Reversal of High-Fat Diet-Induced Cognitive Impairment and Oxidative Stress in the Brain through Zingiber officinale Supplementation

Reversal of High-Fat Diet-Induced Cognitive Impairment and Oxidative Stress in the Brain through Zingiber officinale Supplementation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Reversal of High-Fat Diet-Induced Cognitive Impairment and Oxidative Stress in the Brain through Zingiber officinale Supplementation Thais Fernandes Luciano, Claudio Teodoro Souza, Jade Oilveira, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4206815/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Aug, 2024 Read the published version in Metabolic Brain Disease → Version 1 posted 11 You are reading this latest preprint version Abstract Obesity presents a significant health concern, correlating with various adverse health outcomes. Diet-induced obesity (DIO) has been associated with impair on cognitive function. Pharmacological treatments for obesity are limited and may pose serious adverse effects. Ginger possess anti-inflammatory and antioxidant effects in addition to metabolic effects. The study aimed to assess the effects of ginger supplementation on cognitive function, anxiety levels, neurotrophin levels, as well as inflammatory and oxidative status in the cortex following DIO in mice. Swiss male mice, 2 months old, were fed with DIO or standard chow for 4 months and after were subdivided into (n=10/group): i) CNT (CNT + vehicle); ii) CNT supplemented with ZO (CNT + ZO); iii) obese mice (DIO + vehicle) ; iv) obese mice supplemented with ZO (DIO + ZO) (n=10). Zingiber officinale (ZO) 400 mg/kg/day were supplemented for 35 days by oral gavage. DIO + vehicle group shown impaired on recognition memory task. CNT + ZO group showed a higher number of crossings in the open field. There were no difference between group in plus maze task. DIO + vehicle had increased the DCFH and carbonylation levels in cortex. The DIO + vehicle showed a reduction in catalase activity. The cerebral cortex did not show any difference regarding to inflammatory and neurotrophins markers. In conclusion, our findings indicate that supplementation with ZO reverses cognitive impairment in DIO mice and enhances antioxidant status in the cerebral cortex. Ginger learning and memory obesity brain metabolism Figures Figure 1 Figure 2 Figure 3 1. Introduction Obesity presents a significant health concern, correlating with various adverse health outcomes, including an elevated risk of heart disease and diabetes (Haslam and James 2005; Valenzuela et al. 2023 ). Recent studies have proposed an adipose-brain axis, linking increased adipose mass with cognitive decline and a heightened susceptibility to dementia (Oliveras-Cañellas et al. 2023 ). High consumption of saturated fat has been associated with diminished synaptic plasticity and neuronal apoptosis, both contributing to impair cognitive function (Moraes et al. 2024) [4]. Additionally, animals with diet-induced obesity (DIO) have exhibited poorer performance in tasks requiring the prefrontal cortex, such as the recognition of novel objects (Bocarsly et al 2015 ) even if the exposition to DIO were short period (de Paula et al. 2021 ). DIO has been shown to elevate oxidative stress and inflammation within the brain, potentially impairing cognitive function and heightening the risk of dementia (Miller and Spencer 2014 , Souza et al. 2024 .). The underlying mechanisms of this association are intricate and not yet fully elucidated. It is postulated that the accumulation of body fat can instigate metabolic alterations, heightened lipoperoxidation, and immune system activation, ultimately culminating in brain damage. Both oxidative stress and inflammation are capable of inflicting harm upon brain cells, thereby fostering cognitive decline and augmenting the likelihood of dementia development (Cherbuin et al 2012 ). Pharmacological treatments for obesity are limited and may pose serious adverse effects, prompting many individuals to explore alternative therapies. Among these, ginger stands out as one of the most promising natural compounds for adjunctive obesity treatment (Tramontin et al. 202). Ginger encompasses various phytochemicals, such as phenols, flavonoids, terpenoids, gingerol, and zingerone, which possess anti-inflammatory, antioxidant, and antiemetic properties (Palatty et al. 2013 ; Grzanna et al 2005 ). Studies indicate that ginger extract exhibits antioxidant potential, enhancing the activity of key antioxidant enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) while mitigating the production of reactive oxygen species (ROS) (Morvaridzadeh et al. 2021 ). Ginger supplementation has demonstrated a favorable impact on various aspects of brain health, encompassing the reduction of neuroinflammation, enhancement of cognitive function, and alleviation of anxiety (Zhang et al. 2018 ). In individuals afflicted with chronic inflammatory conditions, ginger supplementation has been observed to significantly decrease TNF-α levels (Morvaridzadeh et al. 2020). Furthermore, ginger supplementation has been associated with enhanced levels of neurotrophins and diminished oxidative stress and inflammation in the cerebral cortex (Choi et al 2018 ). Notably, both ginger and its constituents exhibit notable efficacy in ameliorating memory dysfunctions (Talebi et al. 2021 ; Chang-Yul et al. 2018 ). These findings underscore the potential of ginger as an adjunctive treatment for conditions pertaining to brain health and function. The study aimed to assess the effects of ginger supplementation on cognitive function, anxiety levels, neurotrophin levels, as well as inflammatory and oxidative status in the cortex following DIO in mice. 2. Material and Methods 2.1. Characterization of animals and diet Swiss male mice, 2 months old, were housed with water and food ad libitum. The animals were kept on a 12:12 h light-dark cycle and maintained at 20 ± 2 ºC at UNESC facilities. The study was conducted in accordance with the Brazilian Guidelines for the Care and Use of Animals for Scientific and Didactic Purposes (DOU 27/5/13;MCTI, p. 7). Animals were divided into two groups: control (CNT), fed on standard rodent chow (53.0% carbohydrates, 22.0% proteins, 4% lipids—relative to calories, corresponding to approximately 2.9 kcal/g—Puro Lab 22PB; Porto Alegre, RS, Brazil), and a high-fat diet (DIO) [26% carbohydrates, 14.9% proteins, 59% lipids (oil and lard)] relative to calories, corresponding to approximately 5.35 kcal/g—PragSoluções Serviços e Comércio Ltda, Jaú, SP, Brazil) (Table 1) for 4 months (n = 20/group). After sixteen weeks, lean and obese mice were subdivided into (n = 10/group): i) CNT (CNT + vehicle); ii) CNT supplemented with ZO (CNT + ZO); iii) obese mice (DIO + vehicle) ; iv) obese mice supplemented with ZO (DIO + ZO) (n = 10). The study protocol was approved by the Ethics Committee of the Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil (n. 059/2017-1) and conducted by trained researchers. 2.2. ZO supplementation A dry extract of ZO was acquired from Essential Nutrition® (Florianóplis, Brazil), presenting 5.2% gingerols (6-gingerdiol, 6-gingerol, 8-gingerol, 6-shagaol, 10-gingerol). The extract was dissolved in drinking water and supplemented at a dose of 400 mg/kg∙day by oral gavage for 35 consecutive days, this dose is safe for chronic treatment (Nammi et al. 2009 ; Luciano et al. 2021 ). In addition, non-supplemented groups (DIO + vehicle and CNT + vehicle) were supplemented daily with potable water via oral gavage for 35 days. The size of the cannula was sufficient to reach the oropharynx. During the supplementation period, both groups continued to receive their respective diets. 