Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy fo...

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Published in:Molecular pharmacology 2010-09, Vol.78 (3), p.466-477
Main Authors: Zhang, Feng, Shi, Jing-Shan, Zhou, Hui, Wilson, Belinda, Hong, Jau-Shyong, Gao, Hui-Ming
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - metabolism
Anti-Inflammatory Agents - pharmacology
Anti-Inflammatory Agents - therapeutic use
Dopamine - metabolism
Dopamine - pharmacology
Dopamine - physiology
Embryo, Mammalian
Female
Flavonoids - metabolism
Flavonoids - pharmacology
Flavonoids - therapeutic use
Lipopolysaccharides - antagonists & inhibitors
Lipopolysaccharides - metabolism
Lipopolysaccharides - pharmacology
Mesencephalon - cytology
Mesencephalon - metabolism
Mice
Mice, Inbred C57BL
Microglia - drug effects
Microglia - metabolism
Microglia - physiology
Mitogen-Activated Protein Kinases - metabolism
Mitogen-Activated Protein Kinases - pharmacology
NADPH Oxidases - antagonists & inhibitors
NADPH Oxidases - metabolism
NADPH Oxidases - physiology
Nerve Degeneration - metabolism
Nerve Degeneration - prevention & control
Neuroglia - drug effects
Neuroglia - metabolism
Neurons - drug effects
Neurons - metabolism
Neurons - physiology
Neuroprotective Agents - metabolism
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
Neurotoxicity Syndromes - metabolism
Parkinson Disease - drug therapy
Parkinson Disease - metabolism
Phenols - metabolism
Phenols - pharmacology
Phenols - therapeutic use
Polyphenols
Pregnancy
Rats
Rats, Inbred F344
Reactive Oxygen Species - metabolism
Reactive Oxygen Species - pharmacology
Reactive Oxygen Species - therapeutic use
Stilbenes
Substantia Nigra - metabolism
Vitaceae
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Summary:Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. Resveratrol, a nonflavonoid polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. Although recent studies have shown that resveratrol provided neuroprotective effects against ischemia, seizure, and neurodegenerative disorders, the mechanisms underlying its beneficial effects on dopaminergic neurodegeneration are poorly defined. In this study, rat primary midbrain neuron-glia cultures were used to elucidate the molecular mechanisms underlying resveratrol-mediated neuroprotection. The results clearly demonstrated that resveratrol protected DA neurons against lipopolysaccharide (LPS)-induced neurotoxicity in concentration- and time-dependent manners through the inhibition of microglial activation and the subsequent reduction of proinflammatory factor release. Mechanistically, resveratrol-mediated neuroprotection was attributed to the inhibition of NADPH oxidase. This conclusion is supported by the following observations. First, resveratrol reduced NADPH oxidase-mediated generation of reactive oxygen species. Second, LPS-induced translocation of NADPH oxidase cytosolic subunit p47 to the cell membrane was significantly attenuated by resveratrol. Third and most importantly, resveratrol failed to exhibit neuroprotection in cultures from NADPH oxidase-deficient mice. Furthermore, this neuroprotection was also related to an attenuation of the activation of mitogen-activated protein kinases and nuclear factor-kappaB signaling pathways in microglia. These findings suggest that resveratrol exerts neuroprotection against LPS-induced dopaminergic neurodegeneration, and NADPH oxidase may be a major player in resveratrol-mediated neuroprotection.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.110.064535