17-AAG post-treatment ameliorates memory impairment and hippocampal CA1 neuronal autophagic death induced by transient global cerebral ischemia
17-AAG post-treatment ameliorates memory impairment and hippocampal CA1 neuronal autophagic death induced by transient global cerebral ischemia
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DOI：
10.1016/j.brainres.2015.03.051
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发表时间：
2015-06-12
期刊：
影响因子：
2.9
通讯作者：
Qin, Xinyue
中科院分区：
文献类型：
--
作者：
Li, Jianxiong;Yang, Fei;Qin, Xinyue
神经炎症在全脑缺血（GC）中起重要作用。热休克蛋白70（Hsp 70）是一种分子量为72 kDa的蛋白质，它参与了多种中枢神经系统疾病的炎症反应。临床前研究结果表明，临床抗癌药物17-烯丙氨基-去甲氧基格尔德霉素（17-AAG）在脑外伤大鼠模型中具有神经保护作用，而17-AAG的有益作用具体归因于Hsp 70的上调。然而，没有实验测试17-AAG在GCI的设置中是否具有有益或有害的影响。本研究旨在确定17-AAG给药可以减轻脑梗死和改善神经元存活，从而改善GCI大鼠模型的记忆障碍的假设。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CA 1中多种炎症细胞因子水平以及自噬相关蛋白的表达。我们的研究结果表明，GCI后给予17-AAG显着保护大鼠免受GCI诱导的脑损伤，17-AAG也是一种有效的炎症反应拮抗剂，从而改善海马CA 1区神经元自噬死亡。因此，我们相信，本研究提供了新的线索，了解17-AAG发挥其神经保护活性的机制，在GCI。所有数据表明17-AAG可能是缺血性中风的潜在神经保护剂。(C)2015 Elsevier B. V.版权所有。
Neuro-inflammation plays an important role in global cerebral ischemia (GC). 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. (C) 2015 Elsevier B.V. All rights reserved.