2.3. Behavior tasks The open field test is used to evaluate spontaneous locomotor activity and anxiety. The experiments were conducted in a sound-attenuated room under low-intensity light. The mice (n = 10 per group) were randomly placed into individual square wooden boxes (40 × 60 × 50 cm) that were positioned on the floor of a soundproof and diffusely illuminated room for 5 min. The locomotor activity (number of crossing) and exploratory activity (number of rearing) were evaluated for 5 min. A crossing was registered when the animal crossed the square with the four legs and the rearing characterized by the lifting of the animal supported by the hind legs (Tramontin et al 2021 ). The learning and memory function was analyzed by object recognition task. In the same cage used in open field, the recognition memory task was performed as previously described (de Oliveira et al. 2020 ). In the training day the mice were familiarized with two identical plastic objects that were placed 8.5 cm from the walls of the cage, the explored time was recorded. Following 60 min the novel-place test trial was performed to analyze the short-term memory and, the mice were returned to their home cages. In this tests, one of the objects was replaced with a novel object that differed in shape, color, and texture. All of the objects and the arena were thoroughly cleaned with 10% ethanol between trials to remove any residual odors. The number of times that the animal explored each object during the familiarization training and the testing trials was recorded. Each exploration was defined as an act in which the mouse would approach the object with the nose (within 1 cm), sniff, and touch the object with the tip of its nose and/or with its paws. It was not considered to be explorative activity when the mouse either stood next to the object or on top of it. The anxiety like behavior was analyzed in the plus maze task. The apparatus, made of wood and formica, consists of two open arms (18 x 6 cm), opposite two closed arms (18 x 6 cm), raised 60 cm from the floor. The junction area of the four arms (central platform) measures 6 x 6 cm. The experiments were conducted in a low light environment (12 lux). Mouse was placed on the central platform facing a closed arm. The animals were observed for a period of 5 minutes. The following parameters were analyzed: the number of entries and the time spent in the open arms (an entry was considered when the four legs of the animal were inside the arm). These data were used to calculate the percentage of entries in the open arms [% EA: entries in the open arms / (entry in the open arms + entries in the closed arms) x 100] and percentage of permanence in the open arms [% TBA: time in the arms open / (time in open arms + time in closed arms) x100]. 2.4. Biochemical analyzes 2.4.1 Species reactivity with difluorescein diacetate (DCFH) Reactive species levels were in the cortex were measured based on the oxidation of a 2',7'-dichlorodihydrofluorescein (DCF) acetate probe into a 2',7'-dichlorodihydrofluorescein fluorescent compound in the cortex as previously described (Tramontin et al 2021 ). Briefly, samples was incubated with 80 mM DCF-DA The production of reactive species was quantified using a standard curve of DCF and the data were expressed as mol DCF/mg protein. 2.4.2. Nitric oxide formation indicator The production of nitric oxide (NO) was evaluated in the cortex through stable nitrite dioxide (NO2) in the cortex. The nitrite content was calculated from the standard curve of sodium nitrite (NaNO2)—0 to 200 nM. The results were expressed in µmol nitrite / mg protein (Tramontin et al 2021 ). 2.4.3 Superoxide Dismutase (SOD) The activity of the SOD enzyme was estimated in the cortex by inhibiting the auto-oxidation of adrenaline and reading at a wavelength of 480 nm in the cortex. The results were expressed as U/mg protein (Tramontin et al 2021 ). 2.4.4. Catalase activity The activity of CAT was determined in the cortex by the decay rate of hydrogen peroxide, analyzed in a spectrophotometer at 240 nm, as previously described by Aebi. The results were expressed as U/mg protein (Tramontin et al 2021 ). 2.4.5. Carbonylation of protein The oxidative damage in proteins was measured in the cortex using the determination of carbonyl groups based on reaction with dinitrophenylhydrazine, as previously described by Levine. The carbonyl content was determined spectrophotometrically at 370 nm using the 22,000 M coefficient (Tramontin et al 2021 ). 2.5. Elisa After the treatments animals were euthanized and the cortex was dissected and homogenized in lysis buffer (NaCl, MgCl2, KCl, 1.5 M Tris, triton, glycerol, orthovanadate, aprotinin, pyrophosphate, and phenylmethylsulfonyl fluoride) and frozen at − 80°C until analysis. The IL-1β and TNF-alpha cytokines were analyzed in the cortex using ELISA, according to the manufacturer's specifications (ThermoFisher Scientific, USA). The BDNF and NGF-β were analyzed using ELISA, according to the manufacturer's specifications. 3. Statistical Analysis The results were expressed as mean ± standard deviation. The obtained data were tested for normality (Shapiro-Wilk test) and equality of variance (Levene test) and analyzed statistically by one-way ANOVA test. This was followed by post hoc analysis using Tukey’s test in parametric data or Kruskal-Wallis test in nonparametric data. In order to evaluate the effect of diet or ZO alone, a student's t-test was used within the same diet group using GraphPad Prism 6.0 software. The data from elevated plus maze was evaluated by nonparametric statistical tests. Differences between groups were considered significant when p < 0.05. 4. Results The recognition memory, evaluated by recognition index was higher in all groups, CNT, CNT + ZO, and DIO + ZO, except to DIO + vehicle group, which had no difference between new and old object (Fig. 1 A, * new object > old object, p other groups, p < 0.05), while there were no differences between the groups regarding the number of rearing (Fig. 1 C). In the plus maze task, the percentage of time the animals remained in the open arms and the number of entries in the open arms were similar in all groups (Figure D and E). The evaluation of biochemical parameters on the cerebral cortex showed an increase in DCFH levels in the cortex in the DIO group compared to the CNT and DIO + ZO (Fig. 2 A, * DIO > CNT and DIO + ZO, p CNT and DIO + ZO, p < 0.05). There were no significant differences in the levels of SOD activity between the groups (Fig. 2 D). The DIO group showed a reduction in catalase activity when compared to other groups (Fig. 2 E, * DIO < CNT, CNT + AO and DIO + AO). The cerebral cortex did not show any difference regarding to the levels of TNF-α, IL1-β, and IL-4 (Fig. 3 A, B and C). Moreover, no significant differences were demonstrated in any of the groups, concerning the levels of neurotrophins BDNF and β-NGF (Fig. 3 D and E). 5. Discussion Consumption of saturated fat has been linked to oxidative stress, inflammation, reduced synaptic plasticity, and an increase in neuronal apoptosis, which can impair cognitive function. ROS can cause damage to cells and tissues, including the brain, leading to inflammation and cellular dysfunction. Treatments for obesity are scarce and in need of new options. Our results showed that ZO supplementation reverse cognitive impairment and oxidative parameters in the cortex after the establishment of obesity. Obesity has been linked to cognitive decline and neurodegenerative diseases (Pasinetti and Eberstein 2008 ). Diets rich in fats and sugars not only compromise physiological health but also affect brain regions responsible for cognitive function (Pedroso et al. 2016 ). Studies on mice fed a high-fat diet have shown impaired recognition memory and spatial learning (Denver et al. 2018 ). In our findings, DIO over 4 months led to impaired recognition memory, which was reversed in obese animals supplemented with ZO for 35 days. Additionally, ginger supplementation reversed the detrimental effects of excessive oil consumption on spatial and recognition memory (Zarei et al. 2021 ). Ginger extract has also been found to enhance rats' ability to recognize new objects (Lim et al. 2014 ) and improve short-term memory function compared to long-term memory (Khaliq et al. 2017 ). Neurons are vulnerable to oxidative damage, with obesity exacerbating neuronal fatty acid metabolism and ROS production, resulting in neuronal membrane peroxidation and apoptosis (Gancheva et al. 2017 ). In animals subjected to 8 weeks of DIO regimen, levels of malondialdehyde (MDA) in both peripheral and central tissues increased, exacerbating cerebral lipid peroxidation (Park t al. 2010). ZO extract enhanced antioxidant activity in the cortex of DIO mice by up regulating catalase activity, reducing DCFH production, and lowering protein carbonylation levels. Cognitive impairments stemming from neurodegenerative processes may stem from heightened oxidative stress (Sah et al. 2017 ). Ginger extract has been shown to diminish cerebral infarction and enhance cognitive function in rats, notably by bolstering antioxidant activity in the hippocampus and cortex (Wattanathorn et al. 2011 ). Additionally, ginger protects the brain from oxidative stress neurotoxicity induced by high doses of topiramate (Mabrouk et al. 2022 ), aligning with our study's findings, wherein ZO supplementation potentially improves recognition memory through enhanced antioxidant status and reduced oxidative stress. The findings on anxiogenic effects resulting from dietary protocols vary; while a western diet high in saturated fatty acids is linked to anxiety and depressive states (Jang et al. 2019 ), DIO does not necessarily exhibit signs of anxiety (Hryhorczuk et al. 2017). In our study, DIO did not impact the evaluated anxiety parameters. The brain demonstrates considerable adaptive capacity, and the effects of DIO may be time-dependent (Muller et al. 2013 ); thus, after 5 months, these effects on parameters might no longer be present, or other changes associated with metabolic parameters may be necessary. A western diet inducing obesity resulted in fear memory impairment in rats, whereas 6-shogaol reversed these effects without affecting locomotor activity (Gabriel et al. 2020 ). Ginger has demonstrated potential anxiolytic effects, such as increasing the time spent in the open arms of the elevated plus-maze (Hasenöhrl et al. 1996 ) or decreasing the duration of stay in the closed arms (Vishwakarma et al. 2002 ), suggesting the presence of anxiolytic compounds in this nutraceutical. Additionally, compounds found in ginger are known to inhibit monoamine oxidase (MAO), as evidenced by both in silico and in vivo experiments. MAO inhibition is involved in the metabolism of certain neurotransmitters and is a mechanism of action for some antidepressant drugs (Moorkoth et al. 2021 )]. In our study, there were no differences between groups in the plus maze task. However, there was an increase in locomotor activity observed in the open field test in control animals supplemented with ZO, which may indicate the effects of this nutraceutical on metabolism and anxiety (Sestakova et al. 2013 ). DIO is known to trigger a state of low-grade inflammation characterized by adipocyte hypertrophy (Guillemot-Legris and Muccioli 2017). This peripheral inflammation has the potential to induce neuroinflammation, impacting mood, anxiety, and cognitive functions (Baker et al. 2017). Neuroinflammation induced by DIO involves activated macrophages, elevated levels of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α, and reduced levels and/or activity of neurotrophins such as BDNF and NGF (Cavaliere et al. 2019) with negative impact on cognition (Sahrma 2021). However, in our study, neither inflammation nor neurotrophin levels were affected by DIO or ZO supplementation. The effects of DIO on the brain may be rapid and transient (Kim et al. 2019 ), as could be the case with ginger supplementation (Pagano et al. 2021 ; Mohd and Makpol 2019). Therefore, longer-term consumption may induce adaptive changes without observable effects at the molecular level during experimental assessments. In conclusion, our research underscores the profound impact of ZO supplementation on cognitive function in DIO mice, highlighting its potential as a therapeutic intervention for cognitive impairment. Our findings not only demonstrate a reversal of cognitive deficits but also reveal a notable enhancement in antioxidant status. While our study did not observe significant alterations in the levels of pro-inflammatory cytokines and neurotrophins following treatment, it is imperative to acknowledge the intricate molecular dynamics that may have been modulated, particularly during the initial phases of the experiment. Overall, ZO emerges as a promising and safe phytochemical adjunct for addressing cognitive impairment associated with obesity. Declarations Funding source This work was supported by the Grant CNPq UNIVERSAL 2018, Fundação de Amparo a Pesquisa do Estado de Santa Catarina (FAPESC)-PPSUS-2016 e Universidade do Extremo Sul Catarinense (UNESC). Declaration of Competing Interest The authors declare no competing interests. CRediT authorship contribution statement Thais Fernandes Luciano: Conceptualization, Formal analysis, Data curation; Claudio Teodoro de Souza : Investigation, Conceptualization, Writing – original draft, Funding acquisition; Jade de Oilveira: Methodology, Formal analysis, Data curation; Alexandre Pastoris Muller: Conceptualization, Investigation, Conceptualization, Writing – original draft, Funding acquisition. References Baker K.D., Loughman A., Sar Spencer S.J., Reichelt A.C.The impact of obesity and hypercaloric diet consumption on anxiety and emotional behavior across the lifespan. Neurosci Biobehav Rev. 2017 Dec:83:173-182. doi: 10.1016/j.neubiorev.2017.10.014. Bocarsly ME, Fasolino M, Kane GA, LaMarca EA, Kirschen GW, Karatsoreos IN, McEwen BS, Gould E. Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15731-6. doi: 10.1073/pnas.1511593112. 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Park H.R., Park M., Choi J., Park K.Y., Chung H.Y., Lee J. A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett. 2010;b482(3):235-9. Pasinetti GM, Eberstein JA. Metabolic syndrome and the role of dietary lifestyles in Alzheimer's disease. J Neurochem. 2008;106(4):1503-14. Pedroso JA, Silveira MA, Lima LB, Furigo IC, Zampieri TT, Ramos-Lobo AM et al. Changes in Leptin Signaling by SOCS3 Modulate Fasting-Induced Hyperphagia and Weight Regain in Mice. Endocrinology. 2016; 157(10):3901-3914. Sah N., Peterson B.D., Lubejko S.T., Vivar C., van Praag H. Running reorganizes the circuitry of one-week-old adult-born hippocampal neurons. Sci Rep. 2017; 7(1):10903. Sestakova N., Puzserova A., Kluknavsky M., Bernatova I., Determination of motor activity and anxiety-related behaviour in rodents: methodological aspects and role of nitric oxide. Interdiscip Toxicol. 2013 Sep;6(3):126-35. doi: 10.2478/intox-2013-0020. Sharma S. High fat diet and its effects on cognitive health: alterations of neuronal and vascular components of brain. Physiol Behav. 2021 Oct 15;240:113528. doi: 10.1016/j.physbeh.2021.113528. Talebi M, İlgün S, Ebrahimi V, Talebi M, Farkhondeh T, Ebrahimi H, Samarghandian S. Zingiber officinale ameliorates Alzheimer's disease and Cognitive Impairments: Lessons from preclinical studies. Biomed Pharmacother. 2021 Jan;133:111088. doi: 10.1016/j.biopha.2020.111088. Tramontin N.S., Silveira PCL, TietbohlL.T.W., Pereira B.C., Simon K., Muller A.P. Effects of Low-Intensity Transcranial Pulsed Ultrasound Treatment in a Model of Alzheimer's Disease. Ultrasound Med Biol. 2021 Sep;47(9):2646-2656. doi: 10.1016/j.ultrasmedbio.2021.05.007. Tramontin, N.D.S., Luciano, T.F., Marques, S.O., de Souza, C.T. and Muller, A.P., Ginger and avocado as nutraceuticals for obesity and its comorbidities, Phytother Res. 2020, 34, 1282-1290 Valenzuela PL, Carrera-Bastos P, Castillo-García A, Lieberman DE, Santos-Lozano A, Lucia A. Obesity and the risk of cardiometabolic diseases. Nat Rev Cardiol. 