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S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures

Authors

  • Graham K. Sheridan,

    1. Department of Physiology, Trinity College Institute of Neuroscience (TCIN), School of Medicine, Trinity College Dublin, Dublin 2, Ireland
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  • Kumlesh K. Dev

    Corresponding author
    1. Department of Physiology, Trinity College Institute of Neuroscience (TCIN), School of Medicine, Trinity College Dublin, Dublin 2, Ireland
    • Molecular Neuropharmacology, Department of Physiology, Trinity College Institute of Neuroscience, School of Medicine, Trinity College Dublin, Ireland
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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. © 2011 Wiley Periodicals, Inc.

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