Esketamine for Treatment of Cognitive Decline in Alzheimer’s Disease: A Scoping Review of Pre-clinical Studies

Esketamine for Treatment of Cognitive Decline in Alzheimer’s Disease: A Scoping Review of Pre-clinical Studies | 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 Systematic Review Esketamine for Treatment of Cognitive Decline in Alzheimer’s Disease: A Scoping Review of Pre-clinical Studies Mohamed Wagdy Mohamed ElSayed, Samar Ashraf Hassan, Toqa Abd Raboh, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7528339/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background/Objectives: Alzheimer's disease is a progressive neurodegenerative disorder leading to progressive cognitive decline. While the current pharmacological treatments provide some relief for other symptom domains, the cognitive decline remains a challenging symptom. This systematic review investigates preclinical and clinical literature supporting the use of esketamine for Alzheimer’s disease-associated cognitive decline (ADAC). Methods We searched PubMed, Google Scholar, Web of Science, Scopus, Embase, and Cochrane for relevant studies. Results We identified four preclinical studies supporting the use of esketamine in ADAC. These studies suggest that esketamine exerts its cognitive-enhancing effect through the activation of the Cannabinoid-2 receptor, the activation of the Brain-Derived Neurotrophic Factor signaling pathway, and the reduction of hippocampal Aβ42 and phosphorylated tau levels. Our search did not yield any clinical evidence to support this claim. Conclusion Preclinical studies suggest that esketamine holds promise as a potential therapeutic agent for ADAC due to its anti-inflammatory and neuroprotective properties. However, clinical studies are needed to confirm its efficacy and safety in human subjects before it can be considered for clinical application. Neurobiology of Disease Animal Science Cellular & Molecular Neuroscience Psychiatry Alzheimer’s disease Esketamine Neuroinflammation BDNF Cognition Scoping Reviews Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline and is the leading cause of dementia, currently affecting over 55 million people globally. Central to AD is the progressive neurodegeneration, resulting in a gradual deterioration of memory, attention, and executive function(1) . This AD-associated cognitive decline (ADAC) affects patients' quality of life and adds emotional and financial strain on their caregivers and healthcare systems(2). The current pharmacological treatments offer some improvement in multiple symptom domains for AD. Nevertheless, they have minimal effect on cognitive functions, and there is no evidence that these medications reduce the inflammatory process behind them (Table 1) . Hence, there is an urgent need for a new treatment modality to target this cognitive symptom domain in Alzheimer’s disease(3). Pathophysiology of ADAC Two main neuropathological factors are implicated in the pathology of cognitive dysfunction in AD: the extracellular accumulation of amyloid-beta (Aβ) plaques and neuroinflammation. The Aβ plaques are usually associated with the intracellular formation of neurofibrillary hyperphosphorylated tau protein tangles. These Aβ peptides originate from the abnormal cleavage of amyloid precursor protein (APP), resulting in insoluble fibrils that impede synaptic transmission and exacerbate neuronal toxicity(5) . At the same time, the hyperphosphorylated tau destabilizes microtubules, disrupting axonal transport and promoting the formation of tangles, which further intensifies synaptic dysfunction (6). Additionally, neuroinflammation plays a significant role in cognitive decline. Activated microglia and astrocytes produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), which exacerbate synaptic loss and neuronal damage(7) . These inflammatory processes also interfere with neurotrophic signaling, particularly involving brain-derived neurotrophic factor (BDNF). BDNF is a crucial molecule for the process of neurogenesis. Lower levels of BDNF have been linked to worse cognitive performance in animal models of AD (8). Collectively, these linked pathological mechanisms establish a setting that impairs synaptic plasticity and neuronal survival, particularly in brain areas crucial for cognition, i.e., the hippocampus and prefrontal cortex (9) . The disrupted pathways in ADAC 1. The Cannabinoid receptor type2- protein Kinase C (CB2-PKC) Signaling Axis (Figure 1) (10) In the context of Alzheimer’s disease, the CB2-PKC axis plays a potential protective role. CB2 receptors are primarily located in immune cells, including microglia in the brain, which become activated during inflammation, a significant feature of Alzheimer's disease. When CB2 is activated, it triggers the activation of PKC, which in turn reduces inflammation and clears inflammatory cytokines, such as Interleukin-1 (IL-1) and Interleukin-6 (IL-6). This signaling protects the brain by limiting neuroinflammation (11). In addition, the activation of the CB2 receptor leads to the inhibition of protein kinase A (PKA), further limiting neuroinflammation by inhibiting the formation of Nuclear factor kappa light chain enhancer of activated B cells (NF-kB) and cAMP Response Element-Binding Protein (CREB), both of which are involved in neuroinflammation (12). Additional supporting evidence emerged from a preclinical study, demonstrating that CB2 activation reduced inflammatory cytokine release, supported neuronal survival, and improved cognitive performance. In APP/PS1 transgenic mouse models, the administration of CB2-selective agonist produced significant cognitive improvements, particularly when administered at pre-symptomatic stages. This benefit was linked to attenuated microglial reactivation and suppression of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, ultimately promoting neuronal survival. Notably, CB2 stimulation promoted Aβ clearance by macrophages. The study proposed that CB2 receptor stimulation could improve memory and learning impairment in AD by acting on selected tau kinases (including p38 kinase) downstream and reducing tau hyperphosphorylation around plaques (13). 2. BDNF-TrkB Signaling Pathway (Figure 2) (14) The BDNF and its primary receptor, Tropomyosin Receptor Kinase B (TrkB), are essential for cognition by supporting strong synaptic connections and flexibility. The BDNF-TrkB signaling pathway is evident in the hippocampus and the prefrontal cortex. When BDNF binds to TrkB, it activates several intracellular signaling pathways, including the Phosphoinositide 3-kinase (PI3K) /Protein kinase B (Akt), Mitogen-Activated Protein Kinase (MAPK) /Extracellular signal-regulated Kinase (ERK), and Phospholipase C- Gamma (PLCγ). These pathways collectively enhance neuronal survival, support synaptic plasticity, and facilitate long-term potentiation (LTP), all of which are critical for learning and memory(15) . In ADAC, BDNF levels are markedly diminished in the hippocampus of AD animal models. In addition, TrkB receptor levels and their activity often decline, weakening the neurotrophic support system in the hippocampus. The effect of BDNF-TrkB signaling results in impaired synaptic functionality and neurogenesis, potentially leading to neuronal death (16) . Moreover, the accumulation of amyloid-beta and hyperphosphorylated tau may further inhibit BDNF expression and disrupt TrkB signaling. Eventually, this deterioration of synaptic integrity and plasticity is a key factor in the progressive memory loss and cognitive decline seen in Alzheimer’s disease (17) . Current Pharmacological Treatment of ADAC Despite their hypothetical potential to improve cognition, the current commercially available medications for AD have a frustratingly modest and temporary effect on ADAC. One of the most widely used drug classes is the cholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine. They were hypothesized to enhance cholinergic signaling; however, they provide minimal improvement to memory and attention. This modest effect was also observed with memantine, an NMDA receptor antagonist that acts by alleviating glutamatergic excitotoxicity(18) . Therefore, it is imperative to develop a new modality that can either preserve or restore cognitive functions with a special focus on modulating neuroplasticity, reducing inflammation, and enhancing BDNF signaling. Esketamine, a psychedelic agent approved for the treatment of treatment-resistant depression(19) , has the potential to improve this cognitive impairment. Could Esketamine Treat AD-associated Cognitive Decline? Esketamine, the S-enantiomer of ketamine, is a non-competitive NMDA receptor antagonist (20) (21) that was approved by the Food and Drug Administration (FDA) in 2019 for the treatment of treatment-resistant depression (19) . Esketamine enhances synaptic plasticity by facilitating downstream signaling pathways that promote neurogenesis and expression of BDNF(22) . Additionally, esketamine exhibits anti-inflammatory properties, including the reduction of pro-inflammatory cytokines and the inhibition of microglial activation(23). Esketamine has also exhibited procognitive effects in perioperative neurocognitive disorders (POND) (24) and depression (25) . Since cognitive dysfunction is the paramount symptom of Alzheimer’s disease, we here systematically reviewed the pre-clinical and clinical literature that examined esketamine’s potential role in treating ADAC (26). MATERIALS AND METHODS To ensure a comprehensive, transparent, and precise systematic review, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (27). We utilized the Rayyan application during the screening of the search results, making decisions regarding each article, and building the PRISMA diagram(28). This systematic review was registered in the Open Science Framework database (https://doi.org/10.17605/OSF.IO/EFBU4). Information sources The systematic review was conducted from April 5th, 2025, to June 26th, 2025, using PubMed (last searched on June 15th, 2025), Google Scholar (last searched on June 17th, 2025), Web of Science (last searched on June 26th, 2025), Scopus (last searched on June 26th, 2025), Cochrane (last searched on June 26th, 2025), and Embase (last searched on June 26th, 2025). Search strategy We used the following search terms in each database: PubMed (using the advanced search: esketamine preclinical - esketamine Alzheimer’s - esketamine human studies - esketamine cognitive impairment- esketamine human research - esketamine cognitive dysfunction - esketamine cognitive function - esketamine human research cognitive impairment - esketamine human trials - esketamine cognitive impairment Alzheimer’s human trials ), Google Scholar (esketamine for Alzheimer’s- esketamine cognitive dysfunction - esketamine Alzheimer’s cognitive dysfunction preclinical - esketamine Alzheimer’s cognitive dysfunction human research - esketamine Alzheimer’s cognitive impairment human research - esketamine Alzheimer’s cognitive dysfunction clinical- esketamine Alzheimer’s preclinical - esketamine Alzheimer’s human research - esketamine Alzheimer’s clinical - esketamine cannabinoid receptor 2), Cochrane (using the advanced search: esketamine Alzheimer’s - esketamine Alzheimer’s cognition - esketamine dementia), Scopus , Embase, and Web of Science (esketamine Alzheimer - esketamine Alzheimer cognition - esketamine cognition - esketamine + dementia ) . Across all databases, results were filtered to include only studies conducted since 2020. Eligibility criteria: Each author reviewed their assigned papers and collaborated to screen each study to determine its eligibility based on strict inclusion and exclusion criteria. We included studies according to the following criteria: 1. pre-clinical and clinical studies evaluating the use of esketamine for treating cognitive dysfunction in Alzheimer’s disease (any stage or severity), 2. studies examining the mechanistic pathways affected by esketamine, such as BDNF-glutamate signalling and synaptic plasticity, that explicitly state or support the relevance to memory enhancement not related to other diagnoses and that has the potential to be a therapeutic target in Alzheimer's disease, 3. randomised controlled trials (RCTs), cohort studies, case-control studies, and clinical case reports that used esketamine for treating cognitive impairment and/or memory decline related to Alzheimer’s disease. Due to the lack of studies on esketamine improving cognition in Alzheimer’s disease, we decided to broaden our inclusion criteria to include preprints as well. We excluded studies based on the following criteria: 1. studies focusing on ketamine without specific evaluation of esketamine, 2. studies investigating esketamine for conditions other than Alzheimer’s disease, 3. studies exploring esketamine for symptoms of Alzheimer’s disease other than cognitive dysfunction (e.g., depression), and 4. duplicate publications or studies with insufficient data for extraction or analysis. Data extraction process and items Collaboratively, two reviewers extracted the following data from each study: study title, drug target and mechanism of action, proposed symptom/biological target of the drug and its method of assessment, degree of Alzheimer's disease included in the study (if mentioned), number of cases (or cell grouping) investigated, drug protocol, reported adverse effects (if mentioned), results, conclusion and limitations of each study. Data extraction was done solely through reading; no tools were used. Study synthesis and outcomes We grouped studies for synthesis based on type (preclinical vs. clinical), intervention (esketamine), and outcome domain (e.g., TNF-α, IL-6, BDNF, cognitive performance). Only studies with outcomes relevant to our inclusion criteria and synthesis objectives were included. As our systematic review included multiple preclinical and clinical studies reporting heterogeneous outcome measures, we were unable to combine the data from these different studies. RESULTS (Figure 3) (29) Our systematic review included a total of 11,529 records for screening. We identified and removed 7477 duplicates before proceeding to the screening phase. During the screening process, we assessed 4,047 records, of which we excluded 4,043, and sought 16 reports for full-text retrieval. After full-text assessment of these 16 papers for eligibility and relevance to our research objective, we excluded 12 reports. Ultimately, we identified and included four relevant studies in the final synthesis of our systematic review. We summarized the included literature in Table 2 . DISCUSSION Our study aimed to systematically review the literature supporting the use of esketamine in mitigating cognitive decline associated with Alzheimer’s disease. The study was influenced by two factors: first, the currently available medications for Alzheimer’s disease have a modest effect on cognitive decline(18) , and second, esketamine has shown promising cognitive results in other illnesses, such as major depression(35) . A. Preclinical studies Our search strategy yielded four articles on the effect of esketamine in ADAC. Based on this literature, esketamine has cognitive-enhancing effects through three main mechanisms: mitigating neuroinflammation, enhancing neurogenesis, and possibly reducing the levels of hyperphosphorylated tau proteins. a. The Effect of Esketamine on Neuroinflammation (Figure 1) (10) We found two studies that examined the anti-neuroinflammatory effects of esketamine—the first study used in vitro BV2 microglial cells(31) . After using lipopolysaccharide (LPS) to induce cellular inflammation, the study team found that esketamine upregulated CB2 receptor expression, a key receptor in neuroinflammation (36) and Alzheimer’s disease pathology(37) , activated PKC, and suppressed the expression of NF-κB and iNOS. These molecular changes correlated with a reduction in pro-inflammatory cytokine production and nitric oxide release. Notably, co-treatment with AM630 abolished the anti-inflammatory effects of esketamine. Conversely, the use of chelerythrine partially reduced the anti-neuroinflammatory effects. Since chelerythrine is a PKC inhibitor, we hypothesize that esketamine maintains a degree of anti-neuroinflammatory effect through other CB2-mediated anti-neuroinflammatory pathways, namely Gαi inhibition of cAMP and PKA, as well as Gβ and Gγ reduction of p38 MAPK and ERK1/2 (12) (38). The reduction of p38 MAPK was proposed as the mechanism by which esketamine improves electroconvulsive therapy-induced cognitive dysfunction(39) . The second study investigated the cognitive-enhancing effects of esketamine in a transgenic mouse model for AD (34). Esketamine improved the cognitive performance of AD mice, which correlated with a decrease in the transcription of mRNA for pro-inflammatory cytokines, including cyclooxygenase-2 (COX2 ) , Interleukin-β (IL-1β), and inducible nitric oxide synthase (iNOS), in the hippocampal CA1 region. Interestingly, the expression of tripartite motif-containing protein 24 (TRIM24), a gene associated with multiple types of human cancers(40) , increased after esketamine administration and was found to decrease the pro-inflammatory mRNA transcripts. Additionally, TRIM24 knockdown (TRIM24-KD) resulted in increased expression of COX2, iNOS, and IL-1β in the hippocampal tissues. Both findings suggest a role for TRIM24 expression in mediating esketamine’s anti-neuroinflammatory effects. b. Esketamine’s Neurogenesis is associated with Improved Memory (Figure 2) (14) We found three studies that investigated the contribution of neurogenesis to esketamine’s cognitive-enhancing effects (32) (34); specifically focusing on ADAC. These studies involved different population groups, and therefore, a meta-analysis was not feasible. The first study, currently a preprint, investigated the effect of esketamine on a rat model of AD(32) . The study team found that esketamine improved memory and learning in AD rats, and that correlated with increased BDNF, p-AKT, and p-mTOR expression. The increased p-AKT and p-mTOR expression was also reported in Tu’s study , which strongly suggests this as a possible pathway for esketamine’s cognitive-enhancing effect in ADAC. Tu’s study (34) proposed TRIM24 expression as a needed step for AKT/mTOR activation. Furthermore, increasing the expression of this pathway was associated with esketamine’s improved cognitive dysfunction in other disorders with similar pathology to AD, including perioperative neurocognitive disorders (POND)(25) . Furthermore, clinical trials validated these cognitive benefits of esketamine in human subjects with POND(41) (24) . Although these studies do not replace the necessity of clinical trials specifically investigating esketamine in AD, they suggest potential promise for the use of esketamine in ADAC. c. The effect of Esketamine on hyperphosphorylated tau protein: One study (32) suggested a role for esketamine in decreasing Aβ42 and phosphorylated tau levels. While this finding seems promising for treating AD, the results need to be replicated. One possible mechanism for such action, if it gets replicated, is through the activation of CB2 receptors(37) . B. Clinical Studies Our search process sought meta-analyses, systematic reviews, randomized controlled trials, interventional studies, observational studies, case-control studies, or case reports to identify relevant clinical evidence supporting or refuting esketamine’s potential to improve ADAC. However, we were unable to find any clinical evidence to support this claim. To date, no clinical trials have directly evaluated the efficacy or safety of esketamine in addressing cognitive impairment in Alzheimer's patients. CONCLUSION Our systematic review critically evaluated the emerging evidence regarding the impact of esketamine on cognitive function in Alzheimer's disease (AD). The findings present a complex but promising landscape for this novel therapeutic approach. Current evidence, solely derived from preclinical studies with no clinical studies to support it, suggests that esketamine may exert beneficial effects on certain cognitive domains through CB2 activation (leading to anti-neuroinflammatory effects), enhancing neurogenesis (by activating BDNF/Akt/TrkB pathway), and potentially reducing Aβ42 and phosphorylated tau levels. These unique mechanisms distinguish esketamine from conventional AD treatments. There remains a need to replicate the finding of reduced Aβ42 and phosphorylated tau levels. Moreover, these cognitive benefits need to be replicated in human subjects. The lack of clinical data represents a significant limitation to the use of esketamine in ADAC. It highlights the need for human studies to determine the therapeutic potential and applicability of esketamine in this context. The absence of clinical validation also raises questions regarding dosage, safety profiles in elderly populations, and long-term cognitive outcomes, which remain unaddressed. LIMITATIONS Our search has two limitations. First, the absence of clinical evidence to support the preclinical evidence provides an incomplete picture of the actual effects of esketamine in ADAC. Second, the preclinical studies had different populations (BV2 microglial cells vs. genetic vs. chemical models of AD), variable dosing regimens and administration routes (in culture vs. intraperitoneal), and different outcome measures, which complicated comparisons across different studies. Declarations AUTHOR CONTRIBUTION ● Conceptualization: Mohamed ElSayed and Islam Mohammad Shehata ● Methodology: Samar Ashraf, Samaa Ihab, Mohamed ElSayed, Islam Mohammad Shehata ● Formal Analysis & Data Curation: Samar Ashraf, Samaa Ihab ● Investigation (Literature Search & Screening): Samar Ashraf, Samaa Ihab, Islam AbdelGawad, Toqa Abd Raboh ● Writing – Original Draft: Samar Ashraf, Samaa Ihab, Islam AbdelGawad, Toqa Abd Raboh ● Writing – Review & Editing: [All Authors] ● Supervision: Mohamed ElSayed and Islam Mohammad Shehata ● Project Administration: Mohamed ElSayed CONFLICTS OF INTEREST The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study. DATA STATEMENT The data has not been previously presented orally or by poster at scientific meetings. References Shin JH. Dementia Epidemiology Fact Sheet 2022. Ann Rehabil Med. 2022 Apr;46(2):53–9. 