2023 Jul;20(7):475-494. doi: 10.1038/s41569-023-00847-5. Vishwakarma SL, Pal SC, Kasture VS, Kasture SB. Anxiolytic and antiemetic activity of Zingiber officinale. Phytother Res. 2002;16(7):621-6. Wattanathorn J, Jittiwat J, Tongun T, Muchimapura S, Ingkaninan K. Zingiber officinale Mitigates Brain Damage and Improves Memory Impairment in Focal Cerebral Ischemic Rat. Evid Based Complement Alternat Med. 2011; 2011:429505. Zarei M., Uppin V., Acharya P., Talahalli R. Ginger and turmeric lipid-solubles attenuate heated oil-induced oxidative stress in the brain via the upregulation of NRF2 and improve cognitive function in rats. Metab Brain Dis 2021 Feb;36(2):225-238. doi: 10.1007/s11011-020-00642-y Zhang F, Zhang JG, Yang W, Xu P, Xiao YL, Zhang HT. 6-Gingerol attenuates LPS-induced neuroinflammation and cognitive impairment partially via suppressing astrocyte overactivation. Biomed Pharmacother. 2018 Nov;107:1523-1529. doi: 10.1016/j.biopha.2018.08.136 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 Aug, 2024 Read the published version in Metabolic Brain Disease → Version 1 posted Editorial decision: Revision requested 05 Jun, 2024 Reviews received at journal 03 Jun, 2024 Reviews received at journal 28 May, 2024 Reviews received at journal 20 May, 2024 Reviewers agreed at journal 20 May, 2024 Reviewers agreed at journal 20 May, 2024 Reviewers agreed at journal 20 May, 2024 Reviewers invited by journal 20 May, 2024 Submission checks completed at journal 28 Apr, 2024 Editor assigned by journal 28 Apr, 2024 First submitted to journal 02 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4206815","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":296852818,"identity":"92f24cea-a41e-4c80-a2a6-9baa2d3cbde2","order_by":0,"name":"Thais Fernandes Luciano","email":"","orcid":"","institution":"Universidade do Extremo Sul Catarinense (UNESC)","correspondingAuthor":false,"prefix":"","firstName":"Thais","middleName":"Fernandes","lastName":"Luciano","suffix":""},{"id":296852821,"identity":"9d683072-8730-4200-891c-24996546c9e3","order_by":1,"name":"Claudio Teodoro Souza","email":"","orcid":"","institution":"Universidade Federal de Juiz de Fora","correspondingAuthor":false,"prefix":"","firstName":"Claudio","middleName":"Teodoro","lastName":"Souza","suffix":""},{"id":296852824,"identity":"b2975e64-24bc-4508-8e8c-3e3da9574cb2","order_by":2,"name":"Jade Oilveira","email":"","orcid":"","institution":"Universidade Federal do Rio Grande do Sul (UFRGS)","correspondingAuthor":false,"prefix":"","firstName":"Jade","middleName":"","lastName":"Oilveira","suffix":""},{"id":296852826,"identity":"0d6f0079-7b59-4e9e-856e-b3f5c57c1dc4","order_by":3,"name":"Alexandre Pastoris Muller","email":"data:image/png;base64,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","orcid":"","institution":"Federal University of Santa Catarina (UFSC)","correspondingAuthor":true,"prefix":"","firstName":"Alexandre","middleName":"Pastoris","lastName":"Muller","suffix":""}],"badges":[],"createdAt":"2024-04-02 12:52:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4206815/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4206815/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11011-024-01406-8","type":"published","date":"2024-08-09T15:57:48+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55783048,"identity":"ed565335-94b5-4ca1-874c-99b7b962eda3","added_by":"auto","created_at":"2024-05-03 05:47:23","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":63215,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffects of \u003c/strong\u003e\u003cem\u003eZingiber officinale\u003c/em\u003e \u003cstrong\u003e(ZO) supplementation on cognitive performance and mood parameters on DIO mice. \u003c/strong\u003eA) Recognition memory (* index recognition, new object \u0026gt; old object, p \u0026lt; 0.05). B) Number of crossing in the open field (*CNT ZO \u0026gt; Control, p \u0026lt; 0.05). (C) Number of rearings in the open field. D) Number of entries in open arms. E) Time spent in the open arms. The results of recognition memory and open field are expressed as the mean ± standard deviation. The results of plus maze are expressed as the median and interquartile range. Data were collected from 8–10 animals per group.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4206815/v1/7bb76ac1af3d69ed9ca3f026.jpg"},{"id":55783047,"identity":"78be9fb2-9003-4a50-896a-cb4e326f6cde","added_by":"auto","created_at":"2024-05-03 05:47:23","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57655,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffects of \u003c/strong\u003e\u003cem\u003eZingiber officinale\u003c/em\u003e \u003cstrong\u003e(ZO) supplementation on\u003c/strong\u003e \u003cstrong\u003eproduction of oxidants, oxidative damage and antioxidant defense system in DIO mice. \u003c/strong\u003eA) DCFH levels on cortex (* DIO \u0026gt; CNT and DIO + ZO, p \u0026lt; 0.05). B) Nitrite levels on cortex. C) Carbonyl content of protein on cortex (* DIO \u0026gt; CNT and DIO + ZO, p \u0026lt; 0.05). D) SOD activity on cortex. E) Catalase activity on cortex (* DIO \u0026lt; CNT, CNT + AO and DIO + AO, p \u0026lt; 0.05). Data are expressed as mean ± standard deviation of the mean (n = 5-7 animals per group).\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4206815/v1/c37928eb84684038e0752c21.jpg"},{"id":55783049,"identity":"011ce9dc-ccc7-401b-a198-3c4fb63102ce","added_by":"auto","created_at":"2024-05-03 05:47:23","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43708,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffects of \u003c/strong\u003e\u003cem\u003eZingiber officinale\u003c/em\u003e \u003cstrong\u003e(ZO) supplementation on neurotrophins and inflammatory status in DIO mice. \u003c/strong\u003eA) TNF-β. B) Il-1β. C) IL-4. D) BDNF and E) β-NGF. Data are expressed as mean ± standard deviation of the mean (n = 4-6 animals per group).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4206815/v1/d05db9964064df2918de62a2.jpg"},{"id":62298485,"identity":"eda63884-ab47-4554-8e26-8ad1814f09f9","added_by":"auto","created_at":"2024-08-12 16:13:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":636317,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4206815/v1/8fc00b1f-a28e-496a-b0eb-2fca3f05eada.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Reversal of High-Fat Diet-Induced Cognitive Impairment and Oxidative Stress in the Brain through Zingiber officinale Supplementation","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eObesity presents a significant health concern, correlating with various adverse health outcomes, including an elevated risk of heart disease and diabetes (Haslam and James 2005; Valenzuela et al. \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Recent studies have proposed an adipose-brain axis, linking increased adipose mass with cognitive decline and a heightened susceptibility to dementia (Oliveras-Ca\u0026ntilde;ellas et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). High consumption of saturated fat has been associated with diminished synaptic plasticity and neuronal apoptosis, both contributing to impair cognitive function (Moraes et al. 2024) [4]. Additionally, animals with diet-induced obesity (DIO) have exhibited poorer performance in tasks requiring the prefrontal cortex, such as the recognition of novel objects (Bocarsly et al \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) even if the exposition to DIO were short period (de Paula et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDIO has been shown to elevate oxidative stress and inflammation within the brain, potentially impairing cognitive function and heightening the risk of dementia (Miller and Spencer \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2014\u003c/span\u003e, Souza et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2024\u003c/span\u003e.). The underlying mechanisms of this association are intricate and not yet fully elucidated. It is postulated that the accumulation of body fat can instigate metabolic alterations, heightened lipoperoxidation, and immune system activation, ultimately culminating in brain damage. Both oxidative stress and inflammation are capable of inflicting harm upon brain cells, thereby