{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T13:53:29Z","timestamp":1791986009820,"version":"4.4.0"},"reference-count":32,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010882","name":"Tianjin Municipal Education Commission","doi-asserted-by":"publisher","award":["2023KJ116"],"award-info":[{"award-number":["2023KJ116"]}],"id":[{"id":"10.13039\/501100010882","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Objective<\/jats:title>\n This study aimed to clarify the role of sphingosine\u20101\u2010phosphate receptor 5 (S1PR5) in epileptic pathogenesis and the mechanism by which fingolimod exerts anti\u2010epileptic effects, with a focus on neuroinflammation and blood\u2013brain barrier (BBB) disruption.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Multi\u2010omics integration and machine learning were used to identify S1PR5 as a key candidate gene. Molecular docking was performed to verify the binding affinity between fingolimod and S1PR5. AAV\u2010mediated S1PR5 overexpression was conducted in mouse hippocampi before kainic acid (KA) administration. KA\u2010induced epileptic mice were randomly divided into control, model, and fingolimod intervention groups. Behavioral tests, qRT\u2010PCR, Western blot, immunofluorescence, ELISA, and Evans Blue assay were used for evaluations.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n S1PR5 expression was significantly downregulated in both epileptic patients and mouse hippocampi. Fingolimod bound stably to S1PR5 in silico. S1PR5 overexpression attenuated neuronal loss, microglial activation, and epileptic seizures in KA\u2010treated mice, confirming that S1PR5 exerts protective effects in epilepsy. Fingolimod intervention upregulated S1PR5 expression, inhibited abnormal activation of the Rho\/ROCK\/NF\u2010\u03baB pathway, restored tight junction proteins (Claudin\u20105 and ZO\u20101), reduced BBB leakage, and lowered proinflammatory cytokines (TNF\u2010\u03b1, IL\u20101\u03b2, IL\u20106). These changes were accompanied by alleviated seizure severity and frequency.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n S1PR5 serves as a protective regulator in epilepsy. Fingolimod exerts anti\u2010epileptic effects by upregulating S1PR5, thereby inhibiting the Rho\/ROCK\/NF\u2010\u03baB pathway, reducing neuroinflammation, and preserving BBB integrity. These findings support S1PR5 as a promising target and provide a mechanistic basis for repurposing fingolimod in epilepsy therapy.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/cns.71212","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T13:37:30Z","timestamp":1791985050000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fingolimod Alleviates Neuroinflammation and Blood\u2013Brain Barrier Disruption in Epilepsy by Upregulating\n S1PR5<\/scp>\n and Inhibiting the Rho\/\n ROCK<\/scp>\n \/\n NF<\/scp>\n \u2010\n \u03baB<\/scp>\n Pathway"],"prefix":"10.1002","volume":"32","author":[{"given":"Chen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology Tianjin Medical University General Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Neurology Tianjin Medical University General Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Zhaotong Hospital Affiliated to Kunming Medical University Zhaotong Yunnan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0626-5969","authenticated-orcid":false,"given":"Lin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology Tianjin Medical University General Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2196-9078","authenticated-orcid":false,"given":"Wei\u2010Na","family":"Jin","sequence":"additional","affiliation":[{"name":"China National Clinical Research Center for Neurological Diseases Beijing Tiantan Hospital, Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0036-1135","authenticated-orcid":false,"given":"Zhuoran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology Tianjin Medical University General Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"issue":"3","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.neurot.2023.e00308","article-title":"Neurostimulation Treatments for Epilepsy: Deep Brain Stimulation, Responsive Neurostimulation and Vagus Nerve Stimulation","volume":"21","author":"Gouveia F. 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