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. © 2011 Wiley Periodicals, Inc.