Abstract
We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist of the thiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as determined by tyrosine hydroxylase (TH) immunocytochemistry, and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as determined by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (approximately 20 mg/kg/day) attenuated the MPTP-induced glial activation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little reduction of MPTP-induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone-treated animals. Low levels of PPARgamma expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARgamma-independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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3,4-Dihydroxyphenylacetic Acid / metabolism
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Administration, Oral
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Animals
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Cell Count
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Cell Survival / drug effects
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Corpus Striatum / pathology
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Disease Models, Animal
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Dopamine / metabolism
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Homovanillic Acid / metabolism
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Hypoglycemic Agents / administration & dosage
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Hypoglycemic Agents / pharmacology
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Immunohistochemistry
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Macrophage-1 Antigen / biosynthesis
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Male
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Mice
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Mice, Inbred C57BL
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Neuroglia / drug effects
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Neuroglia / pathology
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / pathology
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Parkinsonian Disorders / prevention & control*
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Pioglitazone
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Substantia Nigra / drug effects
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Substantia Nigra / metabolism
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Substantia Nigra / pathology
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Thiazoles / administration & dosage
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Thiazoles / pharmacology*
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Thiazolidinediones*
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Transcription Factors / agonists*
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Transcription Factors / biosynthesis
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Hypoglycemic Agents
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Macrophage-1 Antigen
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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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3,4-Dihydroxyphenylacetic Acid
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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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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Tyrosine 3-Monooxygenase
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Dopamine
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Pioglitazone
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Homovanillic Acid