sew2871 and Demyelinating-Diseases

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.

Topics: Animals; Animals, Newborn; Astrocytes; Cell Movement; Cerebellum; Chemokine CCL20; Chemokine CCL3; Chemokines; Demyelinating Diseases; Fingolimod Hydrochloride; Gene Expression Regulation; Immunosuppressive Agents; Lysophosphatidylcholines; Myelin Basic Protein; Neurofilament Proteins; Organ Culture Techniques; Oxadiazoles; Propylene Glycols; Rats; Rats, Wistar; Receptors, Lysosphingolipid; Sphingosine; Thiophenes