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Esketamine alleviates cognitive impairment signs induced by modified electroconvulsive therapy in a depression rat model via the KLF4/p38 MAPK pathway. J Affect Disord. 2025 May 1;376:302–12. Yao Y, Zhou S, Yan Y, Fu K, Xiao S. The tripartite motif-containing 24 is a multifunctional player in human cancer. Cell Biosci. 2024 Aug 19;14(1):103. Han C, Ji H, Guo Y, Fei Y, Wang C, Yuan Y, et al. Effect of Subanesthetic Dose of Esketamine on Perioperative Neurocognitive Disorders in Elderly Undergoing Gastrointestinal Surgery: A Randomized Controlled Trial. Drug Des Devel Ther. 2023;17:863–73. Tables Table 1 is available in the Supplementary Files section. Table 2: A summary of the current evidence for the esketamine effect on ADAC. We could not find any clinical studies to support the current available evidence from preclinical studies. Table legend: COX2 (cyclooxygenase-2), IL-1β (Interleukin-β), iNOS (inducible nitric oxide synthase), i.p. (Intraperitoneal), LPS (Lipo-polysaccharide), CB2 (Cannabinoid 2 receptor), AM630 (CB2 receptor antagonist), Chelerythrine (Protein Kinase C antagonist), TRIM24 (tripartite motif-containing protein 24) Article Population Intervention Result Conclusion Anti-Neuroinflammatory Effects of Esketamine Wang Y, Cao M, Zhang Y, Chen Q, Chen Z, Jia J. (2024) (31) In vitro LPS-stimulated BV-2 microglial cells BV2 cells were divided into five different groups, and each was cultured in a separate medium: ● Control (drug-free medium) ● LPS-exposed ● Third, fourth, and fifth groups: Esketamine at 1, 5, and 10 μg/ml concentrations was added to cells and incubated for 24 hours. Tests: 1. Examine the role of CB2 receptor: AM630 was added to 2 cell groups. 2. Examine the role of Protein Kinase C: Chelerythrine was added to 2 cell groups. ● Esketamine markedly upregulated CB2 receptor expression and activated PKC while concurrently suppressing NF-κB and iNOS expression. ● AM630 blocked the Esketamine-induced upregulation of NF-κB. ● Chelerythrine partially reversed Esketamine-induced anti-inflammatory effects. ● Esketamine reduces inflammation in BV-2 microglial cells by activating the CB2 receptor and the protein kinase C pathway, leading to a decrease in the expression of inflammatory proteins (NF-κB (p65) and iNOS), proinflammatory cytokines, and nitric oxide. ● Esketamine’s anti-neuroinflammatory action is mediated via CB2 receptor activation. ● CB2 receptor mediates esketamine’s action partially via activation of Protein Kinase C. Neurogenesis-Enhancing Effects of Esketamine Chengzhi Wang, Fan Xu, Xinran Yu et al. (2023) [Preprint] (32) AD rat model Rats were divided into five groups: ● Control Group: → Healthy rats → Received normal saline only ● AD Model with no treatment: [AD was induced by bilateral intracerebroventricular (ICV) injection of Streptozotocin (STZ) (2.4 mg/kg) + daily intraperitoneal injection of D-galactose (60 mg/kg/day) for 6 weeks] ● AD + Esketamine Group: → AD induction → Intraperitoneal Esketamine (0.5 mg/kg) for 6 days ● AD + Esketamine + Vehicle Control Group: → AD induction → Pre-treatment with Captisol-containing vehicle (30%) → Esketamine (0.5 mg/kg) ● AD + Esketamine + AKT Inhibitor Group: → AD induction → Pre-treatment with AKT inhibitor MK-2206 (33 mg/kg, i.p. on day 1 and 4) → Esketamine (0.5 mg/kg) ● Behavioral: Esketamine improved memory and learning in AD rats. ● Biological: Esketamine protected hippocampal neurons from damage. ● Molecular: → Esketamine increased BDNF, p-AKT, and p-mTOR expression. → Esketamine reduced Aβ42 and phosphorylated tau levels. → AKT inhibitor (MK-2206) blocked these beneficial effects. ● Sub-anesthetic dose of Esketamine improved learning and spatial memory in AD model rats. ● Esketamine activated the BDNF/AKT/mTOR pathway, which plays a key role in neuroprotection and synaptic plasticity. ● Esketamine reduced hippocampal Aβ42 and phosphorylated tau , two main pathological hallmarks of Alzheimer's disease. ● Esketamine preserved neuronal structure in the hippocampal CA3 region. ● Blocking AKT signaling abolished Esketamine's beneficial effects, confirming its action is AKT/mTOR dependent. Li, H., Ying, L., Wan, F., Shiqiao, K., Yijie, F., Chuli, X., Xudong, Y., Xinhong, Y., & Zhiyong, X. (2024) (33) In vivo mice ➢ The study aimed to assess the effect of esketamine on memory reconsolidation. ➢ To investigate the role of AMPA receptors in mediating the esketamine-induced memory reconsolidation effect, the study used NBQX (AMPA-R antagonist). ➢ The Novel Object Recognition task was used to assess memory. ➢ Mice were divided into six groups: ● Vehicle group: → Received saline injection immediately after reactivation. ● Esketamine group: → Received 10 mg/kg i.p. esketamine immediately after reactivation. ● Esketamine 6h post-reactivation group: → Received 10 mg/kg esketamine 6 hours after reactivation. ● Esketamine without reactivation group: → Received 10 mg/kg esketamine 24h after sampling (no reactivation step). ● NBQX group: → Received 5 mg/kg NBQX (i.p.) 5 min after reactivation. ● Esketamine + NBQX group: → Received 10 mg/kg esketamine immediately after reactivation, followed by 5 mg/kg NBQX 5 min later. Timing analysis: 0 h, 6 h, and 24 h administration of esketamine used to study the reconsolidation time window. ● Esketamine (10 mg/kg) enhanced memory only when injected immediately after memory reactivation. ● Esketamine had no effect on memory reconsolidation if injected 6 hours after reactivation or without reactivation. ● NBQX (AMPA antagonist) blocked the memory-enhancing effect of esketamine. ● Esketamine enhances memory reconsolidation when administered immediately after reactivation. ● Esketamine’s effect is time-dependent; no improvement occurs when given 6 hours later. ● Esketamine has no effect without memory reactivation, confirming it targets the reconsolidation phase. ● The AMPA receptor antagonist (NBQX) blocks esketamine’s effect, indicating a reliance on AMPA receptor signaling. Tu Y, Xu B (2024) (34) ● Triple transgenic AD mice (3xTg-AD, a genetic mouse model for AD) ● Wild-type mice (WT) ● TRIM-24 knockdown mice ➢ The study aimed to investigate the contribution of the TRIM24 expression and the PI3K/Akt pathway in esketamine’s cognitive-enhancing effect in AD ➢ The study consisted of 3 batches of experiments: ● Batch 1: → WT + normal saline (NS) → 3xTg-AD + NS → 3xTg-AD + esketamine ● Batch 2: → Negative control (NC)-knockdown (KD) + NS → NCKD + esketamine → TRIM24-KD + esketamine group ● Batch 3: → NS + vehicle → Esketamine + vehicle → Esketamine + LY294002 (PI3K inhibitor) ➢ Drugs used: 1. Esketamine: injected intraperitoneally at 10 mg/kg every week. 2. Normal Saline: injected intraperitoneally at 10 mg/kg every week. 3. PI3K inhibitor LY294002: 25 mg/kg (ip) injected before each esketamine treatment. ➢ Cognitive function tests: Morris Water Maze (MWM) ● Esketamine significantly improved cognitive performance in 3xTg-AD mice, evidenced by improved MWM scores. ● Esketamine upregulated TRIM24 expression in the hippocampus of AD mice. ● TRIM24 knockdown reversed the cognitive benefits of esketamine, confirming its role as a key mediator. ● PI3K/AKT phosphorylation was reduced in AD mice, and that was reversed by esketamine treatment. The phosphorylation was reduced again after TRIM24-KD, proving the role of TRIM24 in esketamine cognitive enhancement. ● AD mice had elevated mRNA transcripts of COX2, iNOS, and IL-1β. Esketamine reduced the mRNA of these neuroinflammatory cytokines in the hippocampal CA1 region. TRIM24-KD increased the expression of COX2, iNOS, and IL-1β in the hippocampal tissues of 3xTg-AD mice. ● LY294002 decreased PI3K and AKT phosphorylation after esketamine treatment. This correlated with a lower degree of cognitive performance and higher proinflammatory cytokine transcripts. ● Esketamine enhances cognitive function in a mouse model of Alzheimer’s disease. ● Esketamine’s neuroprotective effects are mediated via upregulation of TRIM24 expression. ● Esketamine reduces neuroinflammation by reducing mRNA transcription of pro-inflammatory proteins, suggesting an anti-inflammatory role in the AD brain. ● The activation of the AKT/mTOR pathway appears to be a key downstream mechanism behind Esketamine’s effects. ● Blocking TRIM24 negates the benefits of esketamine, highlighting TRIM24 as a potential therapeutic target. Additional Declarations The authors declare no competing interests. Supplementary Files GRAPHICABSTRACT.docx Table1.docx Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7528339","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":509845132,"identity":"838bbdd0-007e-4285-b2c0-856082328487","order_by":0,"name":"Mohamed Wagdy Mohamed ElSayed","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-7598-7645","institution":"Geisel School of Medicine at Dartmouth","correspondingAuthor":true,"prefix":"","firstName":"Mohamed","middleName":"Wagdy Mohamed","lastName":"ElSayed","suffix":""},{"id":509845242,"identity":"c26881a2-7da8-447b-ae56-a0406d8e4dcc","order_by":1,"name":"Samar Ashraf Hassan","email":"","orcid":"","institution":"Modern University for Technology \u0026 Information","correspondingAuthor":false,"prefix":"","firstName":"Samar","middleName":"Ashraf","lastName":"Hassan","suffix":""},{"id":509845243,"identity":"01c07e80-714b-4c22-8f1b-6b9472c36f47","order_by":2,"name":"Toqa Abd Raboh","email":"","orcid":"","institution":"Modern University for Technology \u0026 Information","correspondingAuthor":false,"prefix":"","firstName":"Toqa","middleName":"Abd","lastName":"Raboh","suffix":""},{"id":509845244,"identity":"2a398866-8499-48bd-971f-76d906c85f8f","order_by":3,"name":"Islam AbdelGawad","email":"","orcid":"","institution":"Modern University for Technology \u0026 Information","correspondingAuthor":false,"prefix":"","firstName":"Islam","middleName":"","lastName":"AbdelGawad","suffix":""},{"id":509845245,"identity":"d532011a-aaa0-45d5-a6a8-05f32c4c1355","order_by":4,"name":"Samaa Ihab Zoudy","email":"","orcid":"","institution":"Modern University for Technology \u0026 Information","correspondingAuthor":false,"prefix":"","firstName":"Samaa","middleName":"Ihab","lastName":"Zoudy","suffix":""},{"id":509897751,"identity":"f4cb0fab-4c45-4409-8a8b-5550a5b22576","order_by":5,"name":"Islam Mohammad Shehata","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"prefix":"","firstName":"Islam","middleName":"Mohammad","lastName":"Shehata","suffix":""}],"badges":[],"createdAt":"2025-09-03 14:56:46","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7528339/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7528339/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90758149,"identity":"2dcedfc4-75d8-4d36-8608-57edcf203b17","added_by":"auto","created_at":"2025-09-07 14:15:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":236498,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEsketamine effect on CB2-PKC pathway. \u003c/strong\u003eThis image illustrates the mechanism of neuroinflammation in ADAC and the proposed anti-neuroinflammatory mechanisms of esketamine. In this image, we used a lipopolysaccharide-induced neuroinflammation model in BV2 microglial cells reported in(31) . We also included additional details on CB2 Gαi anti-neuroinflammatory pathways from and further information regarding Gβ and Gγ actions from (38).