Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways
Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways
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DOI：
10.1038/sj.cdd.4401662
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发表时间：
2005-10-01
影响因子：
12.4
通讯作者：
Duarte, CB
中科院分区：
文献类型：
--
作者：
Almeida, RD;Manadas, BJ;Duarte, CB
神经营养物质保护神经元免受谷氨酸的兴奋性毒性，但其信号机制尚未完全阐明。我们研究了磷脂酰肌醇3-激酶（PI3-K）和Ras/丝裂原活化蛋白激酶（MAPK）通路在保护培养海马神经元免受谷氨酸诱导的凋亡细胞死亡中的作用，其特征是核凝聚和caspase-3样酶的激活。与脑源性神经营养因子（BDNF）共孵育24小时，可降低谷氨酸引起的凋亡形态学和caspase-3样活性，并短暂增加PI3-K和Ras/MAPK通路的活性。抑制PI3-K和Ras/MAPK信号通路可以消除BDNF对谷氨酸诱导的神经元死亡的保护作用，抑制蛋白质合成也可以观察到类似的作用。此外，海马神经元与BDNF孵育24小时后，Bcl-2蛋白水平升高。结果表明，海马神经元BDNF对谷氨酸毒性的保护作用是通过PI3-K和Ras/MAPK信号通路介导的，并涉及蛋白质合成的长期变化。
Neurotrophins protect neurons against glutamate excitotoxicity, but the signaling mechanisms have not been fully elucidated. We studied the role of the phosphatidylinositol 3-kinase (PI3-K) and Ras/mitogen-activated protein kinase (MAPK) pathways in the protection of cultured hippocampal neurons from glutamate induced apoptotic cell death, characterized by nuclear condensation and activation of caspase-3-like enzymes. Pre-incubation with the neurotrophin brain-derived neurotrophic factor (BDNF), for 24 h, reduced glutamate-evoked apoptotic morphology and caspase-3-like activity, and transiently increased the activity of the PI3-K and of the Ras/MAPK pathways. Inhibition of the PI3-K and of the Ras/MAPK signaling pathways abrogated the protective effect of BDNF against glutamate-induced neuronal death and similar effects were observed upon inhibition of protein synthesis. Moreover, incubation of hippocampal neurons with BDNF, for 24 h, increased Bcl-2 protein levels. The results indicate that the protective effect of BDNF in hippocampal neurons against glutamate toxicity is mediated by the PI3-K and the Ras/MAPK signaling pathways, and involves a long-term change in protein synthesis.