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 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-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.
La enfermedad del Parkinson es la segunda enfermedad degenerativa caracterizada por una pérdida de dopamina en las neuronas de la sustancia negra. Algunos estudios muestran que la inhibición de la inflamación de la microglía mediada por resveratrol puede actuar como estrategia protectora. En este estudio cultivos celulares de microgia de cerebros de rata se usaron para investigar los mecanismos del resveratrol. Se encontró que el resveratrol reduce la NADPH oxidasa la cual media la producción de productos reactivos del oxigeno. LPS induce la traslocación de la NASDPH oxidasa citosólica, su subunidad p47. Lo último y más importante, el resveratrol no actúa en su función neuroprotectora en cultivos en ratones defici3entes en NADPH oxidasa.