study designs that may complicate outcome interpretation. The findings of this review offer a framework to guide future model selection and experimental design aimed at determining remyelination outcomes for demyelinating diseases such as MS. Declarations Competing Interests The author declares no conflict of financial or non-financial interests that are directly or indirectly related to the work submitted for publication. Ethics approval Not applicable Consent to participate Not applicable Consent to publish Not applicable Funding The work presented in the manuscript is supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program (#Mason2210) to Junhua Xiao; and Swinburne University of Technology Postgraduate TFS Scholarship to Harley Vu. Author Contribution Conceptualisation, Resources, Writing – Original Draft Preparation and Final Review & Editing: Harley Vu and Junhua Xiao; Investigation: Harley Vu, Nelson George and Junhua Xiao. 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Avicenna J Phytomedicine 13(6):675–687. https://doi.org/10.22038/AJP.2023.22784 Nascimento Pires G, Pereira Laurindo R, Dos Santos Heringer L, Calixto da Silva S, Magalhães Portela D, Cardoso R, de Pádua AC, Miranda De Sá AB, Alves Da Cruz SA, Espírito Santo Araújo S, Blanco Martinez AM, Batista Carneiro M, Rocha Mendonça H (2025) Therapeutic potential of pranlukast against cuprizone-induced inflammatory demyelination and sensory impairment in mice: comparison with fingolimod. NeuroToxicology 107:37–52. https://doi.org/10.1016/j.neuro.2025.01.004 Nave KA, Werner HB (2014) Myelination of the nervous system: mechanisms and functions. Annu Rev Cell Dev Biol 30:503–533. https://doi.org/10.1146/annurev-cellbio-100913-013101 Noyes K, Weinstock-Guttman B (2013) Impact of diagnosis and early treatment on the course of multiple sclerosis. Am J Manag Care 19(17 Suppl):s321–331 Nyamoya S, Schweiger F, Kipp M, Hochstrasser T (2017) Cuprizone as a model of myelin and axonal damage. Drug Discovery Today: Disease Models 25–26:63–68. https://doi.org/10.1016/j.ddmod.2018.09.003 Nystad AE, Lereim RR, Wergeland S, Oveland E, Myhr K-M, Bø L, Torkildsen Ø (2020) Fingolimod downregulates brain sphingosine-1-phosphate receptor 1 levels but does not promote remyelination or neuroprotection in the cuprizone model. J Neuroimmunol 339:577091. https://doi.org/10.1016/j.jneuroim.2019.577091 O'Brown NM, Pfau SJ, Gu C (2018) Bridging barriers: a comparative look at the blood-brain barrier across organisms. Genes Dev 32(7–8):466–478. https://doi.org/10.1101/gad.309823.117 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372. https://doi.org/10.1136/bmj.n71 Park SJ, Im DS (2017) Sphingosine 1-phosphate receptor modulators and drug discovery. Biomolecules Ther 25(1):80–90. https://doi.org/10.4062/biomolther.2016.160 Pirko I, Noseworthy JH (2007) Demyelinating disorders of the central nervous system. Textbook Clin Neurol 1103–1133. https://doi.org/10.1016/b978-141603618-0.10048-7 Poitelon Y, Kopec AM, Belin S (2020) Myelin fat facts: an overview of lipids and fatty acid metabolism. Cells 9(4):812. https://doi.org/10.3390/cells9040812 Procaccini C, De Rosa V, Pucino V, Formisano L, Matarese G (2015) Animal models of multiple sclerosis. Eur J Pharmacol 759:182–191. https://doi.org/10.1016/j.ejphar.2015.03.042 Ransohoff RM (2012) Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat Neurosci 15(8):1074–1077. https://doi.org/10.1038/nn.3168 Robichon K, Bibi R, Kiernan M, Denny L, Prisinzano TE, Kivell BM, La Flamme AC (2023) Enhanced and complementary benefits of a nalfurafine and fingolimod combination to treat immune-driven demyelination. Clin Transl Immunol 12(12). https://doi.org/10.1002/cti2.1480 Roggeri A, Schepers M, Tiane A, Rombaut B, van Veggel L, Hellings N, Prickaerts J, Pittaluga A, Vanmierlo T (2020) Sphingosine-1-phosphate receptor modulators and oligodendroglial cells: beyond immunomodulation. Int J Mol Sci 21(20). https://doi.org/10.3390/ijms21207537 Selkirk JV, Dines KC, Yan YG, Ching N, Dalvie D, Biswas S, Bortolato A, Schkeryantz JM, Lopez C, Ruiz I, Hargreaves R (2021) Deconstructing the pharmacological contribution of sphingosine-1 phosphate receptors to mouse models of multiple sclerosis using the species selectivity of ozanimod, a dual modulator of human sphingosine 1-phosphate receptor subtypes 1 and 5. J Pharmacol Exp Ther 379(3):386–399. https://doi.org/10.1124/jpet.121.000741 Seyedsadr MS, Weinmann O, Amorim A, Ineichen BV, Egger M, Mirnajafi-Zadeh J, Becher B, Javan M, Schwab ME (2019) Inactivation of sphingosine-1-phosphate receptor 2 (S1PR2) decreases demyelination and enhances remyelination in animal models of multiple sclerosis. Neurobiol Dis 124:189–201. https://doi.org/10.1016/j.nbd.2018.11.018 Sindi M, Hecker C, Issberner A, Ruck T, Meuth SG, Albrecht P, Dietrich M (2023) S1PR-1/5 modulator RP-101074 shows beneficial effects in a model of central nervous system degeneration. Front Immunol 14. https://doi.org/10.3389/fimmu.2023.1234984 Slowik A, Schmidt T, Beyer C, Amor S, Clarner T, Kipp M (2015) The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination. Br J Pharmacol 172(1):80–92. https://doi.org/10.1111/bph.12938 Spiegel S, Milstien S (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4(5):397–407. https://doi.org/10.1038/nrm1103 Stadelmann C, Timmler S, Barrantes-Freer A, Simons M (2019) Myelin in the central nervous system: structure, function, and pathology. Physiol Rev 99(3):1381–1431. https://doi.org/10.1152/physrev.00031.2018 Tsai HC, Huang Y, Garris CS, Moreno MA, Griffin CW, Han MH (2016) Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation. JCI Insight 1(9):e86462. https://doi.org/10.1172/jci.insight.86462 van Echten-Deckert G (2023) The role of sphingosine 1-phosphate metabolism in brain health and disease. Pharmacol Ther 244:108381. https://doi.org/10.1016/j.pharmthera.2023.108381 Willems E, Schepers M, Piccart E, Wolfs E, Hellings N, Ait-Tihyaty M, Vanmierlo T (2024) The sphingosine-1-phosphate receptor 1 modulator ponesimod repairs cuprizone-induced demyelination and induces oligodendrocyte differentiation. FASEB J 38(2):e23413. https://doi.org/10.1096/fj.202301557RR Xiao J (2023) Sphingosine 1-phosphate lyase in the developing and injured nervous system: a dichotomy? Mol Neurobiol 60(12):6869–6882. https://doi.org/10.1007/s12035-023-03524-3 Yazdi A, Baharvand H, Javan M (2015) Enhanced remyelination following lysolecithin-induced demyelination in mice under treatment with fingolimod (FTY720). Neuroscience 311:34–44. https://doi.org/10.1016/j.neuroscience.2015.10.013 Zhang J, Zhang ZG, Li Y, Ding X, Shang X, Lu M, Elias SB, Chopp M (2015) Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis. Neurobiol Dis 76:57–66. https://doi.org/10.1016/j.nbd.2015.01.006 Zhang Y, Li X, Ciric B, Ma CG, Gran B, Rostami A, Zhang GX (2017) Effect of fingolimod on neural stem cells: a novel mechanism and broadened application for neural repair. Mol Ther 25(2):401–415. https://doi.org/10.1016/j.ymthe.2016.12.008 Additional Declarations No competing interests reported. Supplementary Files SystematicReviewFigures.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 May, 2026 Reviews received at journal 02 May, 2026 Reviewers agreed at journal 19 Apr, 2026 Reviewers agreed at journal 10 Mar, 2026 Reviews received at journal 06 Mar, 2026 Reviewers agreed at journal 23 Feb, 2026 Reviewers invited by journal 21 Feb, 2026 Submission checks completed at journal 19 Feb, 2026 First submitted to journal 17 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8856008","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":608452286,"identity":"049b0508-17ab-42fe-935f-f1a4dfdc55bc","order_by":0,"name":"Harley Vu","email":"","orcid":"","institution":"Swinburne University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Harley","middleName":"","lastName":"Vu","suffix":""},{"id":608452289,"identity":"752894cc-eda2-4244-92a4-1bf82c6d1f57","order_by":1,"name":"Nelson George","email":"","orcid":"","institution":"Swinburne University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Nelson","middleName":"","lastName":"George","suffix":""},{"id":608452295,"identity":"438d6ba8-d62b-4383-a7b9-957dd849c3f3","order_by":2,"name":"Junhua Xiao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYBACxgbGBgaGCgYGNhCPh3gtZ0jRAtHXBmUQpYV5RnLjh4/z6hL7pBsYH7xtY5A3OEDIgp6DzZIztx1ObJM5wGw4t43BcANBLe2NDdK82w7ktkkksEnztjEwEtbSzNj8m3dOHUgL+2+gFntibGmT5m1gBtvCDNSSSFhLz8E2yxnHDte3SSQ2S845J5E8k5AWwxnpj298qKkzlp+RfPDDmzIb2z6CWhoQFoKYEgTUA4E8YSWjYBSMglEw4gEAmItArSMuThwAAAAASUVORK5CYII=","orcid":"","institution":"Swinburne University of Technology","correspondingAuthor":true,"prefix":"","firstName":"Junhua","middleName":"","lastName":"Xiao","suffix":""}],"badges":[],"createdAt":"2026-02-11 23:08:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8856008/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8856008/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105501684,"identity":"59ae3652-3d9b-4cb0-92e5-0e724a58411c","added_by":"auto","created_at":"2026-03-26 17:39:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2035658,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTimeline of key breakthroughs and milestone events in the research of S1P modulators.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA schematic showing the timeline of key breakthroughs and milestone events in the research of S1P modulators. Fingolimod was first identified in 1995 as a synthetic derivative of the natural compound myriocin, which was originally isolated from the fungus Isaria sinclairii (Park and Im 2017). Its immunosuppressive mechanism was subsequently elucidated using in vitro and in vivo rodent models of MS (Brinkmann et al. 2002). Clinical trials of fingolimod were conducted between 2006 and 2007 (Kappos et al. 2010), leading to its FDA approval in 2010 for the treatment of relapsing forms of MS (Coyle et al. 2024). Following this approval, more receptor-selective S1P modulators targeting S1PR1 and/or S1PR5, including siponimod, ozanimod, and ponesimod, underwent clinical evaluation (Kappos et al. 2018; Cohen et al. 2019; Kappos et al. 2021) and were subsequently approved by the FDA in 2019, 2020, and 2021, respectively (Coyle et al. 2024). Figure prepared in Microsoft PowerPoint (available at \u003ca href=\"https://www.microsoft.com/en-us/microsoft-365/powerpoint\"\u003ewww.microsoft.com\u003c/a\u003e).\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-8856008/v1/f3e2ba1a070119a69d7c7b0d.png"},{"id":105501702,"identity":"b94dd701-61fb-4495-b733-61e59c88dcf5","added_by":"auto","created_at":"2026-03-26 17:40:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1327517,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA PRISMA flow diagram showing article selection for the systematic review.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOut of 237 studies from three databases, 24 were eligible for inclusion in this systematic review. Flow diagram created by Covidence.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-8856008/v1/af2e938265a775f385d8e5a5.png"},{"id":105501699,"identity":"ea22fb4a-c0cf-46a8-9b9a-4c87e5824012","added_by":"auto","created_at":"2026-03-26 17:40:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5882632,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSYRCLE risk of bias assessment of selected articles.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 24 studies were reviewed and assessed using the following criteria: D1: Random sequence generation; D2: Baseline characteristics; D3: Allocation concealment; D4: Random housing; D5: Blinding for caregivers and/or investigators; D6: Random outcome assessment; D7: Blinding of outcome assessment; D8: Incomplete outcome data; D9: Selective reporting; and D10: Other sources of bias. Red: High bias; Yellow: Unclear bias; Green: Low bias (Hooijmans et al. 2014). Both the (A) “stop-light” figure and (B) summary graph were created using the \u003cem\u003erobvis\u003c/em\u003eShiny web application (available at \u003ca href=\"https://mcguinlu.shinyapps.io/robvis/\"\u003eshinyapps.io/robvis\u003c/a\u003e) (McGuinness and Higgins 2020).\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-8856008/v1/dce8d83ac7314b32cd11dcde.png"},{"id":105501697,"identity":"1d1fed9e-36f7-488b-bfa6-09c2cdf9a323","added_by":"auto","created_at":"2026-03-26 17:40:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1085894,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of research articles on S1P modulators\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eOf 24 articles, fingolimod (FTY720) was studied most frequently, with 16 studies, followed by siponimod with 4 studies. One study was on ozanimod, RP-101074 (ozanimod metabolite), ponesimod, CYM5442, and JTE-013. One study investigated both the effect of Fingolimod as well as CYM5442 (Kim et al. 2018). Figure prepared in GraphPad Prism (available at \u003ca href=\"https://www.graphpad.com/\"\u003ewww.graphpad.com\u003c/a\u003e)\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-8856008/v1/92589303666d020053994cb6.png"},{"id":105501701,"identity":"cb593d55-a16d-4128-baea-9630b88af1ee","added_by":"auto","created_at":"2026-03-26 17:40:02","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1235490,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of S1P modulator research published over time.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLine graph showing the number of published articles reporting the effect of S1PR modulation on remyelination in mammalian\u003cem\u003e in vivo\u003c/em\u003e models. Figure prepared in GraphPad Prism (available at \u003ca href=\"https://www.graphpad.com/\"\u003ewww.graphpad.com\u003c/a\u003e)\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-8856008/v1/e1d1df119dbc72dfd853838a.png"},{"id":105501710,"identity":"78e69d15-a209-4280-bf0c-ff7ac4891a17","added_by":"auto","created_at":"2026-03-26 17:40:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":13467240,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8856008/v1/0a3f6c51-6a9c-4d44-a245-200b85ae2b7a.pdf"},{"id":105501696,"identity":"ef256488-6f16-426c-b9ff-d319ec3cdbb3","added_by":"auto","created_at":"2026-03-26 17:40:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":53633,"visible":true,"origin":"","legend":"","description":"","filename":"SystematicReviewFigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-8856008/v1/901a29397c6a82d1d5f60719.