\u003c/p\u003e\n\u003cp\u003eIn addition to reporting the effects of esketamine, we included the effects of two pharmacological compounds that were used in Wang’s study. The first is AM630, a CB2 receptor antagonist, and the second is chelerythrine, a protein kinase C antagonist. The left cyan-shaded part of the image indicates the portion of the CB2 pathway inhibited by chelerythrine.\u003cbr\u003e\n \u003cstrong\u003eFigure legend:\u003c/strong\u003e \u003cem\u003eAdenylyl Cyclase enzyme\u003c/em\u003e (isoforms 5 or 6), \u003cem\u003ecAMP \u003c/em\u003e(Cyclic Adenosine Monophosphate), \u003cem\u003eCB2-R \u003c/em\u003e(Cannabinoid 2 receptor), \u003cem\u003eCREB\u003c/em\u003e(cAMP Response Element-Binding Protein), \u003cem\u003eDAG\u003c/em\u003e(Diacylglycerol), \u003cem\u003eER \u003c/em\u003e(Endoplasmic Reticulum), \u003cem\u003eERK1/2 \u003c/em\u003e(Extracellular signal-Regulated Kinase 1/2), \u003cem\u003eIL-1 \u003c/em\u003e(Interleukin-1), \u003cem\u003eIL-6\u003c/em\u003e (Interleukin-6), \u003cem\u003eiNOS\u003c/em\u003e (inducible nitric oxide synthase), \u003cem\u003eIP3 \u003c/em\u003e(Inositol 1,4,5-trisphosphate),\u003cem\u003e NF-κB \u003c/em\u003e(Nuclear factor kappa light chain enhancer of activated B cells), \u003cem\u003eNF-kB (p65)\u003c/em\u003e (Nuclear factor kappa light chain enhancer of activated B cells protein 65), \u003cem\u003ep38 MAPK \u003c/em\u003e(mitogen-activated protein kinase p38 protein), \u003cem\u003ePIP2\u003c/em\u003e(Phosphatidylinositol 4,5-bisphosphate), \u003cem\u003ePKA\u003c/em\u003e(Protein Kinase A), \u003cem\u003ePKC \u003c/em\u003e(Protein Kinase C), \u003cem\u003ePLC \u003c/em\u003e(Phospholipase C), \u003cem\u003eTNF-α \u003c/em\u003e(Tumor Necrosis Factor-α). Light green arrows indicate direct activation. Black arrows indicate the sequence of biological events. T-shaped red arrows indicate inhibitory processes. Cyan arrows indicate the effect of esketamine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathway Description:\u003c/strong\u003e In microglial cells exposed to LPS-induced inflammation, esketamine exerts significant anti-inflammatory action by increasing the expression of CB2 receptor. The CB2 receptor is a Gi/o-coupled G protein receptor. Upon activation, CB2 inhibits adenylyl cyclase (isoforms 5 or 6) via its Gαi/o subunit, leading to a reduction in intracellular cAMP levels and subsequent inhibition of PKA. Since PKA activation promotes transactivation of NF-κB and CREB, its suppression by CB2 prevents the induction of inflammatory genes. Concurrently, the Gαi/o subunit-stimulated PLC hydrolyzes PIP2 into IP3 and DAG. DAG directly activates PKC, and IP3 facilitates the release of calcium from the endoplasmic reticulum, further supporting PKC activation. Through specific isoforms, PKC activity leads to a reduction in NF-κB p65 phosphorylation, thereby suppressing NF-κB activation(12). This resulted in the downregulation of iNOS and a decrease in the production of pro-inflammatory cytokines,\u003c/p\u003e\n\u003cp\u003ei.e., TNF-α, IL-6, and IL-1β. The co-treatment of the LPS-induced neuroinflammation model with AM630 and chelerythrine reversed the anti-inflammatory effect of esketamine, highlighting the essential roles of both CB2 receptor activation and PKC signaling in mediating esketamine-induced suppression of neuroinflammation in microglial cells. Additionally, Gβ and Gγ reduce p38 MAPK and ERK1/2, further decreasing the pro-inflammatory process.\u003c/p\u003e\n\u003cp\u003eCreated in BioRender. ElSayed, M. (2025) https://BioRender.com/zo8j13u (10)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7528339/v1/505559aaee1df0aa2166df46.png"},{"id":90758146,"identity":"e3e236fd-ad6d-4312-8a6c-416f5b75d258","added_by":"auto","created_at":"2025-09-07 14:15:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":246811,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEsketamine effect on BDNF-mTORC1 pathway.\u003c/strong\u003e This image illustrates the formation of the BDNF molecule \u003cem\u003e(left side of the graph in light cyan)\u003c/em\u003e and the downstream effects of the BDNF-TrkB pathway \u003cem\u003e(right side of the graph in white)\u003c/em\u003e. In addition, the figure illustrates the proposed neuroprotective and cognitive-enhancing effects of esketamine in Alzheimer’s disease and related cognitive impairments. \u003cbr\u003e\n \u003cstrong\u003eFigure legend:\u003c/strong\u003e \u003cem\u003eBDNF\u003c/em\u003e (Brain-Derived Neurotrophic Factor), \u003cem\u003eHDACi\u003c/em\u003e (Histone Deacetylase Inhibitors), \u003cem\u003emTORC1\u003c/em\u003e (Mechanistic Target of Rapamycin Complex 1), \u003cem\u003ePI3K-Akt-Beclin-1\u003c/em\u003e (Phosphoinositide 3-Kinase/ Protein Kinase B/ Beclin-1), \u003cem\u003eTrkB\u003c/em\u003e(Tropomyosin Receptor Kinase B), \u003cem\u003eULK-1\u003c/em\u003e(unc-51 like autophagy activating kinase 1). Light green arrows indicate direct activation. Black arrows indicate the sequence of biological events. T-shaped red arrows indicate inhibitory processes. Cyan arrows indicate the effect of esketamine. \u003cbr\u003e\n \u003cstrong\u003eBDNF Formation: \u003c/strong\u003eEsketamine enhances BDNF expression through histone acetylation and chromatin relaxation, possibly aided by HDACi. The increased BDNF supports neuronal survival and plasticity, both of which are impaired in Alzheimer’s disease.\u003cbr\u003e\n \u003cstrong\u003eBDNF-TrkB Action: \u003c/strong\u003eBDNF binds to its receptor, TrkB, triggering the downstream pathway that involves PI3K, Akt, and Beclin-1. Esketamine also activates mTORC1, a key regulator of Synaptic plasticity and Autophagy, which helps clear toxic protein aggregates (Beta-Amyloid and tau) commonly found in Alzheimer’s.\u003c/p\u003e\n\u003cp\u003eCreated in BioRender. ElSayed, M. (2025) https://BioRender.com/3hgzrx3 (14)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7528339/v1/f51d07c6c6e63121589aa8ac.png"},{"id":90758531,"identity":"27b48af9-86e0-4c35-8b4b-b96cc6b639b1","added_by":"auto","created_at":"2025-09-07 14:23:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56912,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA diagram explaining our systematic search process. \u003c/strong\u003e\u0026nbsp;\u003cstrong\u003eFigure legend: *Google Scholar:\u003c/strong\u003e All Google Scholar results were obtained through the Apify Google Scraper tool (30).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e**Preprint:\u003c/strong\u003e These are the preprints we specifically queried in Web of Science, Embase, and Scopus. Other preprints are included under their respective databases.\u003c/p\u003e\n\u003cp\u003eCreated in BioRender. ElSayed, M. (2025) https://BioRender.com/zcuwaxv (29)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7528339/v1/2eef9a8b38243681cd7b4b78.png"},{"id":90759207,"identity":"699ec6c1-299d-423f-b5c3-11bfa69f0ce4","added_by":"auto","created_at":"2025-09-07 14:39:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1688147,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7528339/v1/1afedc92-d17b-4ca5-9742-62f97fa44647.pdf"},{"id":90758148,"identity":"bdaedcfc-d032-49a7-a8d3-3768df582902","added_by":"auto","created_at":"2025-09-07 14:15:38","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":304268,"visible":true,"origin":"","legend":"","description":"","filename":"GRAPHICABSTRACT.docx","url":"https://assets-eu.researchsquare.com/files/rs-7528339/v1/d87e747ab22a5cf2352d9524.docx"},{"id":90758144,"identity":"e0319a2c-4814-4bfe-b309-def57b37c336","added_by":"auto","created_at":"2025-09-07 14:15:38","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":172737,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7528339/v1/3c0e7ace26b44ce32024d713.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEsketamine for Treatment of Cognitive Decline in Alzheimer’s Disease: A Scoping Review of Pre-clinical Studies\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAlzheimer\u0026apos;s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline and is the leading cause of dementia, currently affecting over 55 million people globally. Central to AD is the progressive neurodegeneration, resulting in a gradual deterioration of memory, attention, and executive function(1) . This AD-associated cognitive decline (ADAC) affects patients\u0026apos; quality of life and adds emotional and financial strain on their caregivers and healthcare systems(2). The current pharmacological treatments offer some improvement in multiple symptom domains for AD. Nevertheless, they have minimal effect on cognitive functions, and there is no evidence that these medications reduce the inflammatory process behind them \u003cstrong\u003e(Table 1)\u003c/strong\u003e. Hence, there is an urgent need for a new treatment modality to target this cognitive symptom domain in Alzheimer\u0026rsquo;s disease(3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathophysiology of ADAC\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo main neuropathological factors are implicated in the pathology of cognitive dysfunction in AD: the extracellular accumulation of amyloid-beta (A\u0026beta;) plaques and neuroinflammation. The A\u0026beta; plaques are usually associated with the intracellular formation of neurofibrillary hyperphosphorylated tau protein tangles. These A\u0026beta; peptides originate from the abnormal cleavage of amyloid precursor protein (APP), resulting in insoluble fibrils that impede synaptic transmission and exacerbate neuronal toxicity(5) . At the same time, the hyperphosphorylated tau destabilizes microtubules, disrupting axonal transport and promoting the formation of tangles, which further intensifies synaptic dysfunction (6).\u003c/p\u003e\n\u003cp\u003eAdditionally, neuroinflammation plays a significant role in cognitive decline. Activated microglia and astrocytes produce pro-inflammatory cytokines, such as interleukin-1\u0026beta; (IL-1\u0026beta;) and tumor necrosis factor-alpha (TNF-\u0026alpha;), which exacerbate synaptic loss and neuronal damage(7) . These inflammatory processes also interfere with neurotrophic signaling, particularly involving brain-derived neurotrophic factor (BDNF). BDNF is a crucial molecule for the process of neurogenesis. Lower levels of BDNF have been linked to worse cognitive performance in animal models of AD (8).