中文摘要：

神经退行性疾病的发生过程中,引起神经细胞失活和凋亡的因素有很多,其中有研究显示,细胞周期因子被激活后,会导致神经元的异常反应甚至细胞凋亡。为此,我们用小鼠和PC12细胞建立急性和慢性乙醇诱导神经细胞凋亡的模型,研究细胞周期因子在神经细胞凋亡中的作用。然后,我们在急性乙醇刺激PC12细胞模型上,使用p53抑制剂和CDK4抑制剂来探究p53,cyclin D1和CDK4在caspase-3通路介导的凋亡中的作用。结果表明,一次给予大剂量乙醇会引发小鼠神经元内的p53,CDK4和cyclin D1的高表达和细胞凋亡,而长期低剂量的乙醇对小鼠神经细胞凋亡的作用并不明显。进一步研究显示,p53抑制剂能够降低caspase-3对乙醇刺激的响应,降低PC12细胞凋亡,然而CDK4抑制剂并不具有类似效果。阻断p53/caspase-3通路可以为乙醇代谢、以及细胞自身修复乙醇所致损伤赢得时间。总之,乙醇诱导的神经细胞凋亡与p53/caspase-3通路的激活有关,阻断p53的功能能够防治神经细胞损伤。

英文摘要：

Dysfunction and apoptosis of neurons triggered by various stimulations mainly contribute to neurodegenerative diseases. Gradually appeared reports have indicated that stimulations can initiate activation of aberrant cell cycle factors in neurons, leading to abnormal cell behavior and apoptosis finally. In our study, apoptosis induced by activation of cell cycle factors was investigated using mice and PC12 cells as acute alcohol exposure models in vivo and in vitro, respectively. Moreover, p53 inhibitor and CDK4 inhibitor were applied in alcohol-treated PC12 cells to define the essential roles of p53, cyclin D1 and CDK4 in caspase-3 apoptotic pathway upon acute alcohol exposure. The data showed that acute excessive alcohol exposure up-regulated the expressions of p53, CDK4 and cyclin D1, and it also triggered apoptosis. However, chronic consumption of low content of alcohol did not cause neuronal apoptosis. Inhibition of p53 weakened the activation of caspase-3 and attenuated alcohol-induced apoptosis in PC12 cells, whereas blockage of cyclin D1 and CDK4 did not have such an effect. Blockage of p53/caspase-3 pathway would give cells time to metabolize alcohol and repair alcohol-caused damage. Taken together, neuronal apoptosis triggered by acute excessive alcohol exposure was correlated to activation of the p53/caspase-3 signaling, and blockage of p53 would be a possible way to suppress acute alcohol exposure-induced apoptosis.