Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis.

Abstract	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.
Authors	Douglas L Feinstein, Elena Galea, Vitaliy Gavrilyuk, Celia F Brosnan, Caroline C Whitacre, Lucia Dumitrescu-Ozimek, Gary E Landreth, Harrihar A Pershadsingh, Guy Weinberg, Michael T Heneka
Journal	Annals of neurology (Ann Neurol) Vol. 51 Issue 6 Pg. 694-702 (Jun 2002) ISSN: 0364-5134 [Print] United States
PMID	12112074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	DNA-Binding Proteins Glycoproteins Hypoglycemic Agents I kappa B beta protein I-kappa B Proteins Ligands Myelin-Oligodendrocyte Glycoprotein Oxazoles Peptide Fragments Receptors, Cytoplasmic and Nuclear Thiazoles Thiazolidinediones Transcription Factors myelin oligodendrocyte glycoprotein (35-55) GW 7845 Tyrosine NOS2 protein, human Nitric Oxide Synthase Nitric Oxide Synthase Type II Nos2 protein, mouse Pioglitazone
Topics	Animals Cerebellum (cytology, physiology) Cerebral Cortex (cytology, physiology) DNA-Binding Proteins (genetics, metabolism) Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology, pathology) Female Glycoproteins (administration & dosage, immunology) Humans Hypoglycemic Agents (therapeutic use) I-kappa B Proteins Ligands Lymphocyte Activation Male Mice Mice, Inbred C57BL Multiple Sclerosis (immunology, physiopathology) Myelin-Oligodendrocyte Glycoprotein Nitric Oxide Synthase (genetics, metabolism) Nitric Oxide Synthase Type II Oxazoles (therapeutic use) Peptide Fragments (administration & dosage, immunology) Pioglitazone Receptors, Cytoplasmic and Nuclear (agonists, immunology) Remission Induction Spinal Cord (cytology, pathology) T-Lymphocytes (immunology, metabolism) Thiazoles (therapeutic use) Thiazolidinediones Transcription Factors (agonists, immunology) Tyrosine (analogs & derivatives, therapeutic use)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!