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The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG\n                    <jats:sub>35\u201355<\/jats:sub>\n                    immunized wild type (WT) and BDNF knock-out (BDNF\n                    <jats:sup>ko<\/jats:sup>\n                    ) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro\n                    <jats:italic>,<\/jats:italic>\n                    effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45\u00a0\u00b5g\/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDF\n                    <jats:sup>ko<\/jats:sup>\n                    . Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy.\n                  <\/jats:p>","DOI":"10.1038\/s41598-024-68715-x","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T12:04:29Z","timestamp":1722513869000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Siponimod treatment response shows partial BDNF dependency in multiple sclerosis models"],"prefix":"10.1038","volume":"14","author":[{"given":"Hasan H\u00fcseyin","family":"Hendek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Blusch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neele","family":"Heitmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Oberhagemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seray","family":"Demir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiomara","family":"Pedreiturria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Gold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Faissner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"issue":"12","key":"68715_CR1","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1038\/s41573-019-0035-2","volume":"18","author":"S Faissner","year":"2019","unstructured":"Faissner, S., et al. Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat. Rev. Drug. Discov. 18(12), 905\u2013922 (2019).","journal-title":"Nat. Rev. Drug. Discov."},{"key":"68715_CR2","doi-asserted-by":"publisher","first-page":"175628641987832","DOI":"10.1177\/1756286419878323","volume":"12","author":"S Faissner","year":"2019","unstructured":"Faissner, S. & Gold, R. Progressive multiple sclerosis: Latest therapeutic developments and future directions. Ther. Adv. Neurol. Disord. 12, 1756286419878323 (2019).","journal-title":"Ther. Adv. Neurol. Disord."},{"issue":"1","key":"68715_CR3","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1186\/s12974-016-0686-4","volume":"13","author":"A Gentile","year":"2016","unstructured":"Gentile, A. et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J. Neuroinflam. 13(1), 207 (2016).","journal-title":"J. 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RG serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, Merck and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. SF has received speaker\u2019s and\/or scientific board honoraria from Biogen, BMS, Celgene, Janssen, Merck, Neuraxpharm, Novartis and Roche and grant support from Ruhr-University Bochum, DFG, DMSG, Stiftung f\u00fcr therapeutische Forschung, Lead Discovery Center GmbH and Novartis.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17823"}}