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Sphingosine 1-phosphate Modulators on Central Remyelination: A Systematic Review of Animal Models","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eMyelin is a specialised, lipid-rich membrane that ensheathes many axons in the nervous system (Kister and Kister \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Stadelmann et al. \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Nave and Werner \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2014\u003c/span\u003e), enabling rapid saltatory conduction and providing essential trophic support to neurons (Roggeri et al. \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Approximately 70\u0026ndash;85% of myelin content is comprised of lipids, including cholesterol, phospholipids, and glycolipids, contributing to the structural stability and compaction of the myelin sheath (Poitelon et al. \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Demyelination, defined as the loss or damage of myelin, occurs in both genetic and acquired neurological diseases, disrupting axonal conduction and ultimately leading to progressive neurological disability (Coutinho Costa et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Indeed, demyelination is a pathological hallmark of a plethora of central nervous system (CNS) disorders, particularly inflammatory demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM) (Coutinho Costa et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Pirko and Noseworthy \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). In MS, persistent neuroinflammation eventually leads to irreversible axonal damage and neurodegeneration, emphasising that the prevention of demyelination alone is insufficient to maintain long-term neurological function (Dighriri et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Haki et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Although MS lesions possess an intrinsic capacity for remyelination early in the disease course, many lesions remain chronically demyelinated, leading to irreversible axonal degeneration that drives clinical deficits in later stages. Indeed, incomplete or failure of remyelination remains an obstacle to functional recovery in MS.\u003c/p\u003e \u003cp\u003eRemyelination is a complex, multicellular process influenced by axon-glia interactions, innate and systemic immune responses, and the extracellular milieu (Franklin and Simons \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Bourdette and Wooliscroft \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). It begins with the clearance of myelin debris, followed by the activation of oligodendrocyte precursor cells (OPCs), which migrate to demyelinated regions and differentiate into myelinating oligodendrocytes (OLGs) (Leo and Kipp \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Kotter et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Keirstead and Blakemore \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). This lineage progression is accompanied by stage-specific molecular changes, with markers such as NG2 and PDGFRα identifying OPCs, O1, O4 and protein proteolipid (PLP) marking pre-oligodendrocytes, and CC1, CNPase, myelin-associated glycoprotein (MAG), or myelin basic protein (MBP) characterising mature myelinating cells, enabling the detailed assessment of remyelination dynamics in experimental models (Leo and Kipp \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Roggeri et al. \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Due to the complexity of these coordinated processes and the inflammatory microenvironment in myelin lesions, remyelination cannot be fully recapitulated \u003cem\u003ein vitro\u003c/em\u003e. Therefore, \u003cem\u003ein vivo\u003c/em\u003e mammalian models play a central role in remyelination research by enabling the assessment of efficacy within an intact CNS environment, where factors such as blood-brain barrier (BBB) permeability and cellular interactions can influence therapeutic outcomes (Lubetzki et al. \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Commonly used models such as cuprizone (CPZ), lysolecithin (LPC), and experimental autoimmune encephalomyelitis (EAE) mimic various pathophysiological aspects of MS and provide complementary information on toxin-induced demyelination, focal lesions, and autoimmune-driven neuropathology, respectively (Procaccini et al. \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Ransohoff \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Dedoni et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOver the past decade, significant progress has been made in the landscape of MS therapy with the emergence of novel disease-modifying therapies (DMTs). These therapies primarily act by modulating immune responses, either by controlling immune cells overactivity or by preventing their infiltration into the CNS, subsequently reducing the frequency of relapse and disease severity (Filippi et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Noyes and Weinstock-Guttman \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). However, they display limited efficacy in progressive forms of MS driven by inflammatory demyelination and incomplete repair, presenting an unmet therapeutic gap (Harlow et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Nyamoya et al. \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). With the exception of ocrelizumab, which has shown only a modest effect on slowing disease progression, all 16 United States Food and Drug Administration (FDA)-approved MS therapies fail to halt or substantially delay the progressive accumulation of disability, particularly in progressive forms of MS (Hooijmans et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Indeed, failure of remyelination represents a clear obstacle in the recovery of MS, arguing the urgent need for strategies that extend beyond immunosuppression to preserve axonal integrity and restore myelin.\u003c/p\u003e \u003cp\u003eAmong emerging therapeutic targets, sphingosine 1-phosphate (S1P) has gained substantial attention due to its dual role in immunomodulation and oligodendrocyte lineage biology. S1P exerts its cellular effects through sphingosine 1-phosphate receptors (S1PRs) \u0026ndash; a family of five G protein-coupled receptors (S1PR1-S1PR5) (Spiegel and Milstien \u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Binish and Xiao \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Cartier and Hla \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Among them, S1PR1 is ubiquitously expressed across multiple cell types, including lymphocytes, where it plays a central role in immunomodulation and therefore represents a key therapeutic target in MS (McGinley and Cohen \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chen et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Within the CNS, S1PR1 is expressed by neurons, astrocytes, and microglia, whereas S1PR5 is abundantly and selectively expressed by oligodendrocyte lineage cells, particularly within cortical white matter tracts (Coelho et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Bravo et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Fingolimod, the first S1PR modulator and oral therapeutic approved for MS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e), demonstrated substantial clinical benefit through immunomodulatory mechanisms, but its direct effect on oligodendrocyte lineage cells \u003cem\u003ein vivo\u003c/em\u003e remains uncertain. More recently, selective S1PR1/5 modulators such as siponimod, ozanimod, and ponesimod have been developed, raising the possibility that receptor-specific signalling may differentially influence remyelination (Coyle et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Roggeri et al. \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSince the approval of fingolimod for relapsing-remitting MS (RRMS) in 2010 (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eA), increasing preclinical studies have investigated the potential of S1P-based therapeutics not only in preventing demyelination but also influencing olidogdendroglial dynamics and remyelination \u003cem\u003ein vivo\u003c/em\u003e. Despite these findings, however, the distinction between preventing demyelination, preserving OLGs, and actively promoting new myelin formation remains unclear. Furthermore, despite extensive clinical use and a growing body of preclinical literature, the extent to which S1P-based therapies promote myelin repair remains unclear and has not been systematically synthesised across mammalian models of demyelination. This systematic review, therefore, aims to evaluate the evidence of remyelination concerning S1P-based therapeutics in \u003cem\u003ein vivo\u003c/em\u003e mammalian models of CNS demyelination. Specifically, it examines (i) the efficacy of these treatments in limiting demyelination, (ii) their effects on oligodendroglial dynamics within demyelinated lesions and (iii) their capacity to enhance remyelination as assessed through biochemical, histological, or ultrastructural outcomes. This systematic review provides a comprehensive evaluation, determining the status of current S1P-based therapeutics in regulating myelin repair and identifying key gaps for further research.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design\u003c/h2\u003e \u003cp\u003eThis systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al. \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Search strategy and study selection\u003c/h2\u003e \u003cp\u003eA systematic literature search was performed on three databases: Web of Science, PubMed, and Scopus to identify all studies that have been published up to the research date (2 July 2025), focusing on the following areas of interest: \u0026ldquo;remyelination\u0026rdquo; and \u0026ldquo;sphingosine-1-phosphate\u0026rdquo; and \u0026ldquo;\u003cem\u003ein vivo\u003c/em\u003e\u0026rdquo;. After the selection of appropriate keywords, the search was performed within the \u0026ldquo;Title and Abstract\u0026rdquo; in PubMed, \u0026ldquo;Title, Abstract, and Keyword\u0026rdquo; in Scopus, and within \u0026ldquo;Topic\u0026rdquo; in Web of Science. The publication language was limited to English, and the following advanced searches for each database are reported:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eWeb of Science search\u003c/b\u003e: TS = (\"remyelination\" OR \"myelin repair\" OR \"myelin\" OR \"oligodendrocyte\") AND TS = (\u0026ldquo;Sphingosine-1-phosphate\" OR \"S1P receptor\" OR \"S1PR\" OR \"fingolimod\" OR \"siponimod\" OR \"ozanimod\" OR \"ponesimod\" OR \"etrasimod\u0026rdquo;) AND TS = (\"animal model\" OR \"mouse model\" OR \"rodent\" OR \"\u003cem\u003ein vivo\u003c/em\u003e\" OR \"EAE\" OR \"cuprizone\" OR \"lysolecithin\" OR \"LPS\")\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePubmed search\u003c/b\u003e: (\"remyelination\" OR \"myelin repair\" OR \"myelin\" OR \"oligodendrocyte\" ) AND ( \"Sphingosine-1-phosphate\" OR \"S1P receptor\" OR \"S1PR\" OR \"fingolimod\" OR \"siponimod\" OR \"ozanimod\" OR \"ponesimod\" OR \"etrasimod\") AND (\"animal model\" OR \"mouse model\" OR \"rodent\" OR \"\u003cem\u003ein vivo\u003c/em\u003e\" OR \"EAE\" OR \"cuprizone\" OR \"lysolecithin\" OR \u0026ldquo;LPS\u0026rdquo;) NOT \"review\" NOT \u0026ldquo;comment\u0026rdquo; NOT \u0026ldquo;editorial\u0026rdquo;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eScopus search\u003c/b\u003e: TITLE-ABS-KEY (\"remyelination\" OR \"myelin repair\" OR \"myelin\" OR \"oligodendrocyte\" ) AND TITLE-ABS-KEY ( \"Sphingosine-1-phosphate\" OR \"S1P receptor\" OR \"S1PR\" OR \"fingolimod\" OR \"siponimod\" OR \"ozanimod\" OR \"ponesimod\" OR \"etrasimod\" ) AND TITLE-ABS-KEY ( \"animal model\" OR \"mouse model\" OR \"rodent\" OR \"\u003cem\u003ein vivo\u003c/em\u003e\" OR \"EAE\" OR \"cuprizone\" OR \"lysolecithin\" OR \"LPS\" ) AND NOT \"review\" AND NOT \"comment\" AND NOT \"editorial\"\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Inclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eThe search strategy was structured using the PICOS (population, intervention, comparator, outcome, study) model, which guided the inclusion criteria.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePopulation\u003c/b\u003e: Animals subjected to CNS demyelination via established experimental models (e.g. cuprizone, lysolecithin, EAE, LPS).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eIntervention\u003c/b\u003e: Treatment with S1P-based therapeutics (e.g., fingolimod, siponimod, ozanimod, ponesimod, estrasimod).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eComparator\u003c/b\u003e: Demyelinated animals receiving no treatment, vehicle, or placebo treatment.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eOutcome\u003c/b\u003e: Quantitative or qualitative measures of CNS remyelination (e.g., histological assessment of myelin density, oligodendrocyte maturation, myelin protein expression).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy\u003c/b\u003e: \u003cem\u003eIn vivo\u003c/em\u003e preclinical studies using mammalian models (mouse, rat, etc.)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eOnly articles that report the effects of S1P-based therapeutics on myelin or oligodendrocyte lineage cells (OLGs/OPCs) were included. This included studies in which S1P-based therapeutics were used to validate a novel compound or drug delivery model, provided that the effects of the S1P-based therapeutic alone were reported and could be extracted for this systematic review. All human studies or \u003cem\u003ein vitro\u003c/em\u003e, \u003cem\u003eex vivo\u003c/em\u003e, and \u003cem\u003ein silico\u003c/em\u003e studies were excluded. Studies that used a PNS demyelination model were also excluded. Additionally, studies that do not report the dosage of the S1P-based therapeutic were excluded. Finally, articles examining S1P-based therapeutics in \u003cem\u003ein vivo\u003c/em\u003e CNS demyelination models were excluded if they did not assess at least one of the following outcomes:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eOn preventing myelin damage/demyelination\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eOn promoting myelin repair/remyelination\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eOn OLG or OPC survival, differentiation, and maturation\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eUsing the Covidence software (available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.microsoft.com\" target=\"_blank\"\u003ewww.covidence.org\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.covidence.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), two reviewers independently assessed the titles and abstracts of the identified studies to determine their relevance. Studies that passed the initial screening underwent full-text review using the same process. Any conflicts arising during the screening process were resolved by a third reviewer. This approach allowed enabled the systematic exclusion of studies that did not meet the inclusion criteria and ensured the comprehensive evaluation of study eligibilities for this systematic review. The outcomes of the study selection process are reported in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Data extraction\u003c/h2\u003e \u003cp\u003eA standardised data extraction form was developed and pilot-tested to enable any minor adjustments to be made to the template if required. The primary data were extracted by a single reviewer using a custom-designed template to capture all relevant and necessary information from the included studies, which was subsequently reviewed by an independent reviewer. Extracted data were summarised in the tables and included the following information:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eCharacteristics of the S1P-based therapeutics, including molecular weight, receptor target(s), evidence of molecular binding to S1PRs, and BBB permeability (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDescription of the animal models used in each study, including their characteristics, method of induction, strengths, and limitations (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEfficacy of S1P-based therapeutics in preventing demyelination (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEfficacy of S1P-based therapeutics in promoting remyelination (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCompound (S1PR modulator) characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eName of modulator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMolecular weight\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTargeted S1PR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMolecular binding evidence\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBBB permeability\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFTY720 (Fingolimod/Gilenya)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e307.5 g/mol\u003c/p\u003e \u003cp\u003eCID: 107970\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS1PR1, S1PR3, S1PR4, S1PR5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1PR1 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 0.3 nM)\u003c/p\u003e \u003cp\u003eS1PR3 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 0.9 nM)\u003c/p\u003e \u003cp\u003eS1PR4 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 345 nM)\u003c/p\u003e \u003cp\u003eS1PR5 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 0.50 nM) (Scott et al. 2016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBrain:blood ratio of 14:1 in Lewis rats after 13 days treatment and 27:1 in Dark Agouti (DA) rats after 23-days treatment of 0.3 mg/kg FTY720. Blood and brain samples taken 24 hours after injection. Autoradiography have shown that [\u003csup\u003e14\u003c/sup\u003eC]FTY720 is lipophilic and distributes into the parenchyma of rat CNS following a single oral dose (Foster et al. 2007).