Delayed treatment of α5 GABAA receptor inverse agonist improves functional recovery by enhancing neurogenesis after cerebral ischemia-reperfusion injury in rat MCAO model

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 α5-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 α5 GABA(A)R inhibition on post-middle cerebral artery occlusion (MCAO) functional recovery. To this end, we examined the effects of L655,708 (α5 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 α5 GABA(A)R-mediated tonic inhibition after cerebral ischemia-reperfusion injury may be an effective therapeutic strategy for promoting functional recovery from stroke.