Graduate Program in Cell Biology, Neurobiology, and Anatomy, Loyola University Chicago-Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL 60153, USA.
Brain Res. 2011 Apr 6;1383:13-21. doi: 10.1016/j.brainres.2011.01.113. Epub 2011 Mar 5.
This laboratory showed that ethanol augments apoptosis in fetal rhombencephalic neurons and co-treatment with alpha-lipoic acid (LA) or one of several other antioxidants prevents ethanol-associated apoptosis. Because ethanol increases oxidative stress, which causes apoptosis, it is likely that some of the neuroprotective effects of LA and other antioxidants involve classical antioxidant actions. Considering the reported link of LA with pro-survival cell signaling, it is also possible that LA's neuroprotective effects involve additional mechanisms. The present study investigated the effects of LA on ethanol-treated fetal rhombencephalic neurons with regard to oxidative stress and up-regulation of the pro-survival genes Xiap and Bcl-2. We included parallel gene expression studies with N-acetyl cysteine (NAC) to determine whether LA's effects on Xiap and Bcl-2 were shared by other antioxidants. We also used enzyme inhibitors to determine which signaling pathway(s) might be involved with the effects of LA. The results of this investigation showed that LA treatment of ethanol-treated neurons exerted several pro-survival effects. LA blocked two pro-apoptotic changes, i.e., the ethanol-associated rise in ROS and caspase-3. LA also up-regulated the expression genes that encode the anti-apoptotic proteins Bcl-2 and Xiap by a mechanism that involves NF-κB. NAC also up-regulated Bcl-2 and Xiap. Thus, the neuroprotective effects of LA and NAC could involve up-regulation of pro-survival genes as well as their classical antioxidant actions.
本实验室表明，乙醇可增强胎鼠后脑神经元的细胞凋亡，而与α-硫辛酸（LA）或其他几种抗氧化剂共同处理可预防乙醇相关的细胞凋亡。由于乙醇增加了导致细胞凋亡的氧化应激，因此 LA 和其他抗氧化剂的一些神经保护作用可能涉及经典的抗氧化作用。考虑到 LA 与促进生存的细胞信号转导的报道联系，LA 的神经保护作用也可能涉及其他机制。本研究探讨了 LA 对乙醇处理的胎鼠后脑神经元的影响，包括氧化应激和促生存基因 Xiap 和 Bcl-2 的上调。我们进行了与 N-乙酰半胱氨酸（NAC）的平行基因表达研究，以确定 LA 对 Xiap 和 Bcl-2 的影响是否与其他抗氧化剂共享。我们还使用酶抑制剂来确定可能涉及 LA 作用的信号通路。这项研究的结果表明，LA 处理乙醇处理的神经元发挥了多种促生存作用。LA 阻断了两种促凋亡变化，即乙醇引起的 ROS 和 caspase-3 升高。LA 还通过涉及 NF-κB 的机制上调了编码抗凋亡蛋白 Bcl-2 和 Xiap 的基因表达。NAC 也上调了 Bcl-2 和 Xiap。因此，LA 和 NAC 的神经保护作用可能涉及促生存基因的上调以及它们的经典抗氧化作用。
