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Ras/Raf/Erk 通路通过磷酸化 p53 介导蛛网膜下腔出血诱导的海马神经元凋亡。

The Ras/Raf/Erk Pathway Mediates the Subarachnoid Hemorrhage-Induced Apoptosis of Hippocampal Neurons Through Phosphorylation of p53.

机构信息

Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.

Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.

出版信息

Mol Neurobiol. 2016 Oct;53(8):5737-48. doi: 10.1007/s12035-015-9490-x. Epub 2015 Oct 26.

Abstract

Apoptosis plays a crucial role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). However, the exact molecular mechanisms underlying neuronal apoptosis in EBI after SAH have not been fully elucidated. The present study showed that EBI induced significantly neuronal apoptosis activation of Ras/Raf/Erk signals in hippocampus after SAH. Intracisternal administration of PD98059, an inhibitor of Erk1/2, decreased the hippocampal neuronal apoptosis and alleviated the cognitive deficits induced by SAH. Interestingly, an increase in phosphorylation of p53 was paralleled with p-Erk, and PD98059 also blocked the level of p-p53. In primary cultures, oxyhemoglobin (OxyHb) treatment significantly increased p-Erk, p-p53, and apoptosis, which was used to mimic the pathological injury of SAH. Both p53 small interfering RNA (siRNA) and PD98059 reduced the OxyHb-induced apoptosis. Moreover, PD98059 significantly decreased the levels of p-Erk and p-p53; however, p53 siRNA had little effect on the level of p-Erk. Taken together, our study implicates that the Ras/Raf/Erk signals contribute to neuronal death through the phosphorylation of p53 in hippocampus after SAH and also suggests Erk/p53 as a potential target for clinical drug treatment of SAH.

摘要

细胞凋亡在蛛网膜下腔出血(SAH)后早期脑损伤(EBI)的发病机制中起着至关重要的作用。然而,SAH 后 EBI 中神经元凋亡的确切分子机制尚未完全阐明。本研究表明,SAH 后 EBI 诱导 Ras/Raf/Erk 信号在海马中显著激活神经元凋亡。鞘内给予 Erk1/2 抑制剂 PD98059 可减少海马神经元凋亡,并减轻 SAH 引起的认知功能障碍。有趣的是,p53 的磷酸化与 p-Erk 平行增加,PD98059 也阻断了 p-p53 的水平。在原代培养中,氧合血红蛋白(OxyHb)处理显著增加了 p-Erk、p-p53 和凋亡,用于模拟 SAH 的病理损伤。p53 小干扰 RNA(siRNA)和 PD98059 均可减少 OxyHb 诱导的凋亡。此外,PD98059 显著降低了 p-Erk 和 p-p53 的水平;然而,p53 siRNA 对 p-Erk 水平几乎没有影响。总之,我们的研究表明,Ras/Raf/Erk 信号通过 SAH 后海马中 p53 的磷酸化导致神经元死亡,并提示 Erk/p53 可能成为治疗 SAH 的临床药物治疗的潜在靶点。

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