Differential effect of nerve growth factor on dopaminergic neurotoxin-induced apoptosis
Differential effect of nerve growth factor on dopaminergic neurotoxin-induced apoptosis
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DOI：
10.1111/j.1471-4159.2006.04006.x
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发表时间：
2006-10-01
影响因子：
4.7
通讯作者：
Kiuchi, Kazutoshi
中科院分区：
文献类型：
--
作者：
Hirata, Yoko;Meguro, Tomotaka;Kiuchi, Kazutoshi
鱼藤酮和锰都可能是多种细胞和神经元类型的神经毒素，包括多巴胺能神经元，并诱导各种细胞的凋亡。神经营养因子在用于预防帕金森病时具有治疗发展的潜力。本文主要研究鱼藤酮和锰作为毒素的差异，以及神经营养因子对毒素诱导的PC 12细胞凋亡的影响。鱼藤酮和锰诱导的细胞凋亡之间的细胞内机制有明显的差异，如活性氧的产生，抗氧化剂的反应，以及c-Jun N-末端激酶（JNK）和p38丝裂原活化蛋白激酶（MAPK）的激活。神经生长因子（NGF）几乎完全阻止鱼藤酮诱导的，但不是锰诱导的caspase激活和DNA片段化。神经生长因子的差异效应被认为主要是由于下调的Trk酪氨酸激酶受体锰，而不是鱼藤酮。神经生长因子对鱼藤酮诱导的细胞凋亡的预防作用被磷脂酰肌醇3-激酶（PI 3-kinase）抑制剂LY 294002减弱，但不被MAPK激酶（MEK）抑制剂PD 98059或U 0126减弱。这些结果表明，多巴胺能细胞的潜在的神经毒素发挥其毒性作用，通过激活不同的信号转导途径的凋亡和NGF阻止鱼藤酮诱导的细胞凋亡，通过激活PI 3-激酶途径，而不是MAPK途径。
Both rotenone and manganese are possible neurotoxins for a wide variety of cell and neuronal types including dopaminergic neurons and induce apoptosis in various cells. Neurotrophic factors have the potential for therapeutic development when used to prevent Parkinson's disease. In this paper, we focused on the differences between rotenone and manganese as toxins, and characterized the influence of neurotrophic factors on toxin-induced apoptosis in PC12 cells. There were distinct differences in intracellular mechanisms between rotenone- and manganese-induced apoptosis such as the production of reactive oxygen species, the response to antioxidants, and the activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Nerve growth factor (NGF) almost completely prevented rotenone-induced but not manganese-induced caspase activation and DNA fragmentation. The differential effect of NGF was found to be mainly due to the down-regulation of the Trk tyrosine kinase receptor by manganese but not by rotenone. Prevention of rotenone-induced apoptosis by NGF was attenuated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, but not MAPK kinase (MEK) inhibitors, PD98059 or U0126. These results demonstrate that the potential neurotoxins for dopaminergic cells exert their toxic effect by activation of different signaling pathways of apoptosis and that NGF prevents rotenone-induced apoptosis through the activation of the PI 3-kinase pathway not MAPK pathway.