Wang Xiaoxia, Qin Zheng-Hong, Leng Yan, Wang Yumei, Jin Xiannu, Chase Thomas N, Bennett M Catherine
National Institute of Neurological Disorders and Stroke, Experimental Therapeutics Branch, Bethesda, Maryland, USA.
J Neurochem. 2002 Dec;83(5):1094-102. doi: 10.1046/j.1471-4159.2002.01224.x.
The degeneration of nigral dopamine neurons in Parkinson's disease (PD) reportedly involves a defect in brain mitochondrial complex I in association with the activation of nuclear factor-kappaB (NF-kappaB) and caspase-3. To elucidate molecular mechanisms possibly linking these events, as well as to evaluate the neuroprotective potential of the cyclopentenone prostaglandin A1 (PGA1), an inducer of heat shock proteins (HSPs), we exposed human dopaminergic SH-SY5Y cells to the complex I inhibitor rotenone. Dose-dependent apoptosis was preceded by the nuclear translocation of NF-kappaB and then the activation of caspase-3 over the ensuing 24 h. PGA1 increased the expression of HSP70 and HSP27 and protected against rotenone-induced apoptosis, without increasing necrotic death. PGA1 blocked the rotenone-induced nuclear translocation of NF-kappaB and attenuated, but did not abolish, the caspase-3 elevation. Unexpectedly, the caspase-3 inhibitor, Ac-DEVD.CHO (DEVD), at a concentration that completely prevented the caspase-3 elevation produced by rotenone, failed to protect against apoptosis. These results suggest that complex I deficiency in dopamine cells can induce apoptosis by a process involving early NF-kappaB nuclear translocation and caspase-3 activation. PGA1 appears to protect against rotenone-induced cell death by inducing HSPs and blocking nuclear translocation of NF-kappaB in a process that attenuates caspase-3 activation, but is not mediated by its inhibition.
据报道，帕金森病（PD）中黑质多巴胺神经元的退化与脑线粒体复合物I缺陷有关，并伴有核因子-κB（NF-κB）和半胱天冬酶-3的激活。为了阐明可能将这些事件联系起来的分子机制，以及评估环戊烯酮前列腺素A1（PGA1）（一种热休克蛋白（HSPs）诱导剂）的神经保护潜力，我们将人多巴胺能SH-SY5Y细胞暴露于复合物I抑制剂鱼藤酮。在随后的24小时内，剂量依赖性凋亡先于NF-κB的核转位，然后是半胱天冬酶-3的激活。PGA1增加了HSP70和HSP27的表达，并防止了鱼藤酮诱导的凋亡，而不会增加坏死性死亡。PGA1阻断了鱼藤酮诱导的NF-κB核转位，并减弱了但并未消除半胱天冬酶-3的升高。出乎意料的是，半胱天冬酶-3抑制剂Ac-DEVD.CHO（DEVD）在完全阻止鱼藤酮产生的半胱天冬酶-3升高的浓度下，未能防止凋亡。这些结果表明，多巴胺细胞中的复合物I缺陷可通过涉及早期NF-κB核转位和半胱天冬酶-3激活的过程诱导凋亡。PGA1似乎通过诱导HSPs和阻断NF-κB核转位来防止鱼藤酮诱导的细胞死亡，该过程减弱了半胱天冬酶-3的激活，但不是由其抑制介导的。
