Abstract
The present study underlines the importance of gemfibrozil, a lipid-lowering drug and an activator of peroxisome proliferator-activated receptor-α (PPAR-α), 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-α 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-α. Gemfibrozil consistently inhibited the expression and DNA-binding activity of T-bet, a key regulator of interferon-γ (IFN-γ) 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.
Footnotes
-
This study was supported by National Multiple Sclerosis Society grant RG3422A1/1 and National Institutes of Health grants NS39940 and NS48923.
-
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
-
doi:10.1124/mol.106.033787.
-
ABBREVIATIONS: MS, multiple sclerosis; CNS, central nervous system; EAE, experimental allergic encephalomyelitis; iNOS, inducible nitric-oxide synthase; PPAR, peroxisome proliferator-activated receptor; HDL, high-density lipoprotein; Th, T-helper; RR-EAE, relapsing-remitting EAE; FBS, fetal bovine serum; carboxy-PTIO, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, potassium salt; PCR, polymerase chain reaction; IFA, incomplete Freund's adjuvant; MBP, myelin basic protein; LNC, lymph node cells; dpt, days post-transfer; HPLC, high-performance liquid chromatography; H&E, hematoxylin & eosin; PBST, PBS containing Tween 20; LFB, Luxol fast blue; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; IL, interleukin; WY14643, pirinixic acid; GSNO, S-nitrosoglutathione; IFN, interferon; dpt, days post-transfer.
- Received December 26, 2006.
- Accepted July 11, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|