Zhu Xiaoxia, Park Juyeon, Golinski Julianne, Qiu Jianhua, Khuman Jugta, Lee Christopher C H, Lo Eng H, Degterev Alexei, Whalen Michael J
1] Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [2] Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [3] Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China.
1] Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [2] Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
J Cereb Blood Flow Metab. 2014 Sep;34(9):1531-9. doi: 10.1038/jcbfm.2014.113. Epub 2014 Jun 18.
Akt (protein kinase B) and mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of cell death and cognitive outcome after cerebral contusion in mice; however, a role for Akt/mTOR in concussive brain injury has not been well characterized. In a mouse closed head injury (CHI) concussion traumatic brain injury (TBI) model, phosphorylation of Akt (p-Akt), mTOR (p-mTOR), and S6RP (p-S6RP) was increased by 24 hours in cortical and hippocampal brain homogenates (P<0.05 versus sham for each), and p-S6RP was robustly induced in IBA-1+ microglia and glial fibrillary acidic protein-positive (GFAP+) astrocytes. Pretreatment with inhibitors of Akt or mTOR individually by the intracerebroventricular route reduced phosphorylation of their respective direct substrates FOXO1 (P<0.05) or S6RP (P<0.05) after CHI, confirming the activity of inhibitors. Rapamycin pretreatment significantly worsened hidden platform (P<0.01) and probe trial (P<0.05) performance in CHI mice. Intracerebroventricular administration of necrostatin-1 (Nec-1) before CHI increased hippocampal Akt and S6RP phosphorylation and improved place learning (probe trials, P<0.001 versus vehicle), whereas co-administration of rapamycin or Akt inhibitor with Nec-1 eliminated improved probe trial performance. These data suggest a beneficial role for Akt/mTOR signaling after concussion TBI independent of cell death that may contribute to improved outcome by Nec-1.
Akt（蛋白激酶B）和雷帕霉素哺乳动物靶蛋白（mTOR）与小鼠脑挫伤后的细胞死亡发病机制和认知结果有关；然而，Akt/mTOR在脑震荡性脑损伤中的作用尚未得到充分表征。在小鼠闭合性颅脑损伤（CHI）脑震荡创伤性脑损伤（TBI）模型中，皮质和海马脑匀浆中Akt（p-Akt）、mTOR（p-mTOR）和S6RP（p-S6RP）的磷酸化在24小时时增加（每组与假手术组相比，P<0.05），并且p-S6RP在IBA-1+小胶质细胞和胶质纤维酸性蛋白阳性（GFAP+）星形胶质细胞中被强烈诱导。通过脑室内途径单独用Akt或mTOR抑制剂预处理可降低CHI后其各自直接底物FOXO1（P<0.05）或S6RP（P<0.05）的磷酸化，证实了抑制剂的活性。雷帕霉素预处理显著恶化了CHI小鼠的隐藏平台（P<0.01）和探针试验（P<0.05）表现。在CHI前脑室内注射坏死抑制因子-1（Nec-1）可增加海马Akt和S6RP磷酸化并改善位置学习（探针试验，与载体相比，P<0.001），而将雷帕霉素或Akt抑制剂与Nec-1联合使用可消除改善的探针试验表现。这些数据表明，脑震荡性TBI后Akt/mTOR信号传导具有有益作用，独立于细胞死亡，这可能有助于Nec-1改善结果。
