Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-alpha.
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.
Dasgupta
Subhajit
S
Department of Neurological Sciences, Rush University Medical Center, Cohn Research Building, Suite 320, 1735 West Harrison St, Chicago, IL 60612, USA.
Roy
Avik
A
Jana
Malabendu
M
Hartley
Dean M
DM
Pahan
Kalipada
K
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology* / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D015248:Gemfibrozil