Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of PPAR-{alpha}
Molecular pharmacology 2007 Jul 11; 72(4):934-46
Dasgupta S, Roy A, Jana M, Hartley D DM, Pahan K
Rush University Medical Center.
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 (RR-MS). 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. Interestingly, 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. Consistently, gemfibrozil inhibited the expression and DNA-binding activity of T-bet, a key regulator of IFN-gamma expression, while stimulating 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. While 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 further find its therapeutic use in MS.