\u003c/p\u003e\n\u003cp\u003eCollectively, these linked pathological mechanisms establish a setting that impairs synaptic plasticity and neuronal survival, particularly in brain areas crucial for cognition, i.e., the hippocampus and prefrontal cortex (9) .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe disrupted pathways in ADAC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1. \u0026nbsp; The Cannabinoid receptor type2- protein Kinase C (CB2-PKC) Signaling Axis (Figure 1)\u003c/strong\u003e (10)\u003c/p\u003e\n\u003cp\u003eIn the context of Alzheimer\u0026rsquo;s disease, the CB2-PKC axis plays a potential protective role. CB2 receptors are primarily located in immune cells, including microglia in the brain, which become activated during inflammation, a significant feature of Alzheimer\u0026apos;s disease. When CB2 is activated, it triggers the activation of PKC, which in turn reduces inflammation and clears inflammatory cytokines, such as Interleukin-1 (IL-1) and Interleukin-6 (IL-6). This signaling protects the brain by limiting neuroinflammation (11). In addition, the activation of the CB2 receptor leads to the inhibition of protein kinase A (PKA), further limiting neuroinflammation by inhibiting the formation of Nuclear factor kappa light chain enhancer of activated B cells (NF-kB) and cAMP Response Element-Binding Protein (CREB), both of which are involved in neuroinflammation (12).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditional supporting evidence emerged from a preclinical study, demonstrating that CB2 activation reduced inflammatory cytokine release, supported neuronal survival, and improved cognitive performance. In APP/PS1 transgenic mouse models, the administration of CB2-selective agonist produced significant cognitive improvements, particularly when administered at pre-symptomatic stages. This benefit was linked to attenuated microglial reactivation and suppression of pro-inflammatory cytokines, including IL-1\u0026beta;, IL-6, and TNF-\u0026alpha;, ultimately promoting neuronal survival. Notably, CB2 stimulation promoted A\u0026beta; clearance by macrophages. The study proposed that CB2 receptor stimulation could improve memory and learning impairment in AD by acting on selected tau kinases (including p38 kinase) downstream and reducing tau hyperphosphorylation around plaques (13).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. \u0026nbsp; BDNF-TrkB Signaling Pathway (Figure 2) (14)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe BDNF and its primary receptor, Tropomyosin Receptor Kinase B (TrkB), are essential for cognition by supporting strong synaptic connections and flexibility. The BDNF-TrkB signaling pathway is evident in the hippocampus and the prefrontal cortex. When BDNF binds to TrkB, it activates several intracellular signaling pathways, including the Phosphoinositide 3-kinase (PI3K) /Protein kinase B (Akt), Mitogen-Activated Protein Kinase (MAPK) /Extracellular signal-regulated Kinase (ERK), and Phospholipase C- Gamma (PLC\u0026gamma;). These pathways collectively enhance neuronal survival, support synaptic plasticity, and facilitate long-term potentiation (LTP), all of which are critical for learning and memory(15) .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIn ADAC,\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eBDNF levels are markedly diminished in the hippocampus of AD animal models. In addition, TrkB receptor levels and their activity often decline, weakening the neurotrophic support system in the hippocampus. The effect of BDNF-TrkB signaling results in impaired synaptic functionality and neurogenesis, potentially leading to neuronal death (16) \u0026nbsp;. Moreover, the accumulation of amyloid-beta and hyperphosphorylated tau may further inhibit BDNF expression and disrupt TrkB signaling. Eventually, this deterioration of synaptic integrity and plasticity is a key factor in the progressive memory loss and cognitive decline seen in Alzheimer\u0026rsquo;s disease (17) .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent Pharmacological Treatment of ADAC\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDespite their hypothetical potential to improve cognition, the current commercially available medications for AD have a frustratingly modest and temporary effect on ADAC. One of the most widely used drug classes is the cholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine. They were hypothesized to enhance cholinergic signaling; however, they provide minimal improvement to memory and attention. This modest effect was also observed with memantine, an NMDA receptor antagonist that acts by alleviating glutamatergic excitotoxicity(18) . Therefore, it is imperative to develop a new modality that can either preserve or restore cognitive functions with a special focus on modulating neuroplasticity, reducing inflammation, and enhancing BDNF signaling. Esketamine, a psychedelic agent approved for the treatment of treatment-resistant depression(19) , has the potential to improve this cognitive impairment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCould Esketamine Treat AD-associated Cognitive Decline?\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEsketamine, the S-enantiomer of ketamine, is a non-competitive NMDA receptor antagonist (20) (21) that was approved by the Food and Drug Administration (FDA) in 2019 for the treatment of treatment-resistant depression (19) . Esketamine enhances synaptic plasticity by facilitating downstream signaling pathways that promote neurogenesis and expression of BDNF(22) . Additionally, esketamine exhibits anti-inflammatory properties, including the reduction of pro-inflammatory cytokines and the inhibition of microglial activation(23). \u003cstrong\u003eEsketamine has also exhibited procognitive effects in perioperative neurocognitive disorders (POND)\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(24)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and depression (25)\u003c/strong\u003e\u003cstrong\u003e. Since cognitive dysfunction is the paramount symptom of Alzheimer\u0026rsquo;s disease, we here systematically reviewed the pre-clinical and clinical literature that examined esketamine\u0026rsquo;s potential role in treating ADAC\u003c/strong\u003e(26). \u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eTo ensure a comprehensive, transparent, and precise systematic review, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (27). We utilized the Rayyan application during the screening of the search results, making decisions regarding each article, and building the PRISMA diagram(28). This systematic review was registered in the Open Science Framework database (https://doi.org/10.17605/OSF.IO/EFBU4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformation sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe systematic review was conducted from April 5th, 2025, to June 26th, 2025, using PubMed (last searched on June 15th, 2025), Google Scholar (last searched on June 17th, 2025), Web of Science (last searched on June 26th, 2025), Scopus (last searched on June 26th, 2025), Cochrane (last searched on June 26th, 2025), and Embase (last searched on June 26th, 2025).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSearch strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe used the following search terms in each database: \u003cstrong\u003ePubMed\u003c/strong\u003e (using the advanced search: esketamine preclinical - esketamine Alzheimer\u0026rsquo;s - esketamine human studies - esketamine cognitive impairment- esketamine human research - esketamine cognitive dysfunction - esketamine cognitive function - esketamine human research cognitive impairment - esketamine human trials - esketamine cognitive impairment Alzheimer\u0026rsquo;s human trials ), \u003cstrong\u003eGoogle Scholar\u003c/strong\u003e (esketamine for Alzheimer\u0026rsquo;s- esketamine cognitive dysfunction - esketamine Alzheimer\u0026rsquo;s cognitive dysfunction preclinical - esketamine Alzheimer\u0026rsquo;s cognitive dysfunction human research - esketamine Alzheimer\u0026rsquo;s cognitive impairment human research - esketamine Alzheimer\u0026rsquo;s cognitive dysfunction clinical- esketamine Alzheimer\u0026rsquo;s preclinical - esketamine Alzheimer\u0026rsquo;s human research - esketamine Alzheimer\u0026rsquo;s clinical - esketamine cannabinoid receptor 2), \u003cstrong\u003eCochrane\u0026nbsp;\u003c/strong\u003e(using the advanced search: esketamine Alzheimer\u0026rsquo;s - esketamine Alzheimer\u0026rsquo;s cognition - esketamine dementia), \u003cstrong\u003eScopus\u003c/strong\u003e, \u003cstrong\u003eEmbase,\u003c/strong\u003e and \u003cstrong\u003eWeb of Science\u003c/strong\u003e (esketamine Alzheimer - esketamine Alzheimer cognition - esketamine cognition - esketamine + dementia\u003cstrong\u003e)\u003c/strong\u003e. Across all databases, results were filtered to include only studies conducted since 2020.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach author reviewed their assigned papers and collaborated to screen each study to determine its eligibility based on strict inclusion and exclusion criteria. We included studies according to the following criteria: 1. pre-clinical and clinical studies evaluating the use of esketamine for treating cognitive dysfunction in Alzheimer\u0026rsquo;s disease (any stage or severity), 2. studies examining the mechanistic pathways affected by esketamine, such as BDNF-glutamate signalling and synaptic plasticity, that explicitly state or support the relevance to memory enhancement not related to other diagnoses and that has the potential to be a therapeutic target in Alzheimer\u0026apos;s disease, 3. randomised controlled trials (RCTs), cohort studies, case-control studies, and clinical case reports that used esketamine for treating cognitive impairment and/or memory decline related to Alzheimer\u0026rsquo;s disease. Due to the lack of studies on esketamine improving cognition in Alzheimer\u0026rsquo;s disease, we decided to broaden our inclusion criteria to include preprints as well. We excluded studies based on the following criteria: 1. studies focusing on ketamine without specific evaluation of esketamine, 2. studies investigating esketamine for conditions other than Alzheimer\u0026rsquo;s disease, 3. studies exploring esketamine for symptoms of Alzheimer\u0026rsquo;s disease other than cognitive dysfunction (e.g., depression), and 4. duplicate publications or studies with insufficient data for extraction or analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData extraction process and items\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCollaboratively, two reviewers extracted the following data from each study: study title, drug target and mechanism of action, proposed symptom/biological target of the drug and its method of assessment, degree of Alzheimer\u0026apos;s disease included in the study (if mentioned), number of cases (or cell grouping) investigated, drug protocol, reported adverse effects (if mentioned), results, conclusion and limitations of each study. Data extraction was done solely through reading; no tools were used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy synthesis and outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe grouped studies for synthesis based on type (preclinical vs. clinical), intervention (esketamine), and outcome domain (e.g., TNF-\u0026alpha;, IL-6, BDNF, cognitive performance). Only studies with outcomes relevant to our inclusion criteria and synthesis objectives were included. As our systematic review included multiple preclinical and clinical studies reporting heterogeneous outcome measures, we were unable to combine the data from these different studies.