Lovell Mark A, Xie Chengsong, Xiong Shuling, Markesbery William R
Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY 40536-0230, USA.
J Alzheimers Dis. 2003 Jun;5(3):229-39. doi: 10.3233/jad-2003-5306.
Current evidence supports the role of oxidative stress in the pathogenesis of neuron degeneration in Alzheimer's disease (AD). alpha-Lipoic acid (LA), an essential cofactor in mitochondrial dehydrogenase reactions, functions as an antioxidant and reduces oxidative stress in aged animals. Here, we describe the effects of LA and its reduced form, dihydrolipoic acid (DHLA), in neuron cultures treated with amyloid beta-peptide (Abeta 25-35) and iron/hydrogen peroxide (Fe/H2O2). Pretreatment of dissociated primary hippocampal cultures with LA significantly protected against Abeta and Fe/H2O2 toxicity. In contrast, concomitant treatment of cultures with LA and Fe/H2O2 significantly potentiated the toxicity. Decreased cell survival in cultures treated concomitantly with LA and Fe/H2O2 correlated with increased free radical production measured by dichlorofluorescein fluorescence. Treatment of cortical neurons with DHLA significantly protected glucose-transport against Fe/H2O2 or beta-mediated decreases although treatment with LA did not provide protection. These data suggest that DHLA, the reduced form of LA, significantly protects against both Abeta and Fe/H2O2 mediated toxicity. The data also suggest that concomitant exposure to LA and Fe/H2O2 significantly potentiates the oxidative stress. Overall, these data suggest that the oxidation state of LA is critical to its function and that in the absence of studies of LA/DHLA equilibria in human brain the use of LA as an antioxidant in disorders where there is increased Fe such as AD is of questionable efficacy.
目前的证据支持氧化应激在阿尔茨海默病（AD）神经元变性发病机制中的作用。α-硫辛酸（LA）是线粒体脱氢酶反应中的一种必需辅因子，具有抗氧化作用，并能减轻老龄动物的氧化应激。在此，我们描述了LA及其还原形式二氢硫辛酸（DHLA）在经淀粉样β肽（Aβ 25-35）和铁/过氧化氢（Fe/H₂O₂）处理的神经元培养物中的作用。用LA预处理解离的原代海马培养物可显著保护其免受Aβ和Fe/H₂O₂毒性的影响。相反，培养物同时用LA和Fe/H₂O₂处理则显著增强了毒性。LA和Fe/H₂O₂同时处理的培养物中细胞存活率降低与通过二氯荧光素荧光测量的自由基产生增加相关。用DHLA处理皮质神经元可显著保护葡萄糖转运免受Fe/H₂O₂或β介导的降低，尽管用LA处理未提供保护。这些数据表明，LA的还原形式DHLA可显著保护细胞免受Aβ和Fe/H₂O₂介导的毒性。数据还表明，同时暴露于LA和Fe/H₂O₂会显著增强氧化应激。总体而言，这些数据表明LA的氧化状态对其功能至关重要，并且在缺乏对人脑中LA/DHLA平衡研究的情况下，在诸如AD等铁含量增加的疾病中使用LA作为抗氧化剂的疗效值得怀疑。