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSiponimod (Mayzent)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e516.6 g/mol\u003c/p\u003e \u003cp\u003eCID: 44599207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS1PR1, S1PR5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1PR1 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 0.39 nM)\u003c/p\u003e \u003cp\u003eS1PR5 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 0.38 nM) (Scott et al. 2016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBrain:blood ratio approaching 6:1 in C57BL/6 mice at various doses ranging from 0.1 to 30 mg/kg of food. Autoradiography showed that [\u0026sup1;⁴C]siponimod readily penetrated rat CNS, with particularly high uptake in white matter regions (cerebellum, corpus callosum, medulla oblongata) and lower levels in areas such as the olfactory bulb (Bigaud et al. 2021).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOzanimod (Zeposia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e404.5 g/mol\u003c/p\u003e \u003cp\u003eCID: 52938427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS1PR1, S1PR5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1PR1 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 0.41 nM)\u003c/p\u003e \u003cp\u003eS1PR5 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 11 nM) (Scott et al. 2016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBrain:blood ratio of 10:1 in C57BL/6 mice at 1 mg/kg dose, and brain:blood ratio of 16:1 in Sprague-Dawley rats at 0.5 mg/kg (Scott et al. 2016).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRP-101074 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e360.4 g/mol\u003c/p\u003e \u003cp\u003e(MW referenced from RP-101075; CID: 52938426)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS1PR1, S1PR5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1PR1 (EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.35 nM)\u003c/p\u003e \u003cp\u003eS1PR5 (EC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.5 nM)\u003c/p\u003e \u003cp\u003eRP-101074 data not available, data shown are for RP-101075 (Surapaneni et al. 2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRP-101074 BBB permeability data not reported. RP-101075 has a brain:blood ratio of 31:1 (species and dose not specified) (Scott et al. 2013).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePonesimod (Ponvory)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e461.0 g/mol CID: 11363176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS1PR1, S1PR5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1PR1 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 5.7 nM)\u003c/p\u003e \u003cp\u003eS1PR5 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 11 nM) (Scott et al. 2016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAccording to preclinical and clinical studies, ponesimod does cross the BBB or at least exerts effects within the CNS. However, no quantitative brain:blood ratio or neuroimaging evidence has been disclosed.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYM5442\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e409.5 g/mol CID: 25110406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS1PR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1PR1 (EC\u003csub\u003e50\u003c/sub\u003e\u0026nbsp;= 1.4 nM) (Gonzalez-Cabrera et al. 2008)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBrain:plasma ratio of 35:1 in C57BL/6J mice 24 hours after 10mg/kg CYM5442 injection (Gonzalez-Cabrera et al. 2012).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJTE-013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e408.3\u0026nbsp;g/mol CID: 10223146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS1PR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1PR2 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;17 nM) (Osada et al. 2002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSimilar to ponesimod, no quantitative brain:blood ratio or neuroimaging evidence for JTE-013 has been disclosed.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eNote\u003c/em\u003e. Summary of the characteristics of identified S1P-based therapeutics. Columns include the following: modulator name, molecular weight \u0026ndash; data retrieved from the PubChem Compound Database, National Library of Medicine, Maryland, USA (Kim et al. 2025), targeted S1PR, molecular binding evidence to human S1PRs, and evidence of BBB permeability via brain:blood ratio and imaging evidence. *: RP-101074 molecular weight, molecular binding evidence, and BBB permeability data not available, therefore, the data shown are for RP-101075, another ozanimod metabolite. RP-101074 is the R-isomer of this metabolite. Abbreviations: CID \u0026ndash; PubChem Compound Identifier; EC\u003csub\u003e50\u003c/sub\u003e \u0026ndash; half-maximal effective concentration; IC\u003csub\u003e50\u003c/sub\u003e \u0026ndash; half-maximal inhibitory concentration.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnimal models used to study de- and remyelination\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnimal model\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCharacteristics and induction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStrengths\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEAE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAutoimmune-driven demyelination induced by immunisation with myelin antigens in complete Freund\u0026rsquo;s adjuvant containing pertussis toxin (Constantinescu et al. 2011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMimics the pathological features and disease course of MS\u003c/p\u003e \u003cp\u003eRobust immune-driven demyelination\u003c/p\u003e \u003cp\u003eWell-established model (Constantinescu et al. 2011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDoes not represent progressive MS\u003c/p\u003e \u003cp\u003eNo clear remyelination/recovery phase (Ransohoff \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2012\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eDemyelination mostly confined to the spinal cord with few brain lesions\u003c/p\u003e \u003cp\u003ePathological characteristics dependent on species and myelin epitope (Palumbo and Pellegrini 2017)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPZ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eToxin model causing oligodendrocyte apoptosis and demyelination by dietary administration of CPZ (0.2\u0026ndash;0.3%) in chow (Ransohoff \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2012\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWell-established model with clear demyelination-remyelination timeline (Praet et al. 2014)\u003c/p\u003e \u003cp\u003eMinimal peripheral immune involvement (Zhan et al. 2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDoes not fully recapitulate MS autoimmune pathology\u003c/p\u003e \u003cp\u003eMechanism behind OLG degeneration still poorly understood (Kipp 2024)\u003c/p\u003e \u003cp\u003eRegion-specific demyelination (Zhan et al. 2020)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPZ\u0026thinsp;+\u0026thinsp;EAE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA combination of toxin-induced oligodendrocyte loss with autoimmune infiltration by feeding mice with CPZ chow for 3 weeks, followed by normal chow for 2 weeks, and EAE induction (R\u0026uuml;ther et al. 2017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBetter reflects MS pathology by combining neurodegeneration and inflammation, allowing the study of remyelination under active inflammatory conditions (Scheld et al. 2016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTechnically demanding\u003c/p\u003e \u003cp\u003eAnimal welfare concern\u003c/p\u003e \u003cp\u003eNot a well-established model yet\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEAEON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAutoimmune-driven demyelination of the optic nerve, causing optic neuritis and visual deficits. Mode of induction is similar to EAE (Kezuka et al. 2011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUseful for studying optic neuritis and visual pathways\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLimited to optic nerve\u003c/p\u003e \u003cp\u003eIf not isolated, can occur with systemic EAE\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwitcher mice (Krabbe\u0026rsquo;s disease model)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTransgenic mouse model with mutation in the galactocerebrosidase (GALC) gene, leading to psychosine accumulation and demyelination (Suzuki and Suzuki 1995)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStrong model for congenital demyelination with progressive and severe myelin loss (Suzuki and Taniike 1995)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRapid disease progression \u0026ndash; mice have short lifespan (Suzuki and Suzuki 1995)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLPC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFocal injection of lysolecithin (LPC) into regions of the CNS such as the spinal cord, optic nerve, corpus callosum, causing localised demyelination (Plemel et al. 2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFast, localised, and reproducible demyelination Spontaneous remyelination one week after injection (Blakemore and Franklin 2008)\u003c/p\u003e \u003cp\u003eCan target specific locations of the CNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDoes not represent widespread demyelination like in MS\u003c/p\u003e \u003cp\u003eInvasive injection (Hooijmans et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2019\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLight-induced photoreceptor loss (LI-PRL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetinal and optic nerve degeneration is induced by exposure to high-intensity light (Dietrich et al. 2020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUseful to study retinal and optic nerve degeneration independent of peripheral immune infiltration\u003c/p\u003e \u003cp\u003eNon-invasive method of induction (Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDoes not represent widespread demyelination and lacks systematic immune involvements\u003c/p\u003e \u003cp\u003eNo direct link to MS (Dietrich et al. 2020)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCuprizone/rapamycin demyelination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA combination of CPZ treatment and rapamycin, an inhibitor of the mTOR pathway, providing a more complete demyelination by inhibiting spontaneous remyelination (Yamate-Morgan et al. 2019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEnhances the severity and completeness of demyelination (Sachs et al. 2014)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInhibition of mTOR pathways affect other glia and neurons, making interpretation difficult (Yamate-Morgan et al. 2019)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eNote.\u003c/em\u003e Summary of the characteristics of animal models to study de- and remyelination. Columns include the following: name of animal model, characteristics of the model and mode of induction, strengths, and limitations.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEfficacy of S1PR modulators in preventing demyelination\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModel \u0026amp; species\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTreatment paradigm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDosage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSex \u0026amp; sample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDemyelination Outcomes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"11\" rowspan=\"12\"\u003e \u003cp\u003e\u003cb\u003eFingolimod (FTY720)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAl-Izki et al. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2011\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAE.\u003c/p\u003e \u003cp\u003eBiozzi antibody-high mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFingolimod started from EAE induction (day 0), at first relapse (day 10), or 1-month post-immunological tolerance (secondary progressive phase) until endpoint at 89 dpi.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1mg/kg or 3 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBoth male and female mice included n\u0026thinsp;=\u0026thinsp;8\u0026ndash;9 per treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant difference in toluidine blue staining between FTY720-treated and vehicle groups.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBalatoni et al. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAE. Dark agouti (DA) rats.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProphylactic treatment: FTY720 treatment started at time of EAE induction and continued for 2 to 3 weeks. Therapeutic treatment: FTY720 treatment initiated on day 25 after EAE induction and continued for 3 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale. Sample size not explicitly stated, n\u0026thinsp;=\u0026thinsp;12 per treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eProphylactic treatment: FTY720 prevented detectable demyelination or lesions in the brain \u0026amp; limited SC demyelination\u003c/p\u003e \u003cp\u003eTherapeutic treatment: FTY720 significantly reduced SC demyelination (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) \u0026amp; eliminated detectable lesions vs controls. No differences in LFB staining at day 53 (no statistical analysis performed).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHashemian et al. (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLPC. Wistar rats.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLPC injection followed by FTY720 treatment started on the same day and continued for 7 or 14 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;72.