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003e(Figure 3)\u003c/strong\u003e\u0026nbsp; \u0026nbsp;(29)\u003c/p\u003e\n\u003cp\u003eOur systematic review included a total of 11,529 records for screening. We identified and removed 7477 duplicates before proceeding to the screening phase. During the screening process, we assessed 4,047 records, of which we excluded 4,043, and sought 16 reports for full-text retrieval. After full-text assessment of these 16 papers for eligibility and relevance to our research objective, we excluded 12 reports. Ultimately, we identified and included four relevant studies in the final synthesis of our systematic review. We summarized the included literature in \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur study aimed to systematically review the literature supporting the use of esketamine in mitigating cognitive decline associated with Alzheimer\u0026rsquo;s disease. The study was influenced by two factors: first, the currently available medications for Alzheimer\u0026rsquo;s disease have a modest effect on cognitive decline(18) , and second, esketamine has shown promising cognitive results in other illnesses, such as major depression(35) .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA.\u0026nbsp;\u0026nbsp;Preclinical studies\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur search strategy yielded four articles on the effect of esketamine in ADAC. Based on this literature, esketamine has cognitive-enhancing effects through three main mechanisms: mitigating neuroinflammation, enhancing neurogenesis, and possibly reducing the levels of hyperphosphorylated tau proteins.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u0026nbsp; \u0026nbsp;The Effect of Esketamine on Neuroinflammation (Figure 1) (10)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe found two studies that examined the anti-neuroinflammatory effects of esketamine\u0026mdash;the first study used in vitro BV2 microglial cells(31) . After using lipopolysaccharide (LPS) to induce cellular inflammation, the study team found that esketamine upregulated CB2 receptor expression, a key receptor in neuroinflammation (36) and Alzheimer\u0026rsquo;s disease pathology(37) , activated PKC, and suppressed the expression of NF-\u0026kappa;B and iNOS. These molecular changes correlated with a reduction in pro-inflammatory cytokine production and nitric oxide release. Notably, co-treatment with AM630 abolished the anti-inflammatory effects of esketamine. Conversely, the use of chelerythrine partially reduced the anti-neuroinflammatory effects. Since chelerythrine is a PKC inhibitor, we hypothesize that esketamine maintains a degree of anti-neuroinflammatory effect through other CB2-mediated anti-neuroinflammatory pathways, namely G\u0026alpha;i inhibition of cAMP and PKA, as well as G\u0026beta; and G\u0026gamma; reduction of p38 MAPK and ERK1/2 (12) (38). The reduction of p38 MAPK was proposed as the mechanism by which esketamine improves electroconvulsive therapy-induced cognitive dysfunction(39) \u0026nbsp;.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe second study investigated the cognitive-enhancing effects of esketamine in a transgenic mouse model for AD\u0026nbsp;(34). Esketamine improved the cognitive performance of AD mice, which correlated with a decrease in the transcription of mRNA for pro-inflammatory cytokines, including cyclooxygenase-2 (COX2\u003cem\u003e)\u003c/em\u003e, Interleukin-\u0026beta; (IL-1\u0026beta;), and inducible nitric oxide synthase (iNOS), in the hippocampal CA1 region. Interestingly, the expression of tripartite motif-containing protein 24 (TRIM24), a gene associated with multiple types of human cancers(40) , increased after esketamine administration and was found to decrease the pro-inflammatory mRNA transcripts. Additionally, TRIM24 knockdown (TRIM24-KD) resulted in increased expression of COX2, iNOS, and IL-1\u0026beta; in the hippocampal tissues. Both findings suggest a role for TRIM24 expression in mediating esketamine\u0026rsquo;s anti-neuroinflammatory effects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb. \u0026nbsp; Esketamine\u0026rsquo;s Neurogenesis is associated with Improved Memory (Figure 2) (14)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe found three studies that investigated the contribution of neurogenesis to esketamine\u0026rsquo;s cognitive-enhancing effects (32) (34); specifically focusing on ADAC. These studies involved different population groups, and therefore, a meta-analysis was not feasible.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe first study, currently a preprint, investigated the effect of esketamine on a rat model of AD(32) . \u0026nbsp;The study team found that esketamine improved memory and learning in AD rats, and that correlated with increased BDNF, p-AKT, and p-mTOR expression. The increased p-AKT and p-mTOR expression was also reported in Tu\u0026rsquo;s study , which strongly suggests this as a possible pathway for esketamine\u0026rsquo;s cognitive-enhancing effect in ADAC. Tu\u0026rsquo;s study (34) proposed TRIM24 expression as a needed step for AKT/mTOR activation. Furthermore, increasing the expression of this pathway was associated with esketamine\u0026rsquo;s improved cognitive dysfunction in other disorders with similar pathology to AD, including perioperative neurocognitive disorders (POND)(25) . Furthermore, clinical trials validated these cognitive benefits of esketamine in human subjects with POND(41) (24) . Although these studies do not replace the necessity of clinical trials specifically investigating esketamine in AD, they suggest potential promise for the use of esketamine in ADAC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec. \u0026nbsp; The effect of Esketamine on hyperphosphorylated tau protein:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne study\u0026nbsp;(32)\u0026nbsp;suggested a role for esketamine in decreasing A\u0026beta;42 and phosphorylated tau levels. While this finding seems promising for treating AD, the results need to be replicated. One possible mechanism for such action, if it gets replicated, is through the activation of CB2 receptors(37)\u0026nbsp;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB. Clinical Studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur search process sought meta-analyses, systematic reviews, randomized controlled trials, interventional studies, observational studies, case-control studies, or case reports to identify relevant clinical evidence supporting or refuting esketamine\u0026rsquo;s potential to improve ADAC. However, we were unable to find any clinical evidence to support this claim. To date, no clinical trials have directly evaluated the efficacy or safety of esketamine in addressing cognitive impairment in Alzheimer\u0026apos;s patients.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur systematic review critically evaluated the emerging evidence regarding the impact of esketamine on cognitive function in Alzheimer\u0026apos;s disease (AD). The findings present a complex but promising landscape for this novel therapeutic approach. Current evidence, solely derived from preclinical studies with no clinical studies to support it, suggests that esketamine may exert beneficial effects on certain cognitive domains through CB2 activation (leading to anti-neuroinflammatory effects), enhancing neurogenesis (by activating \u0026nbsp;BDNF/Akt/TrkB pathway), and potentially reducing A\u0026beta;42 and phosphorylated tau levels. These unique mechanisms distinguish esketamine from conventional AD treatments. There remains a need to replicate the finding of reduced A\u0026beta;42 and phosphorylated tau levels. Moreover, these cognitive benefits need to be replicated in human subjects. The lack of clinical data represents a significant limitation to the use of esketamine in ADAC. It highlights the need for human studies to determine the therapeutic potential and applicability of esketamine in this context. The absence of clinical validation also raises questions regarding dosage, safety profiles in elderly populations, and long-term cognitive outcomes, which remain unaddressed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLIMITATIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur search has two limitations. First, the absence of clinical evidence to support the preclinical evidence provides an incomplete picture of the actual effects of esketamine in ADAC. Second, the preclinical studies had different populations (BV2 microglial cells vs. genetic vs. chemical models of AD), variable dosing regimens and administration routes (in culture vs. intraperitoneal), and different outcome measures, which complicated comparisons across different studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Conceptualization: Mohamed ElSayed and Islam Mohammad Shehata\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Methodology: Samar Ashraf, Samaa Ihab, Mohamed ElSayed, Islam Mohammad Shehata\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Formal Analysis \u0026amp; Data Curation: Samar Ashraf, Samaa Ihab\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Investigation (Literature Search \u0026amp; Screening): Samar Ashraf, Samaa Ihab, Islam AbdelGawad, Toqa Abd Raboh\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Writing \u0026ndash; Original Draft: Samar Ashraf, Samaa Ihab, Islam AbdelGawad, Toqa Abd Raboh\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Writing \u0026ndash; Review \u0026amp; Editing: [All Authors]\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Supervision: Mohamed ElSayed and Islam Mohammad Shehata\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Project Administration: Mohamed ElSayed\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICTS OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data has not been previously presented orally or by poster at scientific meetings.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShin JH. 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Racemic Ketamine and Esketamine for Treatment of Refractory and Super-Refractory Status Epilepticus. In. Available from: https://link.springer.com/protocol/10.1007/978-1-0716-4599-4_9\u003c/li\u003e\n\u003cli\u003eShehata IM, Kohaf NA, ElSayed MW, Latifi K, Aboutaleb AM, Kaye AD. Ketamine: Pro or antiepileptic agent? A systematic review. Heliyon. 