{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:31:23Z","timestamp":1792027883712,"version":"4.4.0"},"reference-count":62,"publisher":"National Academy of Sciences","issue":"40","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008792","name":"NOVARTIS | Novartis Pharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012688","name":"Universit&#x00E4;t Rostock","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012688","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KI 1469\/8-1"],"award-info":[{"award-number":["KI 1469\/8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,10,4]]},"abstract":"<jats:p>\n                    Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing\u2013remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)\/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies in\n                    <jats:italic>Rag1<\/jats:italic>\n                    -deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes\/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects in\n                    <jats:italic>S1pr5<\/jats:italic>\n                    -deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon\u2013myelin unit.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2204509119","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T15:21:09Z","timestamp":1664205669000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":27,"title":["Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3245-482X","authenticated-orcid":false,"given":"Newshan","family":"Behrangi","sequence":"first","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"},{"name":"Department of Anatomy II, Ludwig Maximilians University of Munich, 80336 M\u00fcnchen (Munich), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4052-7125","authenticated-orcid":false,"given":"Leo","family":"Heinig","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Frintrop","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Santrau","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6864-4513","authenticated-orcid":false,"given":"Jens","family":"Kurth","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Krause","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1745-7755","authenticated-orcid":false,"given":"Dimitrinka","family":"Atanasova","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"},{"name":"Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"},{"name":"Department of Anatomy, Faculty of Medicine, Trakia University, 6003 Stara Zagora, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8180-7775","authenticated-orcid":false,"given":"Tim","family":"Clarner","sequence":"additional","affiliation":[{"name":"Institute of Neuroanatomy, Uniklinik Rheinisch-Westf\u00e4lische Technische Hochschule (RWTH) Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6973-3080","authenticated-orcid":false,"given":"Athanassios","family":"Fragoulis","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Joksch","sequence":"additional","affiliation":[{"name":"Core Facility Multi-Modal Small Animal Imaging, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9114-3805","authenticated-orcid":false,"given":"Henrik","family":"Rudolf","sequence":"additional","affiliation":[{"name":"Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven G.","family":"Meuth","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8654-8904","authenticated-orcid":false,"given":"Sarah","family":"Joost","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5043-9052","authenticated-orcid":false,"given":"Markus","family":"Kipp","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, 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