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 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.
Zhang
Feng
F
Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Shi
Jing-Shan
JS
Zhou
Hui
H
Wilson
Belinda
B
Hong
Jau-Shyong
JS
Gao
Hui-Ming
HM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D004622:Embryo, Mammalian; D005260:Female; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D059808:Polyphenols; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000077185:Resveratrol; D013267:Stilbenes; D013378:Substantia Nigra / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D005419:Flavonoids; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D010636:Phenols; D059808:Polyphenols; D017382:Reactive Oxygen Species; D013267:Stilbenes; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; D000077185:Resveratrol; D004298:Dopamine