Wang Xiaofei, Perez Evelyn, Liu Ran, Yan Liang-Jun, Mallet Robert T, Yang Shao-Hua
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699, USA.
Brain Res. 2007 Feb 9;1132(1):1-9. doi: 10.1016/j.brainres.2006.11.032. Epub 2006 Dec 15.
Oxidative stress is implicated in neurodegenerative diseases including stroke, Alzheimer's disease and Parkinson's disease, and has been extensively studied as a potential target for therapeutic intervention. Pyruvate, a natural metabolic intermediate and energy substrate, exerts antioxidant effects in brain and other tissues susceptible to oxidative stress. We tested the protective effects of pyruvate on hydrogen peroxide (H(2)O(2)) toxicity in human neuroblastoma SK-N-SH cells and the mechanisms underlying its protection. Hydrogen peroxide insult resulted in 85% cell death, but co-treatment with pyruvate dose-dependently attenuated cell death. At concentrations of >or=1 mM, pyruvate totally blocked the cytotoxic effects of H(2)O(2). Pyruvate exerted its protective effects even when its administration was delayed up to 2 h after H(2)O(2) insult. As a scavenger of reactive oxygen species (ROS), pyruvate dose-dependently attenuated H(2)O(2)-induced ROS formation, assessed from 2,7-dichlorofluorescein diacetate fluorescence. Furthermore, pyruvate suppressed superoxide production by submitochondrial particles, and attenuated oxidative stress-induced collapse of the mitochondrial membrane potential. Collectively, these results suggest that pyruvate protects neuronal cells through its antioxidant actions on mitochondria.
氧化应激与包括中风、阿尔茨海默病和帕金森病在内的神经退行性疾病有关，并且作为治疗干预的潜在靶点已被广泛研究。丙酮酸是一种天然的代谢中间体和能量底物，在大脑和其他易受氧化应激影响的组织中发挥抗氧化作用。我们测试了丙酮酸对人神经母细胞瘤SK-N-SH细胞中过氧化氢（H₂O₂）毒性的保护作用及其保护机制。过氧化氢损伤导致85%的细胞死亡，但与丙酮酸共同处理可剂量依赖性地减轻细胞死亡。在浓度≥1 mM时，丙酮酸完全阻断了H₂O₂的细胞毒性作用。即使在H₂O₂损伤后延迟2小时给予丙酮酸，它仍能发挥保护作用。作为活性氧（ROS）的清除剂，从2,7-二氯荧光素二乙酸酯荧光评估，丙酮酸剂量依赖性地减轻了H₂O₂诱导的ROS形成。此外，丙酮酸抑制了亚线粒体颗粒产生超氧化物，并减轻了氧化应激诱导的线粒体膜电位崩溃。总体而言，这些结果表明丙酮酸通过其对线粒体的抗氧化作用保护神经元细胞。