2024 Jan 30;10(2):e24433.\u003c/li\u003e\n\u003cli\u003eMohammad Shehata I, Masood W, Nemr N, Anderson A, Bhusal K, Edinoff AN, et al. The Possible Application of Ketamine in the Treatment of Depression in Alzheimer\u0026rsquo;s Disease. Neurol Int. 2022 Mar 22;14(2):310\u0026ndash;21.\u003c/li\u003e\n\u003cli\u003eElsaeidy AS, Ahmad AHM, Kohaf NA, Aboutaleb A, Kumar D, Elsaeidy KS, et al. Efficacy and Safety of Ketamine-Dexmedetomidine Versus Ketamine-Propofol Combination for Periprocedural Sedation: A Systematic Review and Meta-analysis. Curr Pain Headache Rep. 2024 Apr;28(4):211\u0026ndash;27.\u003c/li\u003e\n\u003cli\u003eHung KC, Kao CL, Ho CN, Wu JY, Chang YJ, Lin CM, et al. Efficacy and safety of esketamine in preventing perioperative neurocognitive disorders: a meta-analysis of randomized controlled studies. Syst Rev. 2025 Mar 22;14(1):68.\u003c/li\u003e\n\u003cli\u003eWen Y, Xu J, Shen J, Tang Z, Li S, Zhang Q, et al. Esketamine Prevents Postoperative Emotional and Cognitive Dysfunction by Suppressing Microglial M1 Polarization and Regulating the BDNF-TrkB Pathway in Ageing Rats with Preoperative Sleep Disturbance. Mol Neurobiol. 2024 Aug;61(8):5680\u0026ndash;98.\u003c/li\u003e\n\u003cli\u003eKohaf NA, Khan TI, Elbana HH, Hassouna RA, Elfattah MMA, Nasa P, et al. A Promising Route for Established Indications: A Systematic Review of Nebulized Ketamine in Pain. Curr Pain Headache Rep. 2025 Apr 30;29(1):81.\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71.\u003c/li\u003e\n\u003cli\u003eOuzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016 Dec 5;5(1):210.\u003c/li\u003e\n\u003cli\u003eElsayed M. PRISMA diagram explaining our systematic search process.\u003c/li\u003e\n\u003cli\u003eGoogle Scraper [Internet]. Available from: https://apify.com/apify/google-search-scraper\u003c/li\u003e\n\u003cli\u003eWang Y, Cao M, Zhang Y, Chen Q, Chen Z, Jia J. The CB2-PKC pathway is involved in esketamine-induced anti-inflammation in BV-2 microglial cells exposed to lipopolysaccharides. Am J Transl Res. 2024;16(9):4466\u0026ndash;78.\u003c/li\u003e\n\u003cli\u003eWang C, Xu F, Yu X, Yang J, Guo D, Gan J. Sub-anaesthetic doses of Esketamine ameliorate memory impairment in Alzheimer\u0026rsquo;s disease by regulating the BDNF/AKT/mTOR signaling pathway in rats [Internet]. Research Square Platform LLC; 2023 [cited 2025 July 8]. Available from: https://www.researchsquare.com/article/rs-3687417/v1\u003c/li\u003e\n\u003cli\u003eLi H, Ying L, Wan F, Shiqiao K, Yijie F, Chuli X, et al. Esketamine enhances memory reconsolidation in the novel object recognition task. Physiol Behav. 2024 Apr 1;277:114461.\u003c/li\u003e\n\u003cli\u003eTu Y, Xu B. Esketamine induces tripartite motif-containing protein 24 to improve cognitive dysfunction in Alzheimer\u0026rsquo;s disease. Neurosci Lett. 2024 June 21;834:137836.\u003c/li\u003e\n\u003cli\u003eSobreiro M de FM, Silveira PSP, Cavenaghi VB, da Costa LP, de Souza BPF, Takahashi RES, et al. Long-Term Cognitive Outcomes of Esketamine Nasal Spray in Treatment-Resistant Depression: A Preliminary Report. Pharm Basel Switz. 2025 Jan 27;18(2):173.\u003c/li\u003e\n\u003cli\u003eHan QW, Shao QH, Wang XT, Ma KL, Chen NH, Yuan YH. CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways. Acta Pharmacol Sin. 2022 Sept;43(9):2253\u0026ndash;66.\u003c/li\u003e\n\u003cli\u003eAso E, Juv\u0026eacute;s S, Maldonado R, Ferrer I. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in A\u0026beta;PP/PS1 mice. J Alzheimers Dis JAD. 2013;35(4):847\u0026ndash;58.\u003c/li\u003e\n\u003cli\u003eRomero-Sandoval EA, Horvath R, Landry RP, DeLeo JA. Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation. Mol Pain. 2009 May 28;5:25.\u003c/li\u003e\n\u003cli\u003eZhou X, Zhang L, Gao W, Li H, Guo Q, Dai J, et al. Esketamine alleviates cognitive impairment signs induced by modified electroconvulsive therapy in a depression rat model via the KLF4/p38 MAPK pathway. J Affect Disord. 2025 May 1;376:302\u0026ndash;12.\u003c/li\u003e\n\u003cli\u003eYao Y, Zhou S, Yan Y, Fu K, Xiao S. The tripartite motif-containing 24 is a multifunctional player in human cancer. Cell Biosci. 2024 Aug 19;14(1):103.\u003c/li\u003e\n\u003cli\u003eHan C, Ji H, Guo Y, Fei Y, Wang C, Yuan Y, et al. Effect of Subanesthetic Dose of Esketamine on Perioperative Neurocognitive Disorders in Elderly Undergoing Gastrointestinal Surgery: A Randomized Controlled Trial. Drug Des Devel Ther. 2023;17:863\u0026ndash;73.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cb\u003eTable 1 is available in the Supplementary Files section.\u003c/b\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1035\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 1035px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2: A summary of the current evidence for the esketamine effect on ADAC.\u0026nbsp;\u003c/strong\u003eWe could not find any clinical studies to support the current available evidence from preclinical studies.\u003cbr\u003e\u003cstrong\u003eTable legend:\u0026nbsp;\u003c/strong\u003e\u003cem\u003eCOX2 (cyclooxygenase-2), IL-1\u0026beta; (Interleukin-\u0026beta;), iNOS (inducible nitric oxide synthase), i.p.\u0026nbsp;\u003c/em\u003e(Intraperitoneal),\u003cem\u003e\u0026nbsp;LPS\u003c/em\u003e (Lipo-polysaccharide), \u003cem\u003eCB2\u003c/em\u003e (Cannabinoid 2 receptor), \u003cem\u003eAM630\u0026nbsp;\u003c/em\u003e(CB2 receptor antagonist), Chelerythrine (Protein Kinase C antagonist), \u003cem\u003eTRIM24\u0026nbsp;\u003c/em\u003e(tripartite motif-containing protein 24)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArticle\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePopulation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 233px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResult\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 311px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 1035px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnti-Neuroinflammatory Effects of Esketamine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eWang Y, Cao M, Zhang Y, Chen Q, Chen Z, Jia J. (2024) \u0026nbsp;(31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eIn vitro LPS-stimulated BV-2 microglial cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eBV2 cells were divided into five different groups, and each was cultured in a separate medium:\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eControl (drug-free medium)\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eLPS-exposed\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eThird, fourth, and fifth groups:\u003c/u\u003e Esketamine at 1, 5, and 10 \u0026mu;g/ml concentrations was added to cells and incubated for 24 hours.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTests:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1. \u003cu\u003eExamine the role of CB2 receptor:\u003c/u\u003e AM630 was added to 2 cell groups.\u003c/p\u003e\n \u003cp\u003e2. \u003cu\u003eExamine the role of Protein Kinase C:\u003c/u\u003e Chelerythrine was added to 2 cell groups.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 233px;\"\u003e\n \u003cp\u003e● \u0026nbsp;Esketamine markedly upregulated CB2 receptor expression and activated PKC while concurrently suppressing NF-\u0026kappa;B and iNOS expression.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp;AM630 blocked the Esketamine-induced upregulation of NF-\u0026kappa;B.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp;Chelerythrine partially reversed Esketamine-induced anti-inflammatory effects.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine reduces inflammation in BV-2 microglial cells by activating the CB2 receptor and the protein kinase C pathway, leading to a decrease in the expression of inflammatory proteins (NF-\u0026kappa;B (p65) and iNOS), proinflammatory cytokines, and nitric oxide.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine\u0026rsquo;s anti-neuroinflammatory action is mediated via CB2 receptor activation.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;CB2 receptor mediates esketamine\u0026rsquo;s action partially via activation of Protein Kinase C.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 1035px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurogenesis-Enhancing Effects of Esketamine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eChengzhi Wang, Fan Xu, Xinran Yu et al. (2023) [Preprint] \u0026nbsp;(32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eAD rat model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eRats were divided into five groups:\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eControl Group:\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Healthy rats\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Received normal saline only\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eAD Model with no treatment:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e[AD was induced by bilateral intracerebroventricular (ICV) injection of Streptozotocin (STZ) (2.4 mg/kg) + daily intraperitoneal injection of D-galactose (60 mg/kg/day) for 6 weeks]\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eAD + Esketamine Group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;AD induction\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Intraperitoneal Esketamine (0.5 mg/kg) for 6 days\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp; \u003cu\u003eAD + Esketamine + Vehicle Control Group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;AD induction\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Pre-treatment with Captisol-containing vehicle (30%)\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Esketamine (0.5 mg/kg)\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eAD + Esketamine + AKT Inhibitor Group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;AD induction\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Pre-treatment with AKT inhibitor MK-2206 (33 mg/kg, i.p. on day 1 and 4)\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Esketamine (0.5 mg/kg)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 233px;\"\u003e\n \u003cp\u003e● \u0026nbsp; \u003cu\u003eBehavioral:\u003c/u\u003e Esketamine improved memory and learning in AD rats.\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eBiological:\u003c/u\u003e\u0026nbsp; Esketamine protected hippocampal neurons from damage.\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eMolecular:\u003c/u\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;Esketamine increased BDNF, p-AKT, and p-mTOR expression.\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;Esketamine reduced A\u0026beta;42 and phosphorylated tau levels.\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;AKT inhibitor (MK-2206) blocked these beneficial effects.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp; Sub-anesthetic dose of Esketamine improved learning and spatial memory in AD model rats.