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eReduced demyelination at d7 and d14 with FTY720 vs vehicle (quantitative fluoromyelin staining). PLP+ cells increased with FTY720 (no statistical analysis reported).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHu et al. (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLPC. Sprague-Dawley rats.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLPC injection followed by FTY720 treatment started on 2 or 3 dpi and continued for 7 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEither daily 1 mg/kg oral gavage starting 2 days after induction, or daily 2 \u0026micro;L (2 mg/mL) FTY720 injection into LPC lesion starting 3 days after induction.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSex not mentioned. For LFB staining, control n\u0026thinsp;=\u0026thinsp;5, FTY720 n\u0026thinsp;=\u0026thinsp;7. TEM n\u0026thinsp;=\u0026thinsp;3.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLocal FTY720 injection of LPC rats doubled demyelinated lesion size compared to vehicle (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and induced demyelination in non-LPC rats. Oral FTY720 did not increase lesion volume.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKim et al. (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (demyelination phase only). C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks of 0.2% CPZ feeding, FTY720 treatment started on day 1 and continued for 6 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;5\u0026ndash;15 per treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFTY720 attenuated demyelination, increased MBP intensity (p\u0026thinsp;\u0026lt;\u0026thinsp;0.002) and proportion of myelinated fibers compared to vehicle (p\u0026thinsp;\u0026lt;\u0026thinsp;0.002). FTY720 increased CC1+, Nkx2.2+, and NG2+/PCNA+ cell numbers (p\u0026thinsp;\u0026lt;\u0026thinsp;0.013, p\u0026thinsp;\u0026lt;\u0026thinsp;0.04, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0003).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKim et al. (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (demyelination phase only). C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 weeks of 0.2% CPZ feeding, treatment started on day 3 or day 10 until the end of week 3.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Daily intraperitoneal (IP) injection.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, = 3\u0026ndash;11 per analysis per group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEarly FTY720 treatment at d3 reduced demyelination and prevented OLG death (fewer TUNEL+ cells, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). CNPase and MAG WB/PCR confirmed OLG protection (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 WB, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 PCR). Delayed FTY720 treatment at d10 showed no OLG protection (no change in \u003cem\u003eMag/Mbp\u003c/em\u003e gene expression vs vehicle).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMoradi et al. (\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (demyelination phase only). Wistar rats.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTreatment with fingolimod initiated 1 week before the induction of CPZ (0.3%) for 4 weeks. Treatment continued until endpoint.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;49.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFTY720 increased toluidine blue staining, axon diameter, and myelin thickness in CC (TEM, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). MBP and Olig2 levels were elevated vs CPZ/vehicle (PCR, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and approached normal controls (ELISA, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNascimento Pires et al. (\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (demyelination phase only). Swiss mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 weeks of 0.2% CPZ feeding, treatment started on day 1 until the end of week 5.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Daily IP injection.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSex not mentioned, n\u0026thinsp;=\u0026thinsp;6 per group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFTY720 partially restored lipid density in the CC vs CPZ (Sudan black, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). CC cytoarchitecture remained disrupted, with reduced chain-like organisation vs control (H\u0026amp;E, p\u0026thinsp;\u0026lt;\u0026thinsp;0.005). FTY720 preserved myelinated fibers in the 0.75\u0026ndash;0.81 g-ratio range, but mean g-ratio, axon area, and fiber area were unchanged vs CPZ. FTY720 did not increase CC1\u0026thinsp;+\u0026thinsp;cells but statistically decreased NG2\u0026thinsp;+\u0026thinsp;cells vs CPZ (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNystad et al. (\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (demyelination phase). C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks of 0.2% CPZ feeding. Treatment administered from the beginning of week 5 for 2 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;48.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFTY720 did not ameliorate myelin loss vs vehicle during demyelination (p\u0026thinsp;=\u0026thinsp;0.38). No differences observed in LFB or PLP scores in SMC or in myelin levels at any time point. FTY720 did not alter NOGO-A+ mature OLG density in the CC during demyelination (p\u0026thinsp;=\u0026thinsp;0.58). In the SMC, mature OLGs did not increase during demyelination (p\u0026thinsp;=\u0026thinsp;0.23).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRobichon et al. (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAE. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEAE induction on day 0, daily treatment started at disease onset (score\u0026thinsp;\u0026ge;\u0026thinsp;1; 13\u0026ndash;18 dpi) until day 40\u0026ndash;55.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;18\u0026ndash;20 per treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant increase in myelination % with FTY720 vs vehicle (Black-Gold II staining). However, FTY720 significantly reduced lesion percentage vs vehicle (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYazdi et al. (\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLPC. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMice were treated with FTY720 for 8 or 12 days, and LPC was injected from day 6 of the treatment period.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3 or 1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;3 per condition (n\u0026thinsp;=\u0026thinsp;21 total).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAt 6 dpi, LFB staining showed a significant reduction in demyelination in animals treated with FTY720 (0.3 or 1 mg/kg; both p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to the LPC group.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZhang et al. (\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAE. SJL/J mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEAE induction on day 0, daily treatment started on the day of EAE onset until day 7 or day 30 post onset.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15 or 0.3 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;36.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eWestern blotting of MBP is not significant between FTY720 and vehicle-treated mice at d7. NG2\u0026thinsp;+\u0026thinsp;OPCs and BrdU+-NG2\u0026thinsp;+\u0026thinsp;cells increased in CNS and SVZ at d7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). FTY720 restored myelination after EAE (LFB, d30 p.o., p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). At d30, MBP protein for FTY720 significantly higher vs controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). NG2\u0026thinsp;+\u0026thinsp;OPCs and BrdU\u003csup\u003e+\u003c/sup\u003e-NG2\u003csup\u003e+\u003c/sup\u003e cells increased in CNS and SVZ (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). CNPase\u003csup\u003e+\u003c/sup\u003e mature OLGs increased across regions of ST/CC/SC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01/0.05/0.01). BrdU\u003csup\u003e+\u003c/sup\u003e-CNPase\u003csup\u003e+\u003c/sup\u003e cells appeared by d30 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eSiponimod\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBehrangi et al. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (demyelination phase only) and CPZ\u0026thinsp;+\u0026thinsp;EAE model. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTreatment started on the same day of 0.25% CPZ feeding and continued for 1\u0026ndash;3 weeks. Treatment was then discontinued, and CPZ\u0026thinsp;+\u0026thinsp;EAE mice were returned to normal chow for 2 weeks and received MOG immunisation at week 6.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.315 mg/kg, 3.125 mg/kg, or 15.5 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;10 per treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSiponimod increased LFB grading (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and CC1\u0026thinsp;+\u0026thinsp;mature OLGs (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) vs vehicle. This effect was dose-dependent, 0.315mg/kg showed greater demyelination (LFB/PLP) than other doses. Siponimod reduced CPZ-induced increase in Olig2+/PCNA+ OPCs in WT but not S1PR5-KO mice, suggesting OLG protection rather than myelin regeneration.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDietrich et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAEON. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEAEON was inducted and treatment started on the same day (prophylactic), or at 14 or 30 dpi (therapeutic). Treatment continued until either 21, 35, or 90 dpi.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 or 6 mg/kg daily Siponimod intake via chow.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;48 (n\u0026thinsp;=\u0026thinsp;6 per group)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eProphylactic siponimod reduced optic nerve MBP loss vs vehicle (2 mg/kg p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 6 mg/kg p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Late treatment (d14) was beneficial at 2 mg/kg (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while d30 showed no effect on myelin loss. Therapeutic siponimod (d14) improved Olig2\u0026thinsp;+\u0026thinsp;cell survival (2 mg/kg p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; 6 mg/kg p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with no change in PDGFRα\u0026thinsp;+\u0026thinsp;cells.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKrueger et al. (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (demyelination phase only). C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 or 7 weeks of 0.2\u0026ndash;0.55% CPZ feeding. 4-week CPZ group received treatment from day 1, and 7-week CPZ group received treatment from week 5 to endpoint.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.25 mg/kg BW. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;5\u0026ndash;8 per group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSiponimod partially reduced demyelination (LFB/PAS, anti-MAG, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Siponimod treatment from week 5 increased MBP and MAG staining (p\u0026thinsp;=\u0026thinsp;0.0059, p\u0026thinsp;=\u0026thinsp;0.0093) and raised Olig2\u0026thinsp;+\u0026thinsp;cell density (p\u0026thinsp;=\u0026thinsp;0.0869). Treatment from day 1 reduced Olig2+/Ki67\u0026thinsp;+\u0026thinsp;OPCs (p\u0026thinsp;=\u0026thinsp;0.02) but did not significantly increase Olig2\u0026thinsp;+\u0026thinsp;cell density (p\u0026thinsp;=\u0026thinsp;0.0869).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCYM5442\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKim et al. (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (demyelination phase only). C57BL6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 weeks of 0.2% CPZ feeding, treatment started from 3rd day of CPZ to endpoint.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 mg/kg, daily IP injection.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;3\u0026ndash;8 per analysis per group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCYM5442 reduced demyelination vs vehicle (Sudan Black, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Western blotting for CNPase and MAG at 3 weeks confirmed OLG protection and reduced demyelination (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOzanimod\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSelkirk et al. (\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAE. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEAE was induced and treatment started on the same day and continued for 14 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.05, 0.2, or 1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;36 (n\u0026thinsp;=\u0026thinsp;12 per group)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAll ozanimod doses have significantly lower demyelination score vs vehicle (H\u0026amp;E, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eJTE-013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeyedsadr et al. (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAE and LPC models. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEAE was induced and treatment started on day 1 p.o. and continued until endpoint (d18). LPC injection followed by treatment initiated on the same day and continued until day of sacrifice at 3, 7, 14 or 16 dpi.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEAE: 30 mg/kg. Daily IP injection.\u003c/p\u003e \u003cp\u003eLPC: 15 mg/kg. Twice daily IP injection.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEAE: Male, n\u0026thinsp;=\u0026thinsp;3\u0026ndash;4 per group.\u003c/p\u003e \u003cp\u003eLPC: Male, n\u0026thinsp;=\u0026thinsp;13 per group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEAE: JTE-013 reduced demyelinated lesion areas in SC vs vehicle (MBP staining, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). EdU+/CC1\u0026thinsp;+\u0026thinsp;newly differentiated OLGs were higher in JTE-013 mice, but not significantly.\u003c/p\u003e \u003cp\u003eLPC: At 3 dpi, MBP staining showed no significant difference in demyelination between vehicle and JTE-013, in either the spinal lesion or optic chiasm.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRP-101074\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSindi et al. (\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLI-PRL. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLI-PRL induction followed by RP-101074 treatment initiated on the same day and continued for 5 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;5\u0026ndash;6 per treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eProphylactic RP-101074 significantly protected myelin (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0018), increased Sox2⁺ cells (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and upregulated NG2 (p\u0026thinsp;=\u0026thinsp;0.0005) and PDGFRα (p\u0026thinsp;=\u0026thinsp;0.0001) vs vehicle, indicating enhanced OPC activation and myelin preservation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eNote.