title: S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures.
abstract: Sphingosine-1-phosphate receptors (S1PRs) are drug targets for the compound FTY720, which is the first oral therapy developed for treatment of relapsing-remitting multiple sclerosis. S1PRs play a variety of functional roles in the differentiation, proliferation, survival and/or migration of neurons and glia. In this study, rat organotypic cerebellar slice cultures were used to assess whether S1PRs play a role in demyelination induced by lysolecithin (LPC). The data demonstrated that FTY720 and SEW2871 (a S1P1R-specific agonist) inhibited LPC-induced demyelination as assessed by myelin basic protein (MBP) immunofluorescence. Treatment with both drugs for 48 h also induced an increase in S1P1R expression in astrocytes. Moreover, FTY720 and SEW2871 inhibited the release of several chemokines in conditions of LPC-induced demyelination, including LIX (CXCL5), MIP-1alpha, and MIP-3alpha. Taken together, the data suggest that activation of S1P1Rs prevents LPC-induced demyelination via a mechanism involving a reduction of chemotactic chemokine release. The study supports the concept that FTY720 attenuates demyelination by not only preventing S1PR-mediated T cell migration into the CNS but also by limiting cytokine communication between cells of the immune system and the CNS.
authors: Department of Physiology, Trinity College Institute of Neuroscience (TCIN), School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
authors: Graham K
authors: GK
authors: Sheridan
authors: Kumlesh K
authors: KK
authors: Dev
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D054418:Chemokine CCL20 / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity; D008244:Lysophosphatidylcholines / Q000633:toxicity; D004676:Myelin Basic Protein / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D010069:Oxadiazoles / Q000633:toxicity; D011409:Propylene Glycols / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000633:toxicity; D013876:Thiophenes / Q000633:toxicity
chemical_list: C486997:Ccl20 protein, rat; D054418:Chemokine CCL20; D054405:Chemokine CCL3; D018925:Chemokines; D007166:Immunosuppressive Agents; D008244:Lysophosphatidylcholines; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C051774:neurofilament protein H; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine