myelin-oligodendrocyte-glycoprotein-(35-55) and 2-2-bis(4-glycidyloxyphenyl)propane

Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARgamma agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown recently that PPARgamma agonists ameliorate experimental allergic encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). We have further shown that PPARgamma agonists inhibit EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARgamma-deficient heterozygous mice (PPARgamma(+/-)) develop an exacerbated EAE. In this study, we show that in vivo treatment (i.p.) with 100 mug PPARgamma antagonists, Bisphenol A diglycidyl ether (BADGE) or 2-Chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), on every other day from day 0 to 30, increased the severity and duration of EAE in C57BL/6 wild-type and PPARgamma(+/-) mice. The exacerbation of EAE by PPARgamma antagonists associates with an augmented neural antigen-induced T cell proliferation, IFNgamma production or Th1 differentiation. These results further suggest that PPARgamma is a critical physiological regulator of CNS inflammation and demyelination in EAE.

Topics: Animals; Benzamides; Benzhydryl Compounds; Cell Proliferation; Demyelinating Diseases; Dose-Response Relationship, Immunologic; Drug Administration Schedule; Drug Interactions; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Epoxy Compounds; Female; Glycoproteins; Inflammation; Interferon-gamma; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; PPAR gamma; Pyridines; Th1 Cells; Thymidine; Time Factors; Tritium