Mechanisms of pesticides-induced neuronal apoptosis

描述（由申请方提供）：环境毒物（包括农药）可能导致各种神经退行性疾病（包括帕金森病（PD））的发生。神经元凋亡是各种神经退行性变的机制之一。我们发现，毒死蜱和鱼藤酮都刺激神经细胞凋亡，这表明农药诱导的细胞凋亡可能在神经退行性变中发挥作用。因此，阐明农药诱导神经元凋亡的分子机制具有重要意义。本项目的总体目标是阐明毒死蜱和鱼藤酮诱导神经元凋亡的凋亡机制。毒死蜱是一种有机磷农药，是最常用的农药之一。其主要毒性靶点是CNS。用鱼藤酮（一种常见的杀虫剂）治疗大鼠会导致所有PD症状。因此，毒死蜱和鱼藤酮，两个不同的类别的农药，被选为模型，研究农药诱导的神经细胞凋亡。我们的初步数据表明，毒死蜱和鱼藤酮诱导原代培养的皮层神经元和SH-SY5Y细胞凋亡。它们还激活应激激活的MAP激酶、JNK和p38。我们推测，这些激酶的激活是重要的毒死蜱和鱼藤酮诱导的神经元凋亡。我们将测试这一假设，并阐明毒死蜱和鱼藤酮刺激JNK和p38引起神经元凋亡的下游机制。这项研究应该提供有价值的新信息农药诱导的神经元凋亡的分子基础和新的见解有关的环境毒物在神经退行性变的作用。

DESCRIPTION (provided by applicant): Environmental toxicants including pesticides may contribute to the development of various neurodegenerative disorders including Parkinson's disease (PD). One of the mechanisms implicated in various neurodegeneration is neuronal apoptosis. We discovered that chlorpyrifos and rotenone both stimulate apoptosis in neuronal cells, suggesting that pesticide-induced apoptosis may play a role in neurodegeneration. Consequently, it is important to elucidate molecular mechanisms for induction of apoptosis by pesticides in neurons. The overall objective of this project is to elucidate apoptotic mechanisms for chlorpyrifos- and rotenone-induced apoptosis in neurons. Chlorpyrifos, an organophosphate pesticide, is one of the most commonly used pesticides. Its primary target of toxicity is the CNS. Treatment of rats with rotenone, a common insecticide, causes all PD symptoms. Therefore, chlorpyrifos and rotenone, two distinct classes of pesticides, are chosen as models to study pesticide-induced neuronal apoptosis. Our preliminary data suggest that both chlorpyrifos and rotenone induce apoptosis in primary cultured cortical neurons and SH-SY5Y cells. They also activate the stress-activated MAP kinases, JNK and p38. We hypothesize that activation of these kinases is important for chlorpyrifos- and rotenone-induced apoptosis in neurons. We will test this hypothesis and elucidate downstream mechanisms by which chlorpyrifos and rotenone stimulation of JNK and p38 causes neuronal apoptosis. This study should provide valuable new information concerning the molecular basis of pesticide-induced apoptosis in neurons and new insights concerning the role of environmental toxicants in neurodegeneration.