\u003c/em\u003e Summary of the efficacy of S1PR modulators on demyelination in mammalian \u003cem\u003ein vivo\u003c/em\u003e models. Columns include the following: modulator type; author and year of publication; \u003cem\u003ein vivo\u003c/em\u003e model and species; treatment window; dosage; sex and sample size; and demyelination outcome. Abbreviations: CC \u0026ndash; corpus callosum; dpi \u0026ndash; days post-induction; H\u0026amp;E \u0026ndash; hematoxylin and eosin; KO \u0026ndash; knock-out; MAG \u0026ndash; myelin-associated glycoprotein; MBP \u0026ndash; myelin basic protein; PAS \u0026ndash; Periodic acid\u0026ndash;Schiff; PLP \u0026ndash; proteolipid protein; p.o. \u0026ndash; post-onset; SC \u0026ndash; spinal cord; SMC \u0026ndash; secondary motor cortex; ST \u0026ndash; striatum; SVZ \u0026ndash; subventricular zone; WT \u0026ndash; wild-type\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEfficacy of S1PR modulators on promoting remyelination\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModel \u0026amp; species\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTreatment paradigm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDosage and delivery\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSex \u0026amp; sample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRemyelination Outcomes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"9\" rowspan=\"10\"\u003e \u003cp\u003e\u003cb\u003eFingolimod (FTY720)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlme et al. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ with remyelination phase. C57BL/6 mice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks of 0.2% CPZ feeding followed by normal chow. Treatment started from week 5 and continued for 4 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;32.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant differences in remyelination (MBP and PLP staining) and mature OLGs (NOGO-A⁺) compared to vehicle control.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u0026eacute;chet et al. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTwitcher mice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFTY720 treatment started on postnatal day 21 and continued until animal endpoint (postnatal day 40\u0026ndash;45).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Fingolimod reconstituted in drinking water daily.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale and female, n\u0026thinsp;=\u0026thinsp;20\u0026ndash;33.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFTY720 increased MBP expression significantly (IHC, p\u0026thinsp;=\u0026thinsp;0.04) but did not alter MOG expression (IHC, p\u0026thinsp;=\u0026thinsp;0.248) or myelin debris levels in wild-type or twitcher mice (p\u0026thinsp;\u0026gt;\u0026thinsp;0.999). FTY720 significantly increased Olig2 protein expression vs vehicle in cerebellum (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHashemian et al. (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLPC.\u003c/p\u003e \u003cp\u003eWistar rats\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLPC injection followed by treatment on the same day. Treatment continued for 7 or 14 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3 mg/kg. Daily oral gavage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFTY720 significantly increased \u003cem\u003eMBP\u003c/em\u003e gene levels on d7 and d14 post-lesion vs vehicle. \u003cem\u003eOlig2\u003c/em\u003e gene expression increased on d7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but not on d14. Remyelination outcome was not available at protein or structural level.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHu et al. (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ\u0026thinsp;+\u0026thinsp;rapamycin with remyelination phase. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 weeks of 0.3% CPZ\u0026thinsp;+\u0026thinsp;10 mg/kg rapamycin 5 days/week, followed by normal chow for 2 weeks. Treatment initiated during normal chow phase and continued for 2 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg.\u003c/p\u003e \u003cp\u003eDaily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSex not mentioned.\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;4 each group (IHC, 12 total).\u003c/p\u003e \u003cp\u003en values unclear for TEM.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant differences in remyelination between FTY720- and control-treated animals via IHC (MBP) and TEM in either model, although FTY720 increased NG2⁺ cells (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the CPZ model.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKim et al. (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ with remyelination phase. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks of 0.2% CPZ feeding followed by normal chow; treatment started from week 4\u0026ndash;6 of CPZ diet for 4 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3-1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;5\u0026ndash;15 per group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant differences in remyelination by LFB and IHC (MBP) staining as well as OLG/OPC numbers between FTY720 and vehicle.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKim et al. (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ with remyelination phase. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 weeks of 0.2% CPZ feeding followed by normal chow. Treatment administered from the start of week 5 for 2 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 mg/kg, daily intraperitoneal (IP) injection.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;3\u0026ndash;5 per group per analysis.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant differences in myelin intensity (Oil Red staining), Olig2⁺ cells, or Olig2⁺/CC1⁺ cells in the corpus callosum of FTY720 vs vehicle-treated mice. Similarly, PLP⁻ area, lesion area, and Olig2 cellularity in the cerebellum did not differ between groups.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMitra et al. (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ with remyelination phase. Sprague-Dawley rats\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 weeks of 0.2% CPZ feeding followed by normal chow. Treatment administered from the start of week 6 for 2 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 mg/kg, daily IP injection.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;10 for each treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant differences in remyelination by LFB following FTY720 treatment, although it partially restored demyelinated area of the median CC.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNystad et al. (\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ with remyelination phase. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks of 0.2% CPZ feeding followed by normal chow. Treatment administered from week 5 to week 9.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;48.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant differences in remyelination via LFB or IHC (PLP) after 1 (p\u0026thinsp;=\u0026thinsp;1.0; p\u0026thinsp;=\u0026thinsp;0.96), or 3 weeks (p\u0026thinsp;=\u0026thinsp;0.40; p\u0026thinsp;=\u0026thinsp;0.28) of FTY720 vs vehicle. FTY720 exerted no effects on NOGO-A+ mature OLG at 1 week or 3 weeks of remyelination in the CC, although increased mature OLGs after 3 weeks of remyelination (p\u0026thinsp;=\u0026thinsp;0.032) in the SMC, but not after 1 week (p\u0026thinsp;=\u0026thinsp;0.66).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSlowik et al. (\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ (both acute and chronic) with remyelination phase. C57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMice received 0.2% CPZ for 5 weeks (acute) or 12 weeks (chronic), followed by 11 or 28 days of recovery on normal chow. Treatment administered during the recovery phase for 11 or 28 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;72.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant differences in remyelination (PLP, LFB staining) and Olig2\u003csup\u003e+\u003c/sup\u003e cells following FTY720 administration in acute and chronic CPZ models.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYazdi et al. (\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLPC.\u003c/p\u003e \u003cp\u003eC57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMice were treated with FTY720 for 8 or 12 days, and LPC was injected from day 6 of the treatment period.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3 or 1 mg/kg.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;3 per condition (n\u0026thinsp;=\u0026thinsp;21 total).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.3 mg/kg FTY720 increased PLP myelination (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and myelinated axons. Both doses reduced g-ratio (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with 0.3 mg/kg more effective. 0.3 mg/kg increased OLG lineage cells vs vehicle control (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and 1 mg/kg (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). BrdU⁺/Olig2⁺ increased with FTY720 treatment (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eSiponimod\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAl-Otaibi et al. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ with remyelination phase.\u003c/p\u003e \u003cp\u003eSwiss mice (SWR/J).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks of 0.3% CPZ feeding followed by normal chow. Treatment started from week 5 and continued for 4 weeks (until the end of week 9).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.5 mg/kg. Daily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;85.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSiponimod significantly increased the percentage of myelinated areas in the CC at early (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and late (p\u0026thinsp;=\u0026thinsp;0.0026) remyelination stages vs CPZ (LFB staining).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDietrich et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ with remyelination phase.\u003c/p\u003e \u003cp\u003eC57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 weeks of 0.2% CPZ feeding followed by Siponimod or drug-free chow (vehicle) for 2 additional weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 mg/kg.\u003c/p\u003e \u003cp\u003eDaily intake via chow.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale, n\u0026thinsp;=\u0026thinsp;21.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSiponimod exerted a significant effect on remyelination in the CC compared to vehicle control, as assessed via MRI.\u003c/p\u003e \u003cp\u003eNo significant on remyelination (via LFB myelin staining) and mature oligodendrocytes (GSTπ⁺).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOzanimod\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSelkirk et al. (\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ\u0026thinsp;+\u0026thinsp;rapamycin with remyelination phase.\u003c/p\u003e \u003cp\u003eC57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks of 0.3% CPZ feeding with daily treatment and rapamycin injection. Treatment started from day 1 and continued for 18 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 mg/kg.\u003c/p\u003e \u003cp\u003eDaily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;6\u0026ndash;12 per group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo significant differences in remyelination in the cortex, CC, or hippocampus by IHC (PLP staining) and MRI compared to vehicle control.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eJTE-013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeyedsadr et al. (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLPC.\u003c/p\u003e \u003cp\u003eC57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLPC induction and treatment were initiated on the same day. Treatment continued until endpoints at 3, 7, 14 or 16 dpi.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 mg/kg. Twice daily IP injection.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;13 per treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAt 16 dpi, JTE-013 showed a 2.09-fold increase in remyelinated axons vs vehicle (Sudan black staining), confirmed by semithin sections (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). No effect on myelin thickness (via TEM). JTE-013 exerted no significant effect on OLG proliferation at 7 dpi, but increased the number of newly differentiated oligodendrocytes at 14 dpi and 16 dpi (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating potentiated differentiation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePonesimod\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWillems et al. (\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2024\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPZ with remyelination phase.\u003c/p\u003e \u003cp\u003eC57BL/6 mice.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks of 0.3% CPZ feeding followed by normal chow. Treatment initiated 3 days prior to CPZ withdrawal and continued for 10 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1, 3, or 10 mg/kg.\u003c/p\u003e \u003cp\u003eDaily oral gavage.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMale, n\u0026thinsp;=\u0026thinsp;9\u0026ndash;11 per treatment group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePonesimod increased remyelination in the medial CC at all three doses, assessed via IHC (MBP) and TEM (g-ratios). Cortical myelination increased only at 3 mg/kg (p\u0026thinsp;=\u0026thinsp;0.0232).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eNote.\u003c/em\u003e Summary of the efficacy of S1PR modulators on remyelination in mammalian \u003cem\u003ein vivo\u003c/em\u003e models. Columns include the following: modulator type; author and year of publication; \u003cem\u003ein vivo\u003c/em\u003e model and species; treatment window; dosage; sex and sample size; and remyelination outcome. Abbreviations: CC \u0026ndash; corpus callosum; dpi \u0026ndash; days post-induction; SC \u0026ndash; spinal cord; SMC \u0026ndash; secondary motor cortex\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Risk of bias assessment\u003c/h2\u003e \u003cp\u003eTo assess the risk of bias and methodological quality of the included studies, the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool was used. This tool is adapted from the Cochrane risk of bias framework and has been specifically designed to address sources of bias that can be present in animal studies (Hooijmans et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). The SYRCLE assessment contains ten domains: random sequence generation, baseline characteristics, allocation concealment, random housing, blinding for caregivers and/or investigators, random outcome assessment, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. The results of the risk of bias assessment are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study selection\u003c/h2\u003e \u003cp\u003eA total of 237 studies were initially identified through database searches. After removing 97 duplicates, 140 studies progressed to title and abstract screening. Following the screen, 114 studies were excluded, leaving 26 studies for full-text assessment. Of these, two additional studies were excluded, resulting in a final inclusion of 24 studies in this systematic review. Any conflicts that arose between the two primary reviewers during the screening process were resolved by the third reviewer, ensuring a consistent and thorough selection process.