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

• Published in: Molecular neurobiology 2016-10, Vol.53 (8), p.5737-5748
• Main Authors: Feng, Dayun, Wang, Bao, Ma, Yulong, Shi, Wei, Tao, Kai, Zeng, Weijun, Cai, Qing, Zhang, Zhiguo, Qin, Huaizhou
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Apoptosis; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cells, Cultured; Flavonoids - pharmacology; Hemorrhage; Hippocampus - pathology; Male; MAP Kinase Signaling System - drug effects; Models, Biological; Neurobiology; Neurology; Neurons; Neurons - metabolism; Neurons - pathology; Neurosciences; Oxyhemoglobins - pharmacology; Phosphorylation; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; raf Kinases - metabolism; ras Proteins - metabolism; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Ribonucleic acid; RNA; RNA, Small Interfering - metabolism; Subarachnoid Hemorrhage - metabolism; Subarachnoid Hemorrhage - pathology; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-015-9490-x

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.