Delayed treatment of α5 GABAA receptor inverse agonist improves functional recovery by enhancing neurogenesis after cerebral ischemia-reperfusion injury in rat MCAO model
Delayed treatment of α5 GABAA receptor inverse agonist improves functional recovery by enhancing neurogenesis after cerebral ischemia-reperfusion injury in rat MCAO model
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DOI：
10.1038/s41598-019-38750-0
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发表时间：
2019-02-19
影响因子：
4.6
通讯作者：
Peng, Yu-Ping
中科院分区：
文献类型：
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作者：
He, Wei-Ming;Ying-Fu, Li;Peng, Yu-Ping
开发有效的治疗方法和治疗策略以促进脑缺血再灌注损伤后的恢复需要进一步了解缺血性卒中复杂的病理生理学。鉴于α 5-GABA（A）R抑制已被证明参与中风后的功能恢复，本研究旨在评估α 5-GABA（A）R抑制的治疗时机对大脑中动脉闭塞（MCAO）后功能恢复的影响。为此，我们检测了缺血后3或7天L 655，708（α 5 GABA（A）R反向激动剂）治疗对大鼠梗死周围区域的细胞凋亡和神经发生、脑梗死大小以及改良的神经严重性评分（mNSS）和转棒试验时间的影响。与以前的报道一致，我们发现，当在MCAO后第3天开始L 655，708的治疗时，它没有改变大鼠的功能恢复。然而，当在MCAO后第7天开始L 655，708的治疗时，其显示出对大鼠功能恢复的有益作用。有趣的是，这种现象与脑梗死面积的改变和脑细胞凋亡的变化无关。然而，我们发现在MCAO后第7天延迟L 655，708的治疗显著增加了大鼠梗死周围区的神经发生。这些结果表明，消除脑缺血再灌注损伤后α 5 GABA（A）R介导的紧张性抑制可能是促进脑卒中功能恢复的有效治疗策略。
Development of effective therapeutics and treatment strategy to promote recovery after cerebral ischemia-reperfusion injury necessitates further understandings of the complex pathophysiology of ischemic stroke. Given that alpha 5-GABA(A)R inhibition has been shown to be involved in functional recovery after stroke, the present study was designed to evaluate the effects of treatment timing of alpha 5 GABA(A)R inhibition on post-middle cerebral artery occlusion (MCAO) functional recovery. To this end, we examined the effects of L655,708 (alpha 5 GABA(A)R inverse agonist) treatment at 3 or 7 days post-ischemia on apoptosis and neurogenesis in the peri-infarct region, brain infarction size, as well as modified neurological severity score (mNSS) and rotarod test time in rats. Consistent with previous reports, we found that when the treatment of L655,708 was initiated at post-MCAO day 3, it did not alter the functional recovery in rats. However, when the treatment of L655,708 was initiated at post-MCAO day 7, it demonstrated beneficial effects on functional recovery in rats. Interestingly, this phenomenon was not associated with altered brain infarction size nor with changes in brain cell apoptosis. However, we found that delayed treatment of L655,708 at post-MCAO day 7 significantly increased neurogenesis in peri-infarct zone in rats. These results suggested that removing alpha 5 GABA(A)R-mediated tonic inhibition after cerebral ischemia-reperfusion injury may be an effective therapeutic strategy for promoting functional recovery from stroke.