[en] The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARgamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.
Disciplines :
Neurology
Author, co-author :
Feinstein, Douglas L; Department of Anesthesiology, University of Illinois, 11819 West Polk Street, MC519, Chicago, IL 60612, USA. dlfeins@uic.edu
Galea, Elena; Department of Anesthesiology, University of Illinois, Chicago, IL, United States
Gavrilyuk, Vitaliy; Department of Anesthesiology, University of Illinois, Chicago, IL, United States
Brosnan, Celia F; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States
Whitacre, Caroline C; Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH, United States
Dumitrescu-Ozimek, Lucia; Department of Neurology, University of Bonn, Bonn, Germany
Landreth, Gary E; Departments of Neurosciences and Neurology, Case Western Reserve University, Cleveland, OH, United States
Pershadsingh, Harrihar A; Department of Family Medicine, Kern Medical Center, UC Irvine, Irvine, CA, United States
Weinberg, Guy; Department of Anesthesiology, University of Illinois, Chicago, IL, United States
HENEKA, Michael ; Department of Neurology, University of Bonn, Bonn, Germany
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