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Risk of bias and quality assessment\u003c/h2\u003e \u003cp\u003eAll 24 included studies were critically appraised using the SYRCLE risk of bias assessment tool. Most studies were judged to have an unclear risk of bias across several criteria, such as random sequence generation, baseline characteristics, allocation concealment, random housing, blinding for caregivers and/or investigators, random outcome assessment, and incomplete outcome data. In contrast, most studies demonstrated a low risk of bias for blinding of outcome assessment and selective reporting.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Characteristics of S1P modulators and experimental models\u003c/h2\u003e \u003cp\u003eAll 24 studies investigated S1PR modulators; however, no studies identified in the screening process examined the modulation of S1P metabolic pathways, such as inhibition of sphingosine kinases (SphK1/2) or sphingosine-1-phosphate lyase (SPL). The characteristics of the S1P-based modulators, and the number of studies investigating each compound are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Out of the seven compounds identified through the systematic screening, four have been approved by the FDA for the treatment of relapsing forms of MS, including clinically isolated syndrome (CIS), RRMS, and active secondary progressive MS (SPMS). These compounds are fingolimod (approved in 2010), siponimod (approved in 2019), ozanimod (approved in 2020), and ponesimod (approved in 2021) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (Coyle et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). The remaining three compounds, RP-101074, CYM5442, and JTE-013 are research tools used in preclinical studies and have not yet progressed to clinical trial stages (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). While all other modulators are S1PR agonists, JTE-013 is unique as a functional antagonist of S1PR2 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Efficacy of S1P modulator on myelination and oligodendrocytes\u003c/h2\u003e \u003cp\u003eThe studies employed a wide range of methodological approaches to assess demyelination and remyelination. These included myelin-specific histological stains such as Luxol Fast Blue (LFB), Black-Gold II, toluidine blue, and Sudan Black, as well as immunohistochemistry (IHC), transmission electron microscopy (TEM), Western blotting (WB), polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and magnetic resonance imaging (MRI). However, not all studies incorporated a clearly defined remyelination phase in their experimental design. In particular, several studies reported changes in myelin-associated or oligodendrocyte lineage markers during demyelination-focused phases (e.g., CPZ exposure without a subsequent recovery period or progressive EAE models), making it difficult to distinguish myelin preservation from true remyelination. To address this heterogeneity, studies lacking a distinct remyelination phase were grouped in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, which summarises the efficacy of S1P-based modulators in preventing demyelination or preserving myelin during active injury. In contrast, studies that included an explicit remyelination phase, such as CPZ withdrawal paradigms or lysolecithin-induced focal demyelination with tissue collection at defined recovery time points, were grouped in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, which summarises evidence for the effects of S1P-based modulators on promoting.\u003c/p\u003e \u003cp\u003eThe systematic review synthesised 24 mammalian \u003cem\u003ein vivo\u003c/em\u003e studies investigating the effects of S1P-based therapeutics on demyelination and remyelination in mammalian models of CNS injury. Of these, 18 studies evaluated the effects of S1PR modulation on the prevention of demyelination, including 12 studies on fingolimod (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Al-Izki et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Balatoni et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Moradi et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Nascimento Pires et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Robichon et al. \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), three on siponimod (Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Krueger et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), and one study each on CY5442 (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), ozanimod (Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), JTE-013 (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), and RP-101074 (Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Among these studies, 15 reported a reduction in demyelination (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Balatoni et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Moradi et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Nascimento Pires et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Robichon et al. \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Krueger et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), two reported no significant effect of fingolimod (Al-Izki et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), and one reported increased demyelination following local delivery of fingolimod into LPC lesions (Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Across the demyelination-prevention studies, outcomes were assessed using a variety of readouts. Four studies quantified changes in demyelinated lesion number and/or size (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Balatoni et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Robichon et al. \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), 16 reported changes in myelin staining intensity (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Al-Izki et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Moradi et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Nascimento Pires et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Robichon et al. \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Krueger et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), and 11 quantified oligodendrocyte lineage cell numbers (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Nascimento Pires et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Krueger et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Fewer studies assessed biochemical or ultrastructural outcomes, with three reporting change in myelin-associated gene or protein expression (e.g., MBP, MAG, PLP) (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Moradi et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), and only two using TEM analyses (g-ratio, proportion of myelinated axons) (Moradi et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Nascimento Pires et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDuring active demyelination, S1PR modulation consistently altered oligodendrocyte lineage cell dynamics in a manner indicative of enhanced cell preservation and survival. Across models, treatment was associated with increased numbers of mature oligodendrocytes marked by CC1⁺, Nkx2.2⁺ (Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e), and NOGO-A⁺ (Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), alongside reductions in TUNEL⁺ apoptotic oligodendrocytes (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), suggesting protection from injury-induced cell death. Concurrent expansion of oligodendrocyte precursor populations, reflected by increases in Olig2⁺/PCNA⁺ (Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), Olig2⁺/Ki67⁺ (Krueger et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), NG2⁺ and BrdU⁺/NG2⁺ cells (Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), further indicates an enhancement in the proliferative capacity following demyelination.\u003c/p\u003e \u003cp\u003eA total of 15 studies examined the effects of S1PR modulation on enhancing remyelination, including 10 studies on fingolimod (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; B\u0026eacute;chet et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Mitra et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Slowik et al. \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), two on siponimod (Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Al-Otaibi et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), and one study each on ozanimod (Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), JTE-013 (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), and ponesimod (Willems et al. \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Remyelination outcomes were most commonly assessed using immunohistological myelin staining (14/15 studies) (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; B\u0026eacute;chet et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Mitra et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Slowik et al. \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Al-Otaibi et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Willems et al. \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), followed by oligodendrocyte lineage cell quantification (9/15 studies) (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Slowik et al. \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Only two studies reported gene or protein expression analyses (Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; B\u0026eacute;chet et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), four reported TEM assessments (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Willems et al. \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), and two utilised MRI-based measures (Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Overall, the remyelination outcomes were variable. Among fingolimod studies, only one reported significant remyelination (Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), while eight studies reported no significant enhancement compared to controls or no evidence of remyelination at the structural level (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Mitra et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Slowik et al. \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). One study reported mixed findings, with no change in MOG immunostaining but significant in MBP immunostaining and Olig2 protein expression (B\u0026eacute;chet et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Siponimod showed mixed effects in one study (Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) and a significant remyelinating effect in another (Al-Otaibi et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Ozanimod did not significantly enhance remyelination (Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), while JTE-013 increased myelin staining without corresponding improvements in g-ratio measurements (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Ponesimod demonstrated a significant remyelinating effect; however, this finding was based on a single study (Willems et al. \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), a limitation shared by several other S1PR modulators in this review.\u003c/p\u003e \u003cp\u003eThe heterogeneity of remyelination findings is further corroborated by the changes in oligodendrocyte lineage markers following S1P-based therapeutics. Several studies reported no significant changes in mature OLG markers, including NOGO-A⁺, CC1⁺, or Olig2⁺ cells (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), following fingolimod treatment, despite preserved lineage populations during earlier demyelinating phases. Nevertheless, some studies have reported the engagement of reparative pathways by promoting OPC differentiation. Increases in NG2⁺ OPCs and BrdU⁺/Olig2⁺ populations were observed following fingolimod treatment (Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) indicating lineage activation at early and intermediate stages of repair. Modest increases in GST-π⁺ mature oligodendrocytes were also reported following siponimod treatment, although not significant (Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). A pronounced lineage progression was observed following treatment JTE-013, which increased both EdU⁺/PDGFRα⁺ and EdU⁺/CC1⁺ populations (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), and RP-101074, which expanded Sox2⁺ progenitor pools (Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFingolimod was the most extensively studied compound (16/24 studies) and consistently prevented and reduced demyelination across EAE, LPC, and CPZ models based on histological evidence. However, in studies explicitly designed to assess remyelination, fingolimod generally failed to enhance myelin thickness, g-ratio, or the degree of myelin staining. The two studies reporting significant remyelination following fingolimod treatment utilised the LPC and EAE models (Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), which differ fundamentally from the CPZ model and do not always include a clearly defined remyelination phase. In contrast, newer S1PR1/5-selective modulators such as siponimod and ponesimod demonstrated more consistent evidence of remyelination, reflected by increased myelin staining intensity, enhanced oligodendrocyte lineage marker expression, reduced g-ratio values, and a higher proportion of remyelinated axons (Al-Otaibi et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Willems et al. \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnalysis of publication numbers (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e5\u003c/span\u003e) reveals that publication activity within this research topic was initially limited, with a single study published in 2007 (Balatoni et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). Research output increased gradually over the following years, reaching an initial peak of four publications in 2015 (Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Slowik et al. \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). This was followed by a decline in activity, with only one study published in 2018 (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). A second peak of four publications was observed in 2022 (Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Mitra et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Al-Otaibi et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), after which output decreased again, although at least one study has been published each year from 2022 onwards.