Annals of Neurology
Volume 51, Issue 6, 2002. Pages: 694-702
Douglas L. Feinstein, PhD 1 *, Elena Galea, PhD 1, Vitaliy Gavrilyuk, MD 1, Celia F. Brosnan, PhD 2, Caroline C. Whitacre, PhD 3, Lucia Dumitrescu-Ozimek 4, Gary E. Landreth, PhD 5, Harrihar A. Pershadsingh, MD 6, Guy Weinberg, MD 1, Michael T. Heneka, MD 4
1 Department of Anesthesiology, University of Illinois, Chicago, IL
2 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY
3 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH
4 Department of Neurology, University of Bonn, Bonn, Germany
5 Departments of Neurosciences and Neurology, Case Western Reserve University, Cleveland, OH
6 Department of Family Medicine, Kern Medical Center and UC Irvine, Irvine, CA
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 PPARg 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 PPARg agonists, suggesting a role for PPARg 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- production from EAE-derived T cells.
These results suggest that orally administered PPARg agonists could provide therapeutic benefit in demyelinating disease.
Funded by: National Multiple Sclerosis Society; Grant Number: PP0800 (D.L.F.)
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