PT - JOURNAL ARTICLE AU - Feng Zhang AU - Jing-Shan Shi AU - Hui Zhou AU - Belinda C Wilson AU - Jau-Shyong Hong AU - HUI-MING GAO TI - Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions AID - 10.1124/mol.110.064535 DP - 2010 Jan 01 TA - Molecular Pharmacology PG - mol.110.064535 4099 - http://molpharm.aspetjournals.org/content/early/2010/06/16/mol.110.064535.short 4100 - http://molpharm.aspetjournals.org/content/early/2010/06/16/mol.110.064535.full AB - 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 non-flavonoid polyphenol naturally found in red wine and grapes, has been known to possess anti-oxidant, anti-cancer 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 pro-inflammatory 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-κB 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.The American Society for Pharmacology and Experimental Therapeutics