Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-alpha.

Abstract

The present study underlines the importance of gemfibrozil, a lipid-lowering drug and an activator of peroxisome proliferator-activated receptor-alpha (PPAR-alpha), in inhibiting the disease process of adoptively transferred experimental allergic encephalomyelitis (EAE), an animal model of relapsing-remitting multiple sclerosis. Clinical symptoms of EAE, infiltration of mononuclear cells, and demyelination were significantly lower in SJL/J female mice receiving gemfibrozil through food chow than those without gemfibrozil. It is noteworthy that the drug was equally effective in treating EAE in PPAR-alpha wild-type as well as knockout mice. Gemfibrozil also inhibited the encephalitogenicity of MBP-primed T cells and switched the immune response from a Th1 to a Th2 profile independent of PPAR-alpha. Gemfibrozil consistently inhibited the expression and DNA-binding activity of T-bet, a key regulator of interferon-gamma (IFN-gamma) expression and stimulated the expression and DNA-binding activity of GATA3, a key regulator of IL-4. Gemfibrozil treatment decreased the number of T-bet-positive T cells and increased the number of GATA3-positive T cells in spleen of donor mice. The histological and immunohistochemical analyses also demonstrate the inhibitory effect of gemfibrozil on the invasion of T-bet-positive T cells into the spinal cord of EAE mice. Furthermore, we demonstrate that the differential effect of gemfibrozil on the expression of T-bet and GATA3 was due to its inhibitory effect on NO production. Although excess NO favored the expression of T-bet, scavenging of NO stimulated the expression of GATA-3. Taken together, our results suggest gemfibrozil, an approved drug for hyperlipidemia in humans, may find further therapeutic use in multiple sclerosis.

• Authors: Subhajit Dasgupta, Avik Roy, Malabendu Jana, Dean M Hartley, Kalipada Pahan
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 72 Issue 4 Pg. 934-46 (Oct 2007) ISSN: 0026-895X [Print] United States
• PMID: 17625103 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GATA3 Transcription Factor
• Gata3 protein, mouse
• Hypolipidemic Agents
• PPAR alpha
• Interleukin-4
• Interferon-gamma
• Gemfibrozil

Topics

• Animals
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology, physiopathology)
• Female
• GATA3 Transcription Factor (metabolism)
• Gemfibrozil (pharmacology, therapeutic use)
• Hypolipidemic Agents (pharmacology, therapeutic use)
• Interferon-gamma (metabolism)
• Interleukin-4 (metabolism)
• Male
• Mice
• Mice, Knockout
• PPAR alpha (genetics, physiology)
• Th1 Cells (immunology)
• Th2 Cells (immunology)