Abstract
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the nigrostriatal dopaminergic pathway as seen in Parkinson's disease (PD), a common neurodegenerative disorder with no effective protective treatment. Consistent with a role of glial cells in PD neurodegeneration, here we show that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP. In addition, we show that minocycline not only prevents MPTP-induced activation of microglia but also the formation of mature interleukin-1beta and the activation of NADPH-oxidase and inducible nitric oxide synthase (iNOS), three key microglial-derived cytotoxic mediators. Previously, we demonstrated that ablation of iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that iNOS is not the only microglial-related culprit implicated in MPTP-induced toxicity because mutant iNOS-deficient mice treated with minocycline are more resistant to this neurotoxin than iNOS-deficient mice not treated with minocycline. This study demonstrates that microglial-related inflammatory events play a significant role in the MPTP neurotoxic process and suggests that minocycline may be a valuable neuroprotective agent for the treatment of PD.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / metabolism
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Animals
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Anti-Bacterial Agents / pharmacology
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Astrocytes / drug effects
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Astrocytes / pathology
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Corpus Striatum / drug effects
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Corpus Striatum / pathology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Interleukin-1 / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microglia / drug effects
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Microglia / metabolism*
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Microglia / pathology
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Minocycline / pharmacology*
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NADPH Oxidases / metabolism
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Neuroprotective Agents / pharmacology*
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Nitric Oxide Synthase / deficiency
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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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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / pathology
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Parkinsonian Disorders / prevention & control*
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Substantia Nigra / drug effects
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Substantia Nigra / pathology
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Tyrosine / analogs & derivatives*
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Tyrosine / metabolism
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Tyrosine 3-Monooxygenase / metabolism
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Up-Regulation / drug effects
Substances
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Anti-Bacterial Agents
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Interleukin-1
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Neuroprotective Agents
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3-nitrotyrosine
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Tyrosine
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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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NADPH Oxidases
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Minocycline