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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cerebellum / cytology
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Cerebellum / physiology
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Cerebral Cortex / cytology
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Cerebral Cortex / physiology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Glycoproteins / administration & dosage
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Glycoproteins / immunology
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Humans
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Hypoglycemic Agents / therapeutic use
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I-kappa B Proteins*
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Ligands
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred C57BL
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Multiple Sclerosis / immunology
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Multiple Sclerosis / physiopathology
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Myelin-Oligodendrocyte Glycoprotein
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Oxazoles / therapeutic use
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology
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Pioglitazone
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / immunology
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Remission Induction
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Spinal Cord / cytology
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Spinal Cord / pathology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Thiazoles / therapeutic use*
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Thiazolidinediones*
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Transcription Factors / agonists*
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Transcription Factors / immunology
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Tyrosine / analogs & derivatives*
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Tyrosine / therapeutic use
Substances
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DNA-Binding Proteins
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Glycoproteins
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Hypoglycemic Agents
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I kappa B beta protein
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I-kappa B Proteins
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Ligands
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Myelin-Oligodendrocyte Glycoprotein
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Oxazoles
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Peptide Fragments
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Receptors, Cytoplasmic and Nuclear
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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myelin oligodendrocyte glycoprotein (35-55)
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GW 7845
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Tyrosine
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Pioglitazone