Basic fibroblast growth factor protects against rotenone-induced dopaminergic cell death through activation of extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase pathways
Basic fibroblast growth factor protects against rotenone-induced dopaminergic cell death through activation of extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase pathways
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DOI：
10.1523/jneurosci.4922-05.2006
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发表时间：
2006-04-26
影响因子：
5.3
通讯作者：
Xia, ZG
中科院分区：
文献类型：
--
作者：
Hsuan, SL;Klintworth, HM;Xia, ZG
给大鼠施用鱼藤酮再现了帕金森病的许多特征，包括多巴胺能神经元变性，并为研究帕金森病的发病机制提供了有用的模型。然而，鱼藤酮诱导的细胞死亡机制和潜在的神经保护机制还没有很好的定义。在这里，我们报告，鱼藤酮诱导的人多巴胺能SH-SY 5 Y细胞凋亡的衰减预处理与几种生长因子，最显着的碱性成纤维细胞生长因子（bFGF）。bFGF激活SH-SY 5 Y细胞中的细胞外信号调节激酶1/2（ERK 1/2）和磷脂酰肌醇-3激酶（PI 3-kinase）途径。ERK 1/2或PI 3-激酶的异位激活保护对鱼藤酮，而抑制任何途径衰减bFGF的保护。通过小干扰RNA减少促凋亡蛋白Bcl-2相关死亡蛋白（BAD）的表达使SH-SY 5 Y细胞对鱼藤酮产生耐药性，提示BAD与鱼藤酮诱导的细胞死亡有关。有趣的是，bFGFind诱导BAD在丝氨酸112处的持久磷酸化，表明BAD通过ERK 1/2信号通路失活。此外，原代培养的中脑多巴胺能神经元对鱼藤酮诱导的细胞死亡比非多巴胺能神经元更敏感。多巴胺能神经元的损失被bFGF阻断，这种抑制依赖于ERK 1/2和PI 3-激酶信号传导。这些数据表明，鱼藤酮诱导的多巴胺能细胞死亡需要BAD，并确定bFGF及其激活ERK 1/2和PI 3-激酶信号通路作为新的干预策略，以阻止帕金森病鱼藤酮模型中的细胞死亡。
Administration of rotenone to rats reproduces many features of Parkinson's disease, including dopaminergic neuron degeneration, and provides a useful model to study the pathogenesis of Parkinson's disease. However, the cell death mechanisms induced by rotenone and potential neuroprotective mechanisms against rotenone are not well defined. Here we report that rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells is attenuated by pretreatment with several growth factors, most notably basic fibroblast growth factor ( bFGF). bFGF activated both extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3-kinase) pathways in SH-SY5Y cells. Ectopic activation of ERK1/2 or PI3-kinase protected against rotenone, whereas inhibition of either pathway attenuated bFGF protection. Reducing the expression of the proapoptotic protein Bcl-2-associated death protein ( BAD) by small interfering RNA rendered SH-SY5Y cells resistant to rotenone, implicating BAD in rotenone-induced cell death. Interestingly, bFGFinduced a long-lasting phosphorylation of BAD at serine 112, suggesting BAD inactivation through the ERK1/2 signaling pathway. Moreover, primary cultured dopaminergic neurons from mesencephalon were more sensitive to rotenone-induced cell death than nondopaminergic neurons in the same culture. The loss of dopaminergic neurons was blocked by bFGF, an inhibition dependent on ERK1/2 and PI3-kinase signaling. These data suggest that rotenone-induced dopaminergic cell death requires BAD and identify bFGF and its activation of ERK1/2 and PI3-kinase signaling pathways as novel intervention strategies to block cell death in the rotenone model of Parkinson's disease.