fostering cognitive decline and augmenting the likelihood of dementia development (Cherbuin et al \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2012\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePharmacological treatments for obesity are limited and may pose serious adverse effects, prompting many individuals to explore alternative therapies. Among these, ginger stands out as one of the most promising natural compounds for adjunctive obesity treatment (Tramontin et al. 202). Ginger encompasses various phytochemicals, such as phenols, flavonoids, terpenoids, gingerol, and zingerone, which possess anti-inflammatory, antioxidant, and antiemetic properties (Palatty et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Grzanna et al \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). Studies indicate that ginger extract exhibits antioxidant potential, enhancing the activity of key antioxidant enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) while mitigating the production of reactive oxygen species (ROS) (Morvaridzadeh et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGinger supplementation has demonstrated a favorable impact on various aspects of brain health, encompassing the reduction of neuroinflammation, enhancement of cognitive function, and alleviation of anxiety (Zhang et al. \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). In individuals afflicted with chronic inflammatory conditions, ginger supplementation has been observed to significantly decrease TNF-α levels (Morvaridzadeh et al. 2020). Furthermore, ginger supplementation has been associated with enhanced levels of neurotrophins and diminished oxidative stress and inflammation in the cerebral cortex (Choi et al \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Notably, both ginger and its constituents exhibit notable efficacy in ameliorating memory dysfunctions (Talebi et al. \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chang-Yul et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). These findings underscore the potential of ginger as an adjunctive treatment for conditions pertaining to brain health and function. The study aimed to assess the effects of ginger supplementation on cognitive function, anxiety levels, neurotrophin levels, as well as inflammatory and oxidative status in the cortex following DIO in mice.\u003c/p\u003e"},{"header":"2. Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Characterization of animals and diet\u003c/h2\u003e \u003cp\u003eSwiss male mice, 2 months old, were housed with water and food ad libitum. The animals were kept on a 12:12 h light-dark cycle and maintained at 20\u0026thinsp;\u0026plusmn;\u0026thinsp;2 \u0026ordm;C at UNESC facilities. The study was conducted in accordance with the Brazilian Guidelines for the Care and Use of Animals for Scientific and Didactic Purposes (DOU 27/5/13;MCTI, p. 7). Animals were divided into two groups: control (CNT), fed on standard rodent chow (53.0% carbohydrates, 22.0% proteins, 4% lipids\u0026mdash;relative to calories, corresponding to approximately 2.9 kcal/g\u0026mdash;Puro Lab 22PB; Porto Alegre, RS, Brazil), and a high-fat diet (DIO) [26% carbohydrates, 14.9% proteins, 59% lipids (oil and lard)] relative to calories, corresponding to approximately 5.35 kcal/g\u0026mdash;PragSolu\u0026ccedil;\u0026otilde;es Servi\u0026ccedil;os e Com\u0026eacute;rcio Ltda, Ja\u0026uacute;, SP, Brazil) (Table\u0026nbsp;1) for 4 months (n\u0026thinsp;=\u0026thinsp;20/group). After sixteen weeks, lean and obese mice were subdivided into (n\u0026thinsp;=\u0026thinsp;10/group): i) CNT (CNT\u0026thinsp;+\u0026thinsp;vehicle); ii) CNT supplemented with ZO (CNT\u0026thinsp;+\u0026thinsp;ZO); iii) obese mice (DIO\u0026thinsp;+\u0026thinsp;vehicle) ; iv) obese mice supplemented with ZO (DIO\u0026thinsp;+\u0026thinsp;ZO) (n\u0026thinsp;=\u0026thinsp;10). The study protocol was approved by the Ethics Committee of the Universidade do Extremo Sul Catarinense, Crici\u0026uacute;ma, SC, Brazil (n. 059/2017-1) and conducted by trained researchers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. ZO supplementation\u003c/h2\u003e \u003cp\u003eA dry extract of ZO was acquired from Essential Nutrition\u0026reg; (Florian\u0026oacute;plis, Brazil), presenting 5.2% gingerols (6-gingerdiol, 6-gingerol, 8-gingerol, 6-shagaol, 10-gingerol). The extract was dissolved in drinking water and supplemented at a dose of 400 mg/kg∙day by oral gavage for 35 consecutive days, this dose is safe for chronic treatment (Nammi et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Luciano et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In addition, non-supplemented groups (DIO\u0026thinsp;+\u0026thinsp;vehicle and CNT\u0026thinsp;+\u0026thinsp;vehicle) were supplemented daily with potable water via oral gavage for 35 days. The size of the cannula was sufficient to reach the oropharynx. During the supplementation period, both groups continued to receive their respective diets.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Behavior tasks\u003c/h2\u003e \u003cp\u003eThe open field test is used to evaluate spontaneous locomotor activity and anxiety. The experiments were conducted in a sound-attenuated room under low-intensity light. The mice (n\u0026thinsp;=\u0026thinsp;10 per group) were randomly placed into individual square wooden boxes (40 \u0026times; 60 \u0026times; 50 cm) that were positioned on the floor of a soundproof and diffusely illuminated room for 5 min. The locomotor activity (number of crossing) and exploratory activity (number of rearing) were evaluated for 5 min. A crossing was registered when the animal crossed the square with the four legs and the rearing characterized by the lifting of the animal supported by the hind legs (Tramontin et al \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe learning and memory function was analyzed by object recognition task. In the same cage used in open field, the recognition memory task was performed as previously described (de Oliveira et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In the training day the mice were familiarized with two identical plastic objects that were placed 8.5 cm from the walls of the cage, the explored time was recorded. Following 60 min the novel-place test trial was performed to analyze the short-term memory and, the mice were returned to their home cages. In this tests, one of the objects was replaced with a novel object that differed in shape, color, and texture. All of the objects and the arena were thoroughly cleaned with 10% ethanol between trials to remove any residual odors. The number of times that the animal explored each object during the familiarization training and the testing trials was recorded. Each exploration was defined as an act in which the mouse would approach the object with the nose (within 1 cm), sniff, and touch the object with the tip of its nose and/or with its paws. It was not considered to be explorative activity when the mouse either stood next to the object or on top of it.\u003c/p\u003e \u003cp\u003eThe anxiety like behavior was analyzed in the plus maze task. The apparatus, made of wood and formica, consists of two open arms (18 x 6 cm), opposite two closed arms (18 x 6 cm), raised 60 cm from the floor. The junction area of the four arms (central platform) measures 6 x 6 cm. The experiments were conducted in a low light environment (12 lux). Mouse was placed on the central platform facing a closed arm. The animals were observed for a period of 5 minutes. The following parameters were analyzed: the number of entries and the time spent in the open arms (an entry was considered when the four legs of the animal were inside the arm). These data were used to calculate the percentage of entries in the open arms [% EA: entries in the open arms / (entry in the open arms\u0026thinsp;+\u0026thinsp;entries in the closed arms) x 100] and percentage of permanence in the open arms [% TBA: time in the arms open / (time in open arms\u0026thinsp;+\u0026thinsp;time in closed arms) x100].