Abstract
Amantadine is currently used as an antiviral and an antiparkinsonian drug. Although the drug is known to bind a viral proton channel protein, the mechanism of action in Parkinson's disease (PD) remains to be determined. This study investigated whether the drug has an inhibitory effect on microglial activation and neuroinflammation, which have been implicated in the progression of neurodegenerative processes. Using cultured microglial cells, it was demonstrated that the drug inhibited inflammatory activation of microglia and a signaling pathway that governs the microglial activation. The drug reduced the expression and production of proinflammatory mediators in bacterial lipopolysaccharide-stimulated microglia cells. The microglia-inhibiting activity of amantadine was also demonstrated in a microglia/neuron coculture and animal models of neuroinflammation and Parkinson's disease. Collectively, our results suggest that amantadine may act on microglia in the central nervous system to inhibit their inflammatory activation, thereby attenuating neuroinflammation. These results provide a molecular basis of the glia-targeted mechanism of action for amantadine.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amantadine / pharmacology*
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Analysis of Variance
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Animals
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Antiparkinson Agents / pharmacology*
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Calcium-Binding Proteins / metabolism
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Cell Line
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Cell Survival / drug effects
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Coculture Techniques
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Cytokines / genetics
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Cytokines / metabolism
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Disease Models, Animal
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Drug Interactions
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Encephalitis / chemically induced
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Encephalitis / drug therapy
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Enzyme-Linked Immunosorbent Assay
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Gene Expression Regulation / drug effects
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Lipopolysaccharides / pharmacology
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MPTP Poisoning / drug therapy
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MPTP Poisoning / pathology
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Macrophages / drug effects
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Male
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Mice
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Mice, Inbred C57BL
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Microfilament Proteins / metabolism
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Microglia / drug effects*
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Microglia / metabolism*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neurons / drug effects
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / metabolism
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Nitrites / metabolism
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RNA, Messenger / metabolism
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Rats
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Signal Transduction / drug effects
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Time Factors
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Aif1 protein, rat
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Antiparkinson Agents
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Calcium-Binding Proteins
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Cytokines
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Lipopolysaccharides
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Microfilament Proteins
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NF-kappa B
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Nitrites
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RNA, Messenger
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Nitric Oxide
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Amantadine
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Nitric Oxide Synthase
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Tyrosine 3-Monooxygenase