{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:46:32Z","timestamp":1790703992783,"version":"4.1.0"},"reference-count":130,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MMRI PAS","award":["No. 7"],"award-info":[{"award-number":["No. 7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1\u2013S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia\/reperfusion (I\/R) injury and Alzheimer\u2019s disease (AD). In I\/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with \u03b2-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood\u2013brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I\/R injury and AD.<\/jats:p>","DOI":"10.3390\/ijms27125200","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T09:46:54Z","timestamp":1780998414000},"page":"5200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Sphingosine-1-Phosphate Signaling in Cerebral Ischemia\/Reperfusion Injury and Alzheimer\u2019s Disease Pathology"],"prefix":"10.3390","volume":"27","author":[{"given":"Kinga","family":"Czubowicz","sequence":"first","affiliation":[{"name":"Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4170-9732","authenticated-orcid":false,"given":"Joanna Agata","family":"Motyl","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Engineering, Department of Hybrid and Analytical Microbiosystems, Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Ks. Trojdena 4 St., 02-109 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4582-8250","authenticated-orcid":false,"given":"Agnieszka","family":"Wencel","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Engineering, Department of Hybrid and Analytical Microbiosystems, Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Ks. Trojdena 4 St., 02-109 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Piotr","family":"Strosznajder","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.tcb.2011.09.003","article-title":"Sphingosine-1-Phosphate Signaling and Its Role in Disease","volume":"22","author":"Maceyka","year":"2012","journal-title":"Trends Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1194\/jlr.D071068","article-title":"Fluorescence-Based Rapid Measurement of Sphingosine-1-Phosphate Transport Activity in Erythrocytes","volume":"57","author":"Kobayashi","year":"2016","journal-title":"J. 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