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Biochemical analyzes\u003c/h2\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.4.1 Species reactivity with difluorescein diacetate (DCFH)\u003c/h2\u003e \u003cp\u003eReactive species levels were in the cortex were measured based on the oxidation of a 2',7'-dichlorodihydrofluorescein (DCF) acetate probe into a 2',7'-dichlorodihydrofluorescein fluorescent compound in the cortex as previously described (Tramontin et al \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Briefly, samples was incubated with 80 mM DCF-DA The production of reactive species was quantified using a standard curve of DCF and the data were expressed as mol DCF/mg protein.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e2.4.2. Nitric oxide formation indicator\u003c/h2\u003e \u003cp\u003eThe production of nitric oxide (NO) was evaluated in the cortex through stable nitrite dioxide (NO2) in the cortex. The nitrite content was calculated from the standard curve of sodium nitrite (NaNO2)\u0026mdash;0 to 200 nM. The results were expressed in \u0026micro;mol nitrite / mg protein (Tramontin et al \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e2.4.3 Superoxide Dismutase (SOD)\u003c/h2\u003e \u003cp\u003eThe activity of the SOD enzyme was estimated in the cortex by inhibiting the auto-oxidation of adrenaline and reading at a wavelength of 480 nm in the cortex. The results were expressed as U/mg protein (Tramontin et al \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.4.4. Catalase activity\u003c/h2\u003e \u003cp\u003eThe activity of CAT was determined in the cortex by the decay rate of hydrogen peroxide, analyzed in a spectrophotometer at 240 nm, as previously described by Aebi. The results were expressed as U/mg protein (Tramontin et al \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e2.4.5. Carbonylation of protein\u003c/h2\u003e \u003cp\u003eThe oxidative damage in proteins was measured in the cortex using the determination of carbonyl groups based on reaction with dinitrophenylhydrazine, as previously described by Levine. The carbonyl content was determined spectrophotometrically at 370 nm using the 22,000 M coefficient (Tramontin et al \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Elisa\u003c/h2\u003e \u003cp\u003eAfter the treatments animals were euthanized and the cortex was dissected and homogenized in lysis buffer (NaCl, MgCl2, KCl, 1.5 M Tris, triton, glycerol, orthovanadate, aprotinin, pyrophosphate, and phenylmethylsulfonyl fluoride) and frozen at \u0026minus;\u0026thinsp;80\u0026deg;C until analysis. The IL-1β and TNF-alpha cytokines were analyzed in the cortex using ELISA, according to the manufacturer's specifications (ThermoFisher Scientific, USA). The BDNF and NGF-β were analyzed using ELISA, according to the manufacturer's specifications.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Statistical Analysis","content":"\u003cp\u003eThe results were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. The obtained data were tested for normality (Shapiro-Wilk test) and equality of variance (Levene test) and analyzed statistically by one-way ANOVA test. This was followed by post hoc analysis using Tukey\u0026rsquo;s test in parametric data or Kruskal-Wallis test in nonparametric data. In order to evaluate the effect of diet or ZO alone, a student's t-test was used within the same diet group using GraphPad Prism 6.0 software. The data from elevated plus maze was evaluated by nonparametric statistical tests. Differences between groups were considered significant when p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"4. Results","content":"\u003cp\u003eThe recognition memory, evaluated by recognition index was higher in all groups, CNT, CNT\u0026thinsp;+\u0026thinsp;ZO, and DIO\u0026thinsp;+\u0026thinsp;ZO, except to DIO\u0026thinsp;+\u0026thinsp;vehicle group, which had no difference between new and old object (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, * new object\u0026thinsp;\u0026gt;\u0026thinsp;old object, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In the open field, the CNT\u0026thinsp;+\u0026thinsp;ZO group showed a higher number of crossings than the Control\u0026thinsp;+\u0026thinsp;vehicle group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB, * Control\u0026thinsp;+\u0026thinsp;ZO\u0026thinsp;\u0026gt;\u0026thinsp;other groups, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while there were no differences between the groups regarding the number of rearing (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). In the plus maze task, the percentage of time the animals remained in the open arms and the number of entries in the open arms were similar in all groups (Figure D and E).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe evaluation of biochemical parameters on the cerebral cortex showed an increase in DCFH levels in the cortex in the DIO group compared to the CNT and DIO\u0026thinsp;+\u0026thinsp;ZO (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, * DIO\u0026thinsp;\u0026gt;\u0026thinsp;CNT and DIO\u0026thinsp;+\u0026thinsp;ZO, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The nitrite levels did not differ between groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Protein carbonylation was increased in the DIO group compared to the CNT and DIO\u0026thinsp;+\u0026thinsp;ZO groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, * DIO\u0026thinsp;\u0026gt;\u0026thinsp;CNT and DIO\u0026thinsp;+\u0026thinsp;ZO, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There were no significant differences in the levels of SOD activity between the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). The DIO group showed a reduction in catalase activity when compared to other groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, * DIO\u0026thinsp;\u0026lt;\u0026thinsp;CNT, CNT\u0026thinsp;+\u0026thinsp;AO and DIO\u0026thinsp;+\u0026thinsp;AO).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe cerebral cortex did not show any difference regarding to the levels of TNF-α, IL1-β, and IL-4 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, B and C). Moreover, no significant differences were demonstrated in any of the groups, concerning the levels of neurotrophins BDNF and β-NGF (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD and E).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"5. Discussion","content":"\u003cp\u003eConsumption of saturated fat has been linked to oxidative stress, inflammation, reduced synaptic plasticity, and an increase in neuronal apoptosis, which can impair cognitive function. ROS can cause damage to cells and tissues, including the brain, leading to inflammation and cellular dysfunction. Treatments for obesity are scarce and in need of new options. Our results showed that ZO supplementation reverse cognitive impairment and oxidative parameters in the cortex after the establishment of obesity.