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine activated the BDNF/AKT/mTOR pathway, which plays a key role in neuroprotection and synaptic plasticity.\u003c/p\u003e\n \u003cp\u003e● \u003cem\u003eEsketamine reduced hippocampal A\u0026beta;42 and phosphorylated tau\u003c/em\u003e, two main pathological hallmarks of Alzheimer\u0026apos;s disease.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine preserved neuronal structure in the hippocampal CA3 region.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Blocking AKT signaling abolished Esketamine\u0026apos;s beneficial effects, confirming its action is AKT/mTOR dependent.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;Li, H., Ying, L., Wan, F., Shiqiao, K., Yijie, F., Chuli, X., Xudong, Y., Xinhong, Y., \u0026amp; Zhiyong, X. (2024) (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eIn vivo mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e➢\u0026nbsp;The study aimed to assess the effect of esketamine on memory reconsolidation.\u003c/p\u003e\n \u003cp\u003e➢ \u0026nbsp;To investigate the role of AMPA receptors in mediating the esketamine-induced memory reconsolidation effect, the study used NBQX (AMPA-R antagonist).\u003c/p\u003e\n \u003cp\u003e➢ \u0026nbsp;The Novel Object Recognition task was used to assess memory.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e➢ \u0026nbsp;Mice were divided into six groups:\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u003cu\u003eVehicle group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;Received saline injection immediately after reactivation.\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eEsketamine group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;Received 10 mg/kg i.p. esketamine immediately after reactivation.\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eEsketamine 6h post-reactivation group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;Received 10 mg/kg esketamine 6 hours after reactivation.\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eEsketamine without reactivation group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;Received 10 mg/kg esketamine 24h after sampling (no reactivation step).\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eNBQX group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;Received 5 mg/kg NBQX (i.p.) 5 min after reactivation.\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eEsketamine + NBQX group:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr;\u0026nbsp;Received 10 mg/kg esketamine immediately after reactivation, followed by 5 mg/kg NBQX 5 min later.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTiming analysis:\u003c/strong\u003e 0 h, 6 h, and 24 h administration of esketamine used to study the reconsolidation time window.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 233px;\"\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine (10 mg/kg) enhanced memory only when injected immediately after memory reactivation.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine had no effect on memory reconsolidation if injected 6 hours after reactivation or without reactivation.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;NBQX (AMPA antagonist) blocked the memory-enhancing effect of esketamine.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine enhances memory reconsolidation when administered immediately after reactivation.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine\u0026rsquo;s effect is time-dependent; no improvement occurs when given 6 hours later.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine has no effect without memory reactivation, confirming it targets the reconsolidation phase.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;The AMPA receptor antagonist (NBQX) blocks esketamine\u0026rsquo;s effect, indicating a reliance on AMPA receptor signaling.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eTu Y, Xu B (2024)\u003c/p\u003e\n \u003cp\u003e(34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e● \u0026nbsp;Triple transgenic AD mice (3xTg-AD, a genetic mouse model for AD)\u003c/p\u003e\n \u003cp\u003e●\u0026nbsp;Wild-type mice (WT)\u003c/p\u003e\n \u003cp\u003e●\u0026nbsp;TRIM-24 knockdown mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e➢ \u0026nbsp;The study aimed to investigate the contribution of the TRIM24 expression and the PI3K/Akt pathway in esketamine\u0026rsquo;s cognitive-enhancing effect in AD\u003c/p\u003e\n \u003cp\u003e➢ \u0026nbsp;The study consisted of 3 batches of experiments:\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u003cu\u003eBatch 1:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;WT + normal saline (NS)\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;3xTg-AD + NS\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;3xTg-AD + esketamine\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eBatch 2:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Negative control (NC)-knockdown (KD) + NS\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;NCKD + esketamine\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;TRIM24-KD + esketamine group\u003c/p\u003e\n \u003cp\u003e● \u003cu\u003eBatch 3:\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;NS + vehicle\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Esketamine + vehicle\u003c/p\u003e\n \u003cp\u003e\u0026rarr; \u0026nbsp;Esketamine + LY294002 (PI3K inhibitor)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e➢ \u003cstrong\u003eDrugs used:\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1. Esketamine:\u0026nbsp;\u003c/strong\u003einjected intraperitoneally at 10 mg/kg every week.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2. Normal Saline:\u0026nbsp;\u003c/strong\u003einjected intraperitoneally at 10 mg/kg every week.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3. PI3K inhibitor LY294002:\u003c/strong\u003e 25 mg/kg (ip) injected before each esketamine treatment.\u003c/p\u003e\n \u003cp\u003e➢ \u003cstrong\u003eCognitive function tests:\u0026nbsp;\u003c/strong\u003eMorris Water Maze (MWM)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 233px;\"\u003e\n \u003cp\u003e● \u0026nbsp;Esketamine significantly improved cognitive performance in 3xTg-AD mice, evidenced by improved \u0026nbsp;MWM scores.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp;Esketamine upregulated TRIM24 expression in the hippocampus of AD mice.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp;TRIM24 knockdown reversed the cognitive benefits of esketamine, confirming its role as a key mediator.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp;PI3K/AKT phosphorylation was reduced in AD mice, and that was reversed by esketamine treatment. The phosphorylation was reduced again after TRIM24-KD, proving the role of TRIM24 in esketamine cognitive enhancement.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp;AD mice had elevated mRNA transcripts of COX2, iNOS, and IL-1\u0026beta;. Esketamine reduced the mRNA of these neuroinflammatory cytokines in the hippocampal CA1 region. TRIM24-KD increased the expression of COX2, iNOS, and IL-1\u0026beta; in the hippocampal tissues of 3xTg-AD mice.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp;LY294002 decreased PI3K and AKT phosphorylation after esketamine treatment. This correlated with a lower degree of cognitive performance and higher proinflammatory cytokine transcripts. \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine enhances cognitive function in a mouse model of Alzheimer\u0026rsquo;s disease.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;Esketamine\u0026rsquo;s neuroprotective effects are mediated via upregulation of TRIM24 expression.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp; Esketamine reduces neuroinflammation by reducing mRNA transcription of pro-inflammatory proteins, suggesting an anti-inflammatory role in the AD brain.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp;The activation of the AKT/mTOR pathway appears to be a key downstream mechanism behind Esketamine\u0026rsquo;s effects.\u003c/p\u003e\n \u003cp\u003e● \u0026nbsp; \u0026nbsp; Blocking TRIM24 negates the benefits of esketamine, highlighting TRIM24 as a potential therapeutic target.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Geisel School of Medicine at Dartmouth","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s disease, Esketamine, Neuroinflammation, BDNF, Cognition, Scoping Reviews","lastPublishedDoi":"10.21203/rs.3.rs-7528339/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7528339/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground/Objectives:\u003c/h2\u003e\u003cp\u003eAlzheimer's disease is a progressive neurodegenerative disorder leading to progressive cognitive decline. While the current pharmacological treatments provide some relief for other symptom domains, the cognitive decline remains a challenging symptom. This systematic review investigates preclinical and clinical literature supporting the use of esketamine for Alzheimer\u0026rsquo;s disease-associated cognitive decline (ADAC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe searched PubMed, Google Scholar, Web of Science, Scopus, Embase, and Cochrane for relevant studies.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eWe identified four preclinical studies supporting the use of esketamine in ADAC. These studies suggest that esketamine exerts its cognitive-enhancing effect through the activation of the Cannabinoid-2 receptor, the activation of the Brain-Derived Neurotrophic Factor signaling pathway, and the reduction of hippocampal Aβ42 and phosphorylated tau levels. Our search did not yield any clinical evidence to support this claim.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePreclinical studies suggest that esketamine holds promise as a potential therapeutic agent for ADAC due to its anti-inflammatory and neuroprotective properties. However, clinical studies are needed to confirm its efficacy and safety in human subjects before it can be considered for clinical application.\u003c/p\u003e","manuscriptTitle":"Esketamine for Treatment of Cognitive Decline in Alzheimer’s Disease: A Scoping Review of Pre-clinical Studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-07 14:15:33","doi":"10.21203/rs.3.rs-7528339/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d233f92b-7a8f-4577-8b47-5a8175c6f922","owner":[],"postedDate":"September 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54153929,"name":"Neurobiology of Disease"},{"id":54153930,"name":"Animal Science"},{"id":54153931,"name":"Cellular \u0026 Molecular Neuroscience"},{"id":54153932,"name":"Psychiatry"}],"tags":[],"updatedAt":"2025-09-07T14:15:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-07 14:15:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7528339","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7528339","identity":"rs-7528339","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}