Newhouse Kathleen, Hsuan Shih-Ling, Chang Sandra H, Cai Beibei, Wang Yupeng, Xia Zhengui
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195-7234, USA.
Toxicol Sci. 2004 May;79(1):137-46. doi: 10.1093/toxsci/kfh089. Epub 2004 Feb 19.
Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson's disease in animal models. Though rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of rotenone-induced neuronal cell death. Our results suggest that rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, rotenone treatment induces phosphorylation of c-Jun, the c-Jun N-terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated rotenone-induced apoptosis. These data suggest that rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases and caspases. These studies provide insights concerning the molecular mechanisms of rotenone-induced apoptosis in neuronal cells.
鱼藤酮是一种天然衍生的杀虫剂，最近已证明它能在动物模型中引发帕金森病的行为和病理症状。尽管已知鱼藤酮是线粒体复合物I电子传递链的抑制剂，但对于导致其毒性的下游途径却知之甚少。我们使用人多巴胺能SH-SY5Y细胞来研究鱼藤酮诱导神经元细胞死亡的机制。我们的结果表明，纳摩尔浓度的鱼藤酮可诱导SH-SY5Y细胞发生依赖半胱天冬酶的凋亡。此外，鱼藤酮处理可诱导c-Jun、c-Jun氨基末端蛋白激酶（JNK）和p38丝裂原活化蛋白（MAP）激酶的磷酸化，这表明p38和JNK途径被激活。重要的是，JNK或p38途径的显性干扰构建体的表达减弱了鱼藤酮诱导的凋亡。这些数据表明，鱼藤酮在多巴胺能SH-SY5Y细胞中诱导凋亡，这需要JNK和p38 MAP激酶以及半胱天冬酶的激活。这些研究为鱼藤酮诱导神经元细胞凋亡的分子机制提供了见解。
