Isoflurane preconditioning activates HIF-1α, iNOS and Erk1/2 and protects against oxygen-glucose deprivation neuronal injury
Isoflurane preconditioning activates HIF-1α, iNOS and Erk1/2 and protects against oxygen-glucose deprivation neuronal injury
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DOI：
10.1016/j.brainres.2008.09.069
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发表时间：
2008-12-15
期刊：
影响因子：
2.9
通讯作者：
Jiang, Hong
中科院分区：
文献类型：
--
作者：
Li, Qi-fang;Zhu, Ye-sen;Jiang, Hong
在完整的动物模型和体外制剂中，用异氟醚(临床上常用的一种挥发性麻醉剂)对神经元进行预处理可以提高对后续缺血的耐受性。为了探讨这种保护作用的机制，我们原代培养了大鼠海马神经元，并用氧-糖剥夺(OGD)的方法模拟了体外缺血。测定神经元存活率。倒置相差显微镜观察神经元损伤情况，乳酸脱氢酶(LDH)释放量评价神经元损伤程度。用Western印迹和逆转录-聚合酶链式反应(RT-PCR)检测基因表达。异氟醚在24小时暴露2小时后，OGD 2小时可剂量依赖性地减少细胞损伤。异氟醚诱导细胞外信号相关蛋白1和2(ERK1/2)和低氧诱导因子(HIF)-1α的磷酸化/活化，后者是细胞存活的转录因子。抑制磷酸化ERK1/2可部分阻断异氟烷预适应诱导的HIF-1α蛋白积累和神经保护作用。异氟醚还增加了诱导型一氧化氮合酶(INOS)的mRNA水平，iNOS是HIF-1α的下游基因。因此，目前的结果表明，异氟醚预适应在保护OGD神经元损伤的过程中激活了HIF-1α，这种激活可能部分通过ERK1/2通路介导。皇冠版权所有(C)2008由爱思唯尔出版。保留所有权利。
Preconditioning neurons with isoflurane, a commonly used volatile anesthetic in clinical practice, improves tolerance of subsequent ischemia in both intact animal models and in vitro preparations. To investigate the mechanisms of this protection, we primarily cultured rat hippocampal neurons and simulated ischemia in vitro by oxygen-glucose deprivation (OGD). Neuron viability was measured. Neuron injury was observed by inverted phase contrast microscope and assessed by lactate dehydrogenase (LDH) release. Gene expression was examined by Western blot and reverse transcription-polymerase chain reaction (RTPCR). Isoflurane exposure for 2 h at 24 h before a 2 h OGD dose-dependently reduced cell injury. Isoflurane accumulated phosphorylation/activation of extracellular signal-related kinases 1 and 2 (Erk1/2) and hypoxia inducible factor (HIF)-1 alpha, a transcription factor involved in cell survival. inhibition of the phospho-Erk1/2 partially abolished the isoflurane preconditioning-induced HIF-1 alpha protein content accumulation and neuroprotection. Isoflurane also increased inducible nitric oxide synthase (iNOS) mRNA levels, a downstream gene of HIF-1 alpha. Thus, the current results indicate that isoflurane preconditioning activates HIF-1 alpha during protection against OGD neuronal injury and the activation might be partly mediated by the Erk1/2 pathway. Crown Copyright (C) 2008 Published by Elsevier B.V. All rights reserved.