\u003c/p\u003e \u003cp\u003eObesity has been linked to cognitive decline and neurodegenerative diseases (Pasinetti and Eberstein \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Diets rich in fats and sugars not only compromise physiological health but also affect brain regions responsible for cognitive function (Pedroso et al. \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Studies on mice fed a high-fat diet have shown impaired recognition memory and spatial learning (Denver et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). In our findings, DIO over 4 months led to impaired recognition memory, which was reversed in obese animals supplemented with ZO for 35 days. Additionally, ginger supplementation reversed the detrimental effects of excessive oil consumption on spatial and recognition memory (Zarei et al. \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Ginger extract has also been found to enhance rats' ability to recognize new objects (Lim et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) and improve short-term memory function compared to long-term memory (Khaliq et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNeurons are vulnerable to oxidative damage, with obesity exacerbating neuronal fatty acid metabolism and ROS production, resulting in neuronal membrane peroxidation and apoptosis (Gancheva et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). In animals subjected to 8 weeks of DIO regimen, levels of malondialdehyde (MDA) in both peripheral and central tissues increased, exacerbating cerebral lipid peroxidation (Park t al. 2010). ZO extract enhanced antioxidant activity in the cortex of DIO mice by up regulating catalase activity, reducing DCFH production, and lowering protein carbonylation levels. Cognitive impairments stemming from neurodegenerative processes may stem from heightened oxidative stress (Sah et al. \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Ginger extract has been shown to diminish cerebral infarction and enhance cognitive function in rats, notably by bolstering antioxidant activity in the hippocampus and cortex (Wattanathorn et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Additionally, ginger protects the brain from oxidative stress neurotoxicity induced by high doses of topiramate (Mabrouk et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), aligning with our study's findings, wherein ZO supplementation potentially improves recognition memory through enhanced antioxidant status and reduced oxidative stress.\u003c/p\u003e \u003cp\u003eThe findings on anxiogenic effects resulting from dietary protocols vary; while a western diet high in saturated fatty acids is linked to anxiety and depressive states (Jang et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), DIO does not necessarily exhibit signs of anxiety (Hryhorczuk et al. 2017). In our study, DIO did not impact the evaluated anxiety parameters. The brain demonstrates considerable adaptive capacity, and the effects of DIO may be time-dependent (Muller et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2013\u003c/span\u003e); thus, after 5 months, these effects on parameters might no longer be present, or other changes associated with metabolic parameters may be necessary. A western diet inducing obesity resulted in fear memory impairment in rats, whereas 6-shogaol reversed these effects without affecting locomotor activity (Gabriel et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGinger has demonstrated potential anxiolytic effects, such as increasing the time spent in the open arms of the elevated plus-maze (Hasen\u0026ouml;hrl et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e1996\u003c/span\u003e) or decreasing the duration of stay in the closed arms (Vishwakarma et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2002\u003c/span\u003e), suggesting the presence of anxiolytic compounds in this nutraceutical. Additionally, compounds found in ginger are known to inhibit monoamine oxidase (MAO), as evidenced by both \u003cem\u003ein silico\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e experiments. MAO inhibition is involved in the metabolism of certain neurotransmitters and is a mechanism of action for some antidepressant drugs (Moorkoth et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)]. In our study, there were no differences between groups in the plus maze task. However, there was an increase in locomotor activity observed in the open field test in control animals supplemented with ZO, which may indicate the effects of this nutraceutical on metabolism and anxiety (Sestakova et al. \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDIO is known to trigger a state of low-grade inflammation characterized by adipocyte hypertrophy (Guillemot-Legris and Muccioli 2017). This peripheral inflammation has the potential to induce neuroinflammation, impacting mood, anxiety, and cognitive functions (Baker et al. 2017). Neuroinflammation induced by DIO involves activated macrophages, elevated levels of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α, and reduced levels and/or activity of neurotrophins such as BDNF and NGF (Cavaliere et al. 2019) with negative impact on cognition (Sahrma 2021). However, in our study, neither inflammation nor neurotrophin levels were affected by DIO or ZO supplementation. The effects of DIO on the brain may be rapid and transient (Kim et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), as could be the case with ginger supplementation (Pagano et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Mohd and Makpol 2019). Therefore, longer-term consumption may induce adaptive changes without observable effects at the molecular level during experimental assessments.\u003c/p\u003e \u003cp\u003eIn conclusion, our research underscores the profound impact of ZO supplementation on cognitive function in DIO mice, highlighting its potential as a therapeutic intervention for cognitive impairment. Our findings not only demonstrate a reversal of cognitive deficits but also reveal a notable enhancement in antioxidant status. While our study did not observe significant alterations in the levels of pro-inflammatory cytokines and neurotrophins following treatment, it is imperative to acknowledge the intricate molecular dynamics that may have been modulated, particularly during the initial phases of the experiment. Overall, ZO emerges as a promising and safe phytochemical adjunct for addressing cognitive impairment associated with obesity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding source\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Grant CNPq UNIVERSAL 2018, Funda\u0026ccedil;\u0026atilde;o de Amparo a Pesquisa do Estado de Santa Catarina (FAPESC)-PPSUS-2016 e Universidade do Extremo Sul Catarinense (UNESC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThais Fernandes Luciano: Conceptualization, Formal analysis, Data curation; Claudio Teodoro de Souza\u003csup\u003e:\u0026nbsp;\u003c/sup\u003eInvestigation, Conceptualization, Writing \u0026ndash; original draft, Funding acquisition; Jade de Oilveira: Methodology, Formal analysis, Data curation;\u0026nbsp;Alexandre Pastoris Muller: Conceptualization,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eInvestigation, Conceptualization, Writing \u0026ndash; original draft, Funding acquisition. \u003csup\u003e\u0026nbsp;\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBaker K.D., Loughman A., Sar Spencer S.J., Reichelt A.C.The impact of obesity and hypercaloric diet consumption on anxiety and emotional behavior across the lifespan. 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PLoS One. 2009; 4(4):e5045.\u003c/li\u003e\n\u003cli\u003eMorvaridzadeh M., Fazelian S., Agah S., Khazdouz M., Rahimlou M., Agh F., Potter E., Heshmati S., Heshmati J. Effect of ginger (Zingiber officinale) on inflammatory markers: A systematic review and meta-analysis of randomized controlled trials). Cytokine. 2020 Nov:135:155224. doi: 10.1016/j.cyto.2020.155224\u003c/li\u003e\n\u003cli\u003eMorvaridzadeh M., Sadeghi E., Agah S., Fazelian S., Rahimlou M., Kern F.G., Heshmati S., Omidi A., Persad E., Heshmati J. Effect of ginger (Zingiber officinale) supplementation on oxidative stress parameters: A systematic review and meta-analysis. J Food Biochem. 2021 Feb;45(2):e13612. doi: 10.1111/jfbc.13612. \u003c/li\u003e\n\u003cli\u003eMuller AP, Dietrich Mde O, Martimbianco de Assis A, Souza DO, Portela LV. High saturated fat and low carbohydrate diet decreases lifespan independent of body weight in mice. Longev Healthspan. 2013 Jun 3;2(1):10. doi: 10.1186/2046-2395-2-10.\u003c/li\u003e\n\u003cli\u003eNammi S., Sreemantula S., Roufogalis BD. Protective effects of ethanolic extract of Zingiber officinale rhizome on the development of metabolic syndrome in high-fat diet-fed rats. Basic Clin Pharmacol Toxicol, 2009, 104, 366-373.