Li Jianxiong, Yang Fei, Guo Jia, Zhang Rongrong, Xing Xiangfeng, Qin Xinyue
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Department of Neurology, Chinese PLA General Hospital, Beijing 100853, China.
Brain Res. 2015 Jun 12;1610:80-8. doi: 10.1016/j.brainres.2015.03.051. Epub 2015 Apr 7.
Neuro-inflammation plays an important role in global cerebral ischemia (GCI). The 72-kDa heat shock protein (Hsp70) has been reported to be involved in the inflammatory response of many central nervous system diseases. Preclinical findings implicate that 17-allylamino-demethoxygeldanamycin (17-AAG), an anticancer drug in clinical, provide neuroprotection actions in a rat model of traumatic brain injury, and the beneficial effects of 17-AAG were specifically due to up-regulation of Hsp70. However, no experiments have tested whether 17-AAG has beneficial or harmful effects in the setting of GCI. The present study was designed to determine the hypothesis that administration of 17-AAG could attenuate cerebral infarction and improve neuronal survival, thereby ameliorating memory impairment in a rat model of GCI. Furthermore, to test whether any neuroprotective effect of 17-AAG was associated with inflammatory response and neuronal autophagy, we examined the expression of multiplex inflammatory cytokine levels as well as autophagy-associate protein in hippocampal CA1 of rat brain. Our results showed that post-GCI administration of 17-AAG significantly protected rats against GCI induced brain injury, and 17-AAG is also an effective antagonist of the inflammatory response and thereby ameliorates hippocampal CA1 neuronal autophagic death. We therefore believe that the present study provides novel clues in understanding the mechanisms by which 17-AAG exerts its neuroprotective activity in GCI. All data reveal that 17-AAG might be a potential neuroprotective agent for ischemic stroke.
神经炎症在全脑缺血（GCI）中起重要作用。据报道，72-kDa热休克蛋白（Hsp70）参与许多中枢神经系统疾病的炎症反应。临床前研究结果表明，临床用抗癌药17-烯丙基氨基-去甲氧基格尔德霉素（17-AAG）在创伤性脑损伤大鼠模型中具有神经保护作用，且17-AAG的有益作用具体归因于Hsp70的上调。然而，尚无实验测试17-AAG在GCI情况下是有益还是有害。本研究旨在验证以下假设：给予17-AAG可减轻脑梗死并改善神经元存活，从而改善GCI大鼠模型的记忆障碍。此外，为了测试17-AAG的任何神经保护作用是否与炎症反应和神经元自噬相关，我们检测了大鼠脑海马CA1区多种炎性细胞因子水平以及自噬相关蛋白的表达。我们的结果表明，GCI后给予17-AAG可显著保护大鼠免受GCI诱导的脑损伤，并且17-AAG也是炎症反应的有效拮抗剂，从而改善海马CA1神经元的自噬性死亡。因此，我们认为本研究为理解17-AAG在GCI中发挥神经保护活性的机制提供了新线索。所有数据表明，17-AAG可能是缺血性中风的潜在神经保护剂。
