Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Brain Res. 2011 Jul 21;1402:109-21. doi: 10.1016/j.brainres.2011.05.049. Epub 2011 May 27.
Our previous studies have demonstrated that hyperbaric oxygen (HBO) preconditioning induces tolerance to focal cerebral ischemia. The present study aimed to investigate whether autophagy is involved in the neuroprotection elicited by HBO preconditioning in a rat model of transient focal cerebral ischemia. Twenty-four hours after the completion of HBO preconditioning (2.5 atm absolute in 100% oxygen for 60 min per day for 5 consecutive days), male Sprague-Dawley rats were subjected to focal cerebral ischemia by middle cerebral artery occlusion (MCAO) for 120 min. The neurobehavioral score and infarct volume were used to evaluate cerebral ischemic injury. An intracerebroventricular injection of the autophagy inhibitor 3-methyladenine (3-MA) or the autophagy inducer rapamycin was administered before HBO preconditioning or MCAO. We found that after reperfusion the protein expression of LC3-II and Beclin 1 and the formation of autophagosomes were increased by HBO preconditioning or ischemia, but the increase following HBO preconditioning was higher than the increase following ischemia. 3-MA suppressed the increases in LC3-II and Beclin 1 induced by HBO preconditioning and attenuated the neuroprotection of HBO preconditioning against cerebral ischemia. Furthermore, 3-MA treatment before MCAO aggravated subsequent cerebral ischemic injury. In contrast, pretreatment with rapamycin up-regulated LC3-II and Beclin 1 after reperfusion and mimicked the neuroprotective effect of HBO preconditioning. These results indicate that HBO preconditioning elevates autophagic activity, which elicits a neuroprotective effect against ischemic injury in the brain, and suggest a novel mechanism of HBO preconditioning-induced tolerance against transient focal cerebral ischemia.
我们之前的研究表明，高压氧（HBO）预处理诱导对局部脑缺血的耐受。本研究旨在探讨自噬是否参与 HBO 预处理在短暂性大脑中动脉闭塞（MCAO）大鼠模型中引起的神经保护作用。在 HBO 预处理完成后 24 小时（2.5 绝对大气压下，100%氧气，每天 60 分钟，连续 5 天），雄性 Sprague-Dawley 大鼠通过大脑中动脉闭塞（MCAO）进行 120 分钟的局部脑缺血。神经行为评分和梗死体积用于评估脑缺血损伤。在 HBO 预处理或 MCAO 之前，通过脑室内注射自噬抑制剂 3-甲基腺嘌呤（3-MA）或自噬诱导剂雷帕霉素进行干预。我们发现，再灌注后，LC3-II 和 Beclin 1 的蛋白表达以及自噬体的形成增加，而 HBO 预处理后增加的幅度高于缺血后增加的幅度。3-MA 抑制了 HBO 预处理诱导的 LC3-II 和 Beclin 1 的增加，并减弱了 HBO 预处理对脑缺血的神经保护作用。此外，MCAO 前给予 3-MA 治疗加重了随后的脑缺血损伤。相反，雷帕霉素预处理可上调再灌注后 LC3-II 和 Beclin 1 的表达，并模拟 HBO 预处理的神经保护作用。这些结果表明，HBO 预处理可提高自噬活性，对脑缺血损伤产生神经保护作用，并提示 HBO 预处理诱导的短暂性大脑中动脉闭塞耐受性的一种新机制。