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBetween 2007 and 2015, all eight published studies focused exclusively on fingolimod (Balatoni et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Al-Izki et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Slowik et al. \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). The scope of investigated compounds began to expand afterwards, with CYM5442 studied in 2018 alongside fingolimod (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), followed by the investigation of the S1PR2 antagonist JTE-013 in 2019 (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). More selective and newer S1PR1/5 dual modulators were introduced in subsequent years, including ozanimod in 2021 (Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), RP-101074 in 2023 (Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), and ponesimod in 2024 (Willems et al. \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Siponimod was examined in three studies published in 2022 (Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Al-Otaibi et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) and in another study in 2025 (Krueger et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Fingolimod remained the most extensively studied compound throughout the entire publication period, with additional studies reported in 2019 (Hashemian et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), 2020 (Nystad et al. \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; B\u0026eacute;chet et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), 2022 (Mitra et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), 2023 (Moradi et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Robichon et al. \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), and 2025 (Nascimento Pires et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Overall, these results suggest that research on S1P modulators focusing on understanding remyelination still remains limited.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOverall, the findings of this review reveal a clear distinction between the capacity of S1P-based modulators in preventing demyelination and actively promoting remyelination. Across \u003cem\u003ein vivo\u003c/em\u003e models, modulation of S1P signalling consistently limits myelin loss and preserves oligodendroglial populations following demyelination; however, these protective effects do not uniformly translate into enhanced myelin repair. This observation suggests that myelin protection and remyelination represent biologically distinctive processes rather than sequential outcomes of the same therapeutic effect. Consequently, the efficacy of S1P receptor modulation appears to be highly dependent on the disease stage and lesion environment, highlighting the importance of treatment timing, dosage, and model selection when evaluating a compound\u0026rsquo;s therapeutic potential.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Trends in S1P modulator development\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the initial peak in publications in 2015 likely reflects increased research interest following the approval of fingolimod as the first oral therapy for multiple sclerosis in 2010. During this period, preclinical studies primarily focused on characterising fingolimod\u0026rsquo;s effects on demyelination, oligodendrocyte lineage dynamics, and early remyelination across toxin-induced and autoimmune models. The second peak observed in 2022 coincided with the emergence of more selective S1PR modulators, including siponimod and ozanimod, within the clinical development pipeline. This shift was accompanied by an expansion in research focus from validating fingolimod to investigating subtype-specific S1PR modulation. These newer compounds preferentially target S1PR1 and S1PR5, receptors implicated in neuroinflammation and oligodendrocyte lineage cell survival, potentially reducing the cardiovascular adverse effects associated with S1PR3 signalling seen with fingolimod\u0026rsquo;s non-specific receptor modulation (Calabresi et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Khatri et al. \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Forrest et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Together, current research investigating S1P modulators in remyelination heavily focuses on targeting individual S1PRs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Efficacy of S1P modulators on myelin protection and repair\u003c/h2\u003e \u003cp\u003eAcross \u003cem\u003ein vivo\u003c/em\u003e models of demyelination, S1P modulators consistently demonstrate efficacy in preserving myelin integrity during active demyelination, with more than 80% (15/18) of studies reporting a reduction in myelin loss following treatment. These protective effects are most evident in immune-mediated models such as EAE, where modulation of neuroinflammatory processes limits oligodendrocyte injury and subsequent myelin loss. In toxin-based models, including CPZ and LPC, treatment during the demyelination phase frequently reduces lesion severity and preserves myelin-associated markers. However, distinguishing true myelin repair from protection of existing myelin remains challenging, as evidence for effective remyelination was considerably heterogeneous. In many cases, remyelination did not exceed the level of spontaneous repair observed following toxin withdrawal or resolution of inflammation, particularly in fingolimod, where only 1/10 study showed significant enhancement following fingolimod treatment (Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Interpretation of remyelination outcomes is further constrained by the limited number of studies available for several compounds, including ozanimod, JTE-013, and ponesimod, which prevents definitive conclusions regarding their therapeutic potential.\u003c/p\u003e \u003cp\u003eThe interpretation of remyelination outcomes \u003cem\u003ein vivo\u003c/em\u003e is complicated due to a range of methodological and biological factors. A major source of variability arises from differences in drug dosage, treatment timing, and therapeutic strategy across studies. In this systematic review, S1P-based therapeutics were administered using both prophylactic and therapeutic paradigms, with some studies initiating treatment before (Moradi et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) or at the onset of demyelination (Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Nascimento Pires et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), while others commenced treatment during defined recovery phases to initiate remyelination, most commonly following CPZ withdrawal (Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Although prophylactic paradigms are valuable for studying drug mechanisms, they do not fully reflect the clinical context of demyelinating diseases such as MS, where treatment is typically initiated following diagnosis. This distinction is especially important, as early intervention in patients with undiagnosed or alternative inflammatory CNS conditions may carry an increased risk of adverse effects, further limiting the translational relevance of prophylactic treatment strategies (Ford \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAcross the remyelination studies included in this review, enhanced remyelination was often inferred from increases in myelin protein expression or histological staining alone, without concurrent assessment of axonal ensheathment, internode length, or myelin thickness. This limitation was evident in studies such as JTE-013 treatment, where increased myelin staining was not supported by corresponding ultrastructural changes in myelin thickness (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). While these measures can reflect enhanced myelination at different levels, their interpretation is limited when demyelination and recovery phases are not clearly separated and when ultrastructural or complementary analyses are lacking. Ultrastructural assessment using TEM therefore remains the gold standard for evaluating remyelination, as it enables the direct assessment of compact, functionally relevant myelin wrapping around axons (Franklin and Ffrench-Constant \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Keough and Yong \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). However, relatively few studies incorporated such analyses, with only four remyelination studies reporting ultrastructural evaluation, contributing to uncertainty in the interpretation of remyelination outcomes.\u003c/p\u003e \u003cp\u003eSubstantial heterogeneity is also introduced by differences in the models of CNS demyelination, animal species and strain, age, and sex. Different \u003cem\u003ein vivo\u003c/em\u003e models exhibit markedly different intrinsic remyelination efficiencies. Toxin-induced models such as LPC or CPZ often display robust and rapid remyelination, whereas immune-mediated models such as EAE exhibit incomplete or delayed repair due to persistent inflammation and an unfavourable lesion microenvironment that limits reliable assessment of remyelination. Consequently, therapeutic efficacy observed in one model may not translate directly to another. Several studies also reported remyelination-related outcomes without incorporating a defined remyelination phase from CPZ withdrawal, making it difficult to distinguish enhanced myelin repair from myelin preservation. Additional challenges also involve pharmacokinetics, as many studies did not report the receptor engagement or BBB permeability of S1PR modulators such as ponesimod, RP-101074, and JTE-013, making it difficult to link observed biological effects to specific pharmacological mechanisms. Differences in BBB permeability across models, species, and disease stages can further complicate interpretation (O'Brown et al. \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Together, these limitations hinder cross-study comparison and make it difficult to distinguish true pro-remyelinating effects from myelin protection, underscoring the need for more rigorous and standardised experimental designs when evaluating S1PR-targeting therapeutics (Moradi et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Krueger et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Despite the study heterogeneities, our systematic analysis indicates that current S1P modulators possess efficacy in protecting myelin against a demyelinating insult, but their roles in potentiating myelin formation after injury remain to be determined.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Efficacy of S1P modulators on oligodendroglial dynamics in demyelinated lesions\u003c/h2\u003e \u003cp\u003eAcross demyelination models, S1P-based therapeutics exert a consistent effect on oligodendroglial lineage preservation and early lineage activation during active demyelination but display limited capacity to drive full lineage progression during recovery. Increases in markers of mature OLG such as CC1, NOGO-A, and Nkx2.2, together with reduced apoptotic TUNEL labelling (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Kim et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e), indicate that S1PR modulation primarily enhances OLG survival and resistance to injury rather than replacement of lost cells during demyelination. The concurrent expansion of OPC populations, reflected by increased Olig2⁺/Ki67⁺, Olig2⁺/PCNA⁺, NG2⁺, and BrdU⁺/NG2⁺ cells, further suggests that S1PR modulation maintains OPC pools during demyelinating phases, which may preserve the cellular substrate required for subsequent myelin repair (Zhang et al. \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Krueger et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, preservation of oligodendroglial lineage cells does not uniformly translate into increased numbers of mature, myelinating OLG during the remyelination phase. The absence of significant changes in CC1⁺, NOGO-A⁺, or Olig2⁺ oligodendroglial lineage populations following fingolimod treatment across several studies suggests that OLG survival alone is insufficient to overcome barriers to differentiation and myelin formation once demyelination is established, particularly in the context of persistent neuroinflammation within lesions (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Hu et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Alme et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). This dissociation between oligodendroglial lineage preservation and differentiation highlights a key limitation of S1PR modulators in promoting de novo remyelination, particularly in environments where inflammatory signalling, myelin debris, or axonal damage persists.\u003c/p\u003e \u003cp\u003eNevertheless, a subset of studies reported engagement of reparative lineage dynamics, characterised by expansion of OPCs and intermediate-stage lineage populations, including BrdU⁺/Olig2⁺ proliferating oligodendroglial cells and modest increases in GST-π⁺ post-mitotic oligodendrocytes (Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). More pronounced lineage progression was observed following treatment with JTE-013 and RP-101074, which increased both early progenitor pools (EdU⁺/PDGFRα⁺, Sox2⁺) and differentiated oligodendrocytes (EdU⁺/CC1⁺) (Seyedsadr et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), suggesting that certain S1P-targeting strategies may more effectively support coordinated lineage progression. These findings align with evidence from progressive MS indicating that remyelination failure reflects not only impaired OPC recruitment, but also deficits in oligodendrocyte differentiation and survival, all governed by disease stage and lesion microenvironment (Kuhlmann et al. \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Together, our evaluations indicate that while S1P modulators consistently support oligodendroglial survival within myelin lesions, their role in promoting the differentiation of newly formed or existing OLG, a key remyelinating process, remains inconclusive.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Mechanism of S1P modulators: how do they work?\u003c/h2\u003e \u003cp\u003eA key question is what mechanism underpins the effects of S1P modulators in myelin lesions. Currently available S1P modulators were originally designed as receptor-selective ligands to modulate S1PR signalling, most notably S1PR1, by inducing receptor internalisation and degradation, thereby preventing the lymphocyte egress from secondary lymphoid organs (Aoki et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Brinkmann et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). This mechanism effectively reduces immune cell infiltration into the CNS and limits inflammatory demyelination. Preclinical studies suggest they may also affect oligodendrocyte lineage cells via S1PR5, but these mechanisms remain incompletely defined. Fingolimod shows strong evidence supporting an S1PR1-mediated immune mechanism, where conditional deletion of S1PR1 in glial fibrillary acidic protein (GFAP)-expressing astrocytes or a phosphorylation defect in the S1PR1 gene abolishes fingolimod\u0026rsquo;s efficacy, confirming its dependence on S1PR1 (Choi et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Tsai et al. \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Although fingolimod has been proposed to exert direct CNS effects, including oligodendrocyte support and modulation of myelin membrane dynamics, these findings are largely restricted to \u003cem\u003ein vitro\u003c/em\u003e or \u003cem\u003eex vivo\u003c/em\u003e systems (Miron et al. \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2010\u003c/span\u003e), while \u003cem\u003ein vivo\u003c/em\u003e remyelination outcomes remain inconsistent across models. Kim et al. demonstrated that fingolimod selectively downregulates S1PR1 but not S1PR5, providing a mechanistic explanation for its robust effect on preventing immune-mediated demyelination but comparatively weak effect on OPC-driven remyelination, which appears to depend on S1PR5 signalling (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Therefore, the comparatively stronger remyelination outcomes reported for siponimod, ponesimod, and RP-101074 are consistent with direct engagement of oligodendrocyte lineage signalling via S1PR5, rather than indirect immunosuppressive effects from S1PR1 signalling alone.