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

Glia. 2012 Mar;60(3):382-92. doi: 10.1002/glia.22272. Epub 2011 Nov 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Cell Movement / drug effects
  • Cerebellum / cytology
  • Cerebellum / drug effects
  • Chemokine CCL20 / metabolism
  • Chemokine CCL3 / metabolism
  • Chemokines / metabolism*
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / drug therapy
  • Demyelinating Diseases / metabolism*
  • Fingolimod Hydrochloride
  • Gene Expression Regulation / drug effects
  • Immunosuppressive Agents / toxicity
  • Lysophosphatidylcholines / toxicity
  • Myelin Basic Protein / metabolism
  • Neurofilament Proteins / metabolism
  • Organ Culture Techniques
  • Oxadiazoles / toxicity
  • Propylene Glycols / toxicity
  • Rats
  • Rats, Wistar
  • Receptors, Lysosphingolipid / antagonists & inhibitors
  • Receptors, Lysosphingolipid / metabolism*
  • Sphingosine / analogs & derivatives
  • Sphingosine / toxicity
  • Thiophenes / toxicity


  • Ccl20 protein, rat
  • Chemokine CCL20
  • Chemokine CCL3
  • Chemokines
  • Immunosuppressive Agents
  • Lysophosphatidylcholines
  • Myelin Basic Protein
  • Neurofilament Proteins
  • Oxadiazoles
  • Propylene Glycols
  • Receptors, Lysosphingolipid
  • SEW2871
  • Thiophenes
  • neurofilament protein H
  • Fingolimod Hydrochloride
  • Sphingosine