Mechanisms of pesticides-induced neuronal apoptosis

描述（由申请人提供）：包括农药在内的环境毒物可能导致各种神经退行性疾病的发展，包括帕金森病（PD）。神经细胞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能刺激神经元细胞凋亡，提示农药诱导的细胞凋亡可能在神经退行性变中起作用。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机制。毒死蜱是一种有机磷农药，是最常用的农药之一。它的主要毒性目标是中枢神经系统。用鱼藤酮（一种常见的杀虫剂）治疗大鼠会引起所有PD症状。因此，我们选择毒死蜱和鱼藤酮这两种不同类型的农药作为模型来研究农药诱导的神经元凋亡。我们的初步数据表明，毒死蜱和鱼藤酮均可诱导原代培养的皮质神经元和SH-SY5Y细胞凋亡。它们还激活应激激活的MAP激酶，JNK和p38。我们假设这些激酶的激活对毒死蜱和鱼藤酮诱导的神经元凋亡很重要。我们将验证这一假设，并阐明毒死蜱和鱼藤酮刺激JNK和p38导致神经元凋亡的下游机制。该研究将为农药诱导神经元凋亡的分子基础提供有价值的新信息，并为环境毒物在神经变性中的作用提供新的见解。

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.