\u003c/p\u003e \u003cp\u003eSiponimod, a selective S1PR1/5 modulator, was developed to enhance CNS-specific actions while retaining immunomodulatory efficacy. Studies included in this review demonstrate preservation of OLGs and reduced demyelination, with some evidence of improved remyelination compared to fingolimod (Al-Otaibi et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Siponimod-mediated OLG protection occurs without activation of classical remyelination pathways or direct suppression of glial inflammatory signalling \u003cem\u003ein vitro\u003c/em\u003e, indicating that its effects may reflect S1PR5-dependent OLG survival rather than induction of OPC differentiation. Supporting this mechanism, Behrangi et al. showed that S1PR5 genetic deletion abolishes siponimod\u0026rsquo;s protective effects, while \u003cem\u003ein vitro\u003c/em\u003e it does not suppress cytokine production in glia, indicating \u003cem\u003ein vivo\u003c/em\u003e anti-inflammatory effects are indirect (Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Despite also targeting S1PR1 and S1PR5, the mechanistic profile of ozanimod appears to be dominated by S1PR1 engagement. Selkirk et al. found that unbound plasma and brain concentrations sufficient for ozanimod\u0026rsquo;s therapeutic efficacy in the EAE model exceed the EC\u003csub\u003e50\u003c/sub\u003e for S1PR1 but remain below that required for S1PR5 activation, indicating that its effects are mediated by peripheral immune modulation and possibly oligodendrocyte survival, but unlikely direct remyelination (Selkirk et al. \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). These findings provide a mechanistic explanation for the modest and inconsistent remyelination observed with ozanimod and support the conclusion that S1PR1 activation alone is insufficient to drive effective remyelination.\u003c/p\u003e \u003cp\u003eAcross the included studies, dose dependency emerged as an important determinant of therapeutic outcome, with higher doses generally associated with stronger protection against demyelination, whereas intermediate or lower doses more consistently supported remyelination. For example, 0.3 mg/kg fingolimod enhanced PLP⁺ myelination and oligodendrocyte differentiation more effectively than 1 mg/kg in the LPC model (Yazdi et al. \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), and a lower dose of 2 mg/kg of siponimod was more protective than 6 mg/kg (Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), although very low doses of 0.3 mg/kg were insufficient (Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Clear evidence for a bell-shaped dose-response relationship was provided by Sindi et al., who demonstrated that a 1 mg/kg dose of RP-101074 was more effective than 5 mg/kg at preventing visual function loss (Sindi et al. \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). This pattern likely reflects dose-dependent differences in S1PR engagement and internalisation, where higher doses promote more extensive downregulation and bias signalling towards S1PR1-mediated immunomodulation, which may limit optimal engagement of S1PR5-dependent remyelination pathways. Moderate levels of receptor engagement may better support S1PR5-associated signalling within the oligodendrocyte lineage, whereas insufficient dosing might fail to activate either pathways (Behrangi et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). This interpretation is consistent with \u003cem\u003ein vitro\u003c/em\u003e studies demonstrating dose-dependent effects between S1P-mediated OLG survival and OPC differentiation (Miron et al. \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOverall, pharmacological and genetic evidence support that S1P modulators such fingolimod and ozanimod primarily target S1PR1 for immune modulation, subsequent oligodendrocyte survival, whilst others such as siponimod primarily target S1PR5 for oligodendrocyte protection, although their capacity to drive remyelination remains largely unknown. Except for fingolimod and siponimod, other modulators reported in the selected articles lack sufficient pharmacokinetic or genetic validation, highlighting a key gap in understanding their mechanism of action.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Future research perspectives\u003c/h2\u003e \u003cp\u003eDespite significant effort in understanding S1P modulators using \u003cem\u003ein vivo\u003c/em\u003e models of central demyelination, their efficacy in remyelination is lacking, highlighting a clear gap for future research. An appropriate experimental paradigm and treatment window in a combination with molecular, histological, and ultrastructural approaches, will enable more complete understanding as to whether S1P-based therapeutics promote \u003cem\u003ede novo\u003c/em\u003e myelin formation or merely preserve existing myelin. While prophylactic modulation of S1PR often yields more pronounced protective effects on myelin compared to therapeutic treatments (Kim et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Dietrich et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), such designs are predominantly used investigate mechanisms of demyelination prevention rather than remyelination. Future studies should therefore emphasise therapeutic treatment paradigms initiated after demyelination, to better model clinical scenarios and directly examine repair processes.\u003c/p\u003e \u003cp\u003eNotably, no studies identified in this review investigated modulation of S1P metabolism, such as targeting its synthesis through sphingosine kinases 1 and 2 (Sphk1/2) or its degradation through sphingosine 1-phosphate lyase (SPL). The level of bioactive S1P is tightly regulated through an equilibrium between its synthesis, mediated by SphK1/2, and its degradation by SPL, within a complex sphingolipid metabolic network (George and Xiao \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Xiao \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; van Echten-Deckert \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). As the terminal enzyme in the catabolic pathway of sphingolipids, SPL also regulates the degradation of sphingosines, sphingomyelins, and ceramides \u0026ndash; all of which contribute to myelin synthesis and neural repair (Giussani et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Despite their therapeutic potential, approaches that selectively modulate endogenous S1P levels remain limited due to the complexity of the sphingolipid metabolic network. Nonetheless, manipulating endogenous S1P synthesis or degradation represents a promising alternative strategy that may mitigate adverse effects associated with disease-modifying therapies such as lymphopenia, myocardial infarction, atrioventricular block, and bradycardia (Coyle et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Unlike S1PR modulators, which induce irreversible receptor internalisation and degradation, endogenous S1P signalling involves receptor recycling, potentially allowing more physiologically regulated signalling (Xiao \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Exploration of these metabolic pathways may therefore offer a novel direction for promoting CNS repair. Finally, future research can prioritise \u003cem\u003ein vivo\u003c/em\u003e mapping of receptor-specific downstream signalling pathways, particularly those linked to oligodendrocyte differentiation and myelin formation. Improved understanding of how different S1PR subtypes engage intracellular pathways in different lesion environments will be critical for developing more selective and effective strategies to enhance remyelination.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis review for the first time systematically evaluated the effects of S1P-based therapeutics on \u003cem\u003ein vivo\u003c/em\u003e remyelination in the mammalian CNS, with particular emphasis on myelin protection and oligodendrocyte lineage dynamics. Across all selected studies, S1P receptor modulators consistently limited demyelination; however, their capacity to promote remyelination and oligodendrocyte lineage progression was variable and somewhat inconclusive. Collectively, these findings support a hypothesis that therapeutics focusing on targeting individual S1PRs may possess limited capacity to enable oligodendrocyte survival and differentiation and ultimately myelin repair in myelin lesions where there is ongoing and often aggressive inflammation. While future research should continue to optimise siponimod and ponesimod for remyelination, this review argues the need to develop new S1P-based therapeutics, such as modulating S1P levels via its metabolic pathways, which could circumvent non-specific effects associated with non-selective receptor modulation (e.g. incomplete S1PRs internalisation). In addition, the heterogeneity of reported outcomes and remyelination phases further underscores the influence of experimental model and study designs that may complicate outcome interpretation. The findings of this review offer a framework to guide future model selection and experimental design aimed at determining remyelination outcomes for demyelinating diseases such as MS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe author declares no conflict of financial or non-financial interests that are directly or indirectly related to the work submitted for publication.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to publish\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe work presented in the manuscript is supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program (#Mason2210) to Junhua Xiao; and Swinburne University of Technology Postgraduate TFS Scholarship to Harley Vu.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualisation, Resources, Writing \u0026ndash; Original Draft Preparation and Final Review \u0026amp; Editing: Harley Vu and Junhua Xiao; Investigation: Harley Vu, Nelson George and Junhua Xiao.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe author would like to acknowledge the research support from the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program (#Mason2210) to Junhua Xiao; and Swinburne University of Technology Postgraduate TFS Scholarship to Harley Vu.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAl-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D (2011) Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. 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Mol Ther 25(2):401\u0026ndash;415. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ymthe.2016.12.008\u003c/span\u003e\u003cspan address=\"10.1016/j.ymthe.2016.12.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-neurobiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cemn","sideBox":"Learn more about [Cellular and Molecular Neurobiology](https://www.springer.com/journal/10571)","snPcode":"10571","submissionUrl":"https://submission.nature.com/new-submission/10571/3","title":"Cellular and Molecular Neurobiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"S1P, remyelination, demyelination, oligodendrocyte, multiple sclerosis, in vivo","lastPublishedDoi":"10.21203/rs.3.rs-8856008/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8856008/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePromoting remyelination is a key therapeutic goal in demyelinating diseases such as multiple sclerosis (MS), yet effective strategies remain limited. Sphingosine-1-phosphate (S1P), a ubiquitous bioactive lipid, has emerged as a key therapeutic target in MS due to its dual roles in immune regulation and neuroprotection; however, the therapeutic efficacy of current S1P-based therapies in remyelination remains unclear. This systematic review evaluated \u003cem\u003ein vivo\u003c/em\u003e studies up to July 2025, in accordance with PRISMA guidelines, to assess the efficacy of S1P modulators on remyelination in mammalian models of demyelination. A comprehensive search across three databases identified 24 eligible studies that investigated S1P receptor (S1PR) modulation in both acute and chronic models of demyelination, with or without immune-mediated components. Fingolimod was the most extensively studied compound (16 studies). Of the 18 studies assessing demyelination outcomes, S1P modulation consistently attenuated myelin loss and oligodendrocyte depletion. In contrast, remyelination outcomes were inconsistent: among 15 studies assessing repair, most reported no significant enhancement. While fingolimod showed limited evidence on remyelination, more promising effects were observed with selective S1PR1/5 modulators such as siponimod and ponesimod. Overall, current evidence supports a model in which S1P modulators act primarily through S1PR1-mediated immunomodulation and S1PR5-associated oligodendroglial protection, preserving oligodendrocyte lineage cells rather than driving terminal differentiation or \u003cem\u003ede novo\u003c/em\u003e remyelination. Several compounds displayed bell-shaped dose-response patterns, highlighting the importance of dosing and treatment paradigms. Collectively, these findings indicate S1PR-based therapies primarily limit demyelination, with limited evidence of remyelination, emphasising the need for more efficacious S1P modulators to improve MS outcomes.\u003c/p\u003e","manuscriptTitle":"Effects of Sphingosine 1-phosphate Modulators on Central Remyelination: A Systematic Review of Animal Models","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-26 17:39:06","doi":"10.21203/rs.3.rs-8856008/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-04T17:14:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T16:19:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"277576351968722606182219106744670081574","date":"2026-04-19T19:09:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87350148344570189759007921693423570336","date":"2026-03-10T18:31:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-06T09:40:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286984355674366810658171395728945015558","date":"2026-02-23T07:03:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-21T19:45:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-19T14:34:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular and Molecular Neurobiology","date":"2026-02-18T04:27:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-neurobiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cemn","sideBox":"Learn more about [Cellular and Molecular Neurobiology](https://www.springer.com/journal/10571)","snPcode":"10571","submissionUrl":"https://submission.nature.com/new-submission/10571/3","title":"Cellular and Molecular Neurobiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0dd156eb-8f1e-4ac8-b74f-d5a9df2a4b82","owner":[],"postedDate":"March 26th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-04T17:14:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T16:19:43+00:00","index":54,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-10T17:09:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-26 17:39:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8856008","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8856008","identity":"rs-8856008","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}