\u003c/li\u003e\n\u003cli\u003eOliveras-Ca\u0026ntilde;ellas N., Castells-Nobau A., Vega-Correa L., Latorre-Luque J.4, Motger-Albert\u0026iacute; A., Arnoriaga-Rodriguez M., Garre-Olmo J., Zapata-Tona C., Coll-Mart\u0026iacute;nez C., Rami\u0026oacute;-Torrent\u0026agrave; L., Moreno-Navarrete J.M., JPuig J., Villarroya F, Ramos R., Casad\u0026oacute;-Anguera V, Mart\u0026iacute;n-Garc\u0026iacute;a E., Maldonado R., Mayneris-Perxachs J., Fern\u0026aacute;ndez-Real J.M. Adipose tissue coregulates cognitive function. Sci Adv 2023 Aug 11;9(32):eadg4017. doi: 10.1126/sciadv.adg4017 \u003c/li\u003e\n\u003cli\u003ePagano E., Souto E.B., Durazzo A., Sharifi-Rad J., Lucarini M., Souto S.B, Salehi B., Wissam Zam W., Montanaro V., Lucariello G., Izzo A.A., Santini A., Romano B. Ginger (Zingiber officinale Roscoe) as a nutraceutical: Focus on the metabolic, analgesic, and antiinflammatory effects. Phytother Res. 2021 May;35(5):2403-2417. doi: 10.1002/ptr.6964.\u003c/li\u003e\n\u003cli\u003ePalatty PL, Haniadka R, Valder B, Arora R, Baliga MS. Ginger in the prevention of nausea and vomiting: a review. Crit Rev Food Sci Nutr. 2013; 53(7):659-69. \u003c/li\u003e\n\u003cli\u003ePark H.R., Park M., Choi J., Park K.Y., Chung H.Y., Lee J. A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett. 2010;b482(3):235-9. \u003c/li\u003e\n\u003cli\u003ePasinetti GM, Eberstein JA. 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High fat diet and its effects on cognitive health: alterations of neuronal and vascular components of brain. Physiol Behav. 2021 Oct 15;240:113528. doi: 10.1016/j.physbeh.2021.113528.\u003c/li\u003e\n\u003cli\u003eTalebi M, İlg\u0026uuml;n S, Ebrahimi V, Talebi M, Farkhondeh T, Ebrahimi H, Samarghandian S. Zingiber officinale ameliorates Alzheimer\u0026apos;s disease and Cognitive Impairments: Lessons from preclinical studies. Biomed Pharmacother. 2021 Jan;133:111088. doi: 10.1016/j.biopha.2020.111088.\u003c/li\u003e\n\u003cli\u003eTramontin N.S., Silveira PCL, TietbohlL.T.W., Pereira B.C., Simon K., Muller A.P. Effects of Low-Intensity Transcranial Pulsed Ultrasound Treatment in a Model of Alzheimer\u0026apos;s Disease. Ultrasound Med Biol. 2021 Sep;47(9):2646-2656. doi: 10.1016/j.ultrasmedbio.2021.05.007. \u003c/li\u003e\n\u003cli\u003eTramontin, N.D.S., Luciano, T.F., Marques, S.O., de Souza, C.T. and Muller, A.P., Ginger and avocado as nutraceuticals for obesity and its comorbidities, Phytother Res. 2020, 34, 1282-1290\u003c/li\u003e\n\u003cli\u003eValenzuela PL, Carrera-Bastos P, Castillo-Garc\u0026iacute;a A, Lieberman DE, Santos-Lozano A, Lucia A. Obesity and the risk of cardiometabolic diseases. Nat Rev Cardiol. 2023 Jul;20(7):475-494. doi: 10.1038/s41569-023-00847-5.\u003c/li\u003e\n\u003cli\u003eVishwakarma SL, Pal SC, Kasture VS, Kasture SB. Anxiolytic and antiemetic activity of Zingiber officinale. Phytother Res. 2002;16(7):621-6.\u003c/li\u003e\n\u003cli\u003eWattanathorn J, Jittiwat J, Tongun T, Muchimapura S, Ingkaninan K. Zingiber officinale Mitigates Brain Damage and Improves Memory Impairment in Focal Cerebral Ischemic Rat. Evid Based Complement Alternat Med. 2011; 2011:429505. \u003c/li\u003e\n\u003cli\u003eZarei M., Uppin V., Acharya P., Talahalli R. Ginger and turmeric lipid-solubles attenuate heated oil-induced oxidative stress in the brain via the upregulation of NRF2 and improve cognitive function in rats. Metab Brain Dis 2021 Feb;36(2):225-238. doi: 10.1007/s11011-020-00642-y\u003c/li\u003e\n\u003cli\u003eZhang F, Zhang JG, Yang W, Xu P, Xiao YL, Zhang HT. 6-Gingerol attenuates LPS-induced neuroinflammation and cognitive impairment partially via suppressing astrocyte overactivation. Biomed Pharmacother. 2018 Nov;107:1523-1529. doi: 10.1016/j.biopha.2018.08.136\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"metabolic-brain-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mebr","sideBox":"Learn more about [Metabolic Brain Disease](https://www.springer.com/journal/11011)","snPcode":"11011","submissionUrl":"https://submission.nature.com/new-submission/11011/3","title":"Metabolic Brain Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Ginger, learning and memory, obesity, brain metabolism","lastPublishedDoi":"10.21203/rs.3.rs-4206815/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4206815/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObesity presents a significant health concern, correlating with various adverse health outcomes. Diet-induced obesity (DIO) has been associated with impair on cognitive function. Pharmacological treatments for obesity are limited and may pose serious adverse effects. Ginger possess anti-inflammatory and antioxidant effects in addition to metabolic effects. The study aimed to assess the effects of ginger supplementation on cognitive function, anxiety levels, neurotrophin levels, as well as inflammatory and oxidative status in the cortex following DIO in mice. Swiss male mice, 2 months old, were fed with DIO or standard chow for 4 months and after were subdivided into (n=10/group): i) CNT (CNT + vehicle); ii) CNT supplemented with ZO (CNT + ZO); iii) obese mice (DIO + vehicle) ; iv) obese mice supplemented with ZO (DIO + ZO) (n=10). Zingiber officinale (ZO) 400 mg/kg/day were supplemented for 35 days by oral gavage. DIO + vehicle group shown impaired on recognition memory task. CNT + ZO group showed a higher number of crossings in the open field. There were no difference between group in plus maze task. DIO + vehicle had increased the DCFH and carbonylation levels in cortex. The DIO + vehicle showed a reduction in catalase activity. The cerebral cortex did not show any difference regarding to inflammatory and neurotrophins markers. In conclusion, our findings indicate that supplementation with ZO reverses cognitive impairment in DIO mice and enhances antioxidant status in the cerebral cortex.\u003c/p\u003e","manuscriptTitle":"Reversal of High-Fat Diet-Induced Cognitive Impairment and Oxidative Stress in the Brain through Zingiber officinale Supplementation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-03 05:47:18","doi":"10.21203/rs.3.rs-4206815/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-06T02:41:38+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-03T22:56:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-28T21:29:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-20T22:26:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"251744919750725298283082651591482556465","date":"2024-05-20T20:46:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269060899980630683450153842938494694218","date":"2024-05-20T18:25:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"139834541619498653177990388487383265618","date":"2024-05-20T17:14:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-20T16:40:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-29T03:32:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-29T03:32:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Metabolic Brain Disease","date":"2024-04-02T12:50:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"metabolic-brain-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mebr","sideBox":"Learn more about [Metabolic Brain Disease](https://www.springer.com/journal/11011)","snPcode":"11011","submissionUrl":"https://submission.nature.com/new-submission/11011/3","title":"Metabolic Brain Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"45941116-1760-4d3a-a6ff-ee7aec9cf88a","owner":[],"postedDate":"May 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-12T16:04:24+00:00","versionOfRecord":{"articleIdentity":"rs-4206815","link":"https://doi.org/10.1007/s11011-024-01406-8","journal":{"identity":"metabolic-brain-disease","isVorOnly":false,"title":"Metabolic Brain Disease"},"publishedOn":"2024-08-09 15:57:48","publishedOnDateReadable":"August 9th, 2024"},"versionCreatedAt":"2024-05-03 05:47:18","video":"","vorDoi":"10.1007/s11011-024-01406-8","vorDoiUrl":"https://doi.org/10.1007/s11011-024-01406-8","workflowStages":[]},"version":"v1","identity":"rs-4206815","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4206815","identity":"rs-4206815","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}