Almeida R D, Manadas B J, Melo C V, Gomes J R, Mendes C S, Grãos M M, Carvalho R F, Carvalho A P, Duarte C B
Center for Neuroscience and Cell Biology and Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.
Cell Death Differ. 2005 Oct;12(10):1329-43. doi: 10.1038/sj.cdd.4401662.
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.
神经营养因子可保护神经元免受谷氨酸兴奋性毒性作用，但其信号传导机制尚未完全阐明。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）信号通路在保护培养的海马神经元免受谷氨酸诱导的凋亡性细胞死亡中的作用，该凋亡性细胞死亡以核固缩和类半胱天冬酶-3样酶的激活为特征。用神经营养因子脑源性神经营养因子（BDNF）预孵育24小时，可减少谷氨酸诱发的凋亡形态和类半胱天冬酶-3样活性，并短暂增加PI3-K和Ras/MAPK信号通路的活性。抑制PI3-K和Ras/MAPK信号通路可消除BDNF对谷氨酸诱导的神经元死亡的保护作用，并且在抑制蛋白质合成时也观察到类似的效果。此外，用BDNF孵育海马神经元24小时可增加Bcl-2蛋白水平。结果表明，BDNF对海马神经元谷氨酸毒性的保护作用是由PI3-K和Ras/MAPK信号通路介导的，并且涉及蛋白质合成的长期变化。
