Post-acute administration of the GABAA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats

Abstract

BackgroundIschemic stroke induces hypoexcitability of the peri-infarct cortex by increased tonic GABA activity, which impairs stroke recovery. The GABAA 5 antagonist S44819 has recently been shown to promote post-ischemic motor-coordination recovery after transient proximal middle cerebral artery occlusion (MCAO) in mice. The effects of S44819 on post-ischemic skilled limb movement recovery have so far not yet been assessed in rats.\n\nMethodsMale Sprague-Dawley rats were subjected to permanent distal MCAO. Starting 3 days post-stroke, vehicle or S44819 (3 or 10 mg/kg) were delivered orally twice a day for 28 days. A single pellet reaching test was performed at baseline, before treatment onset and at weekly intervals thereafter. Animals were sacrificed at 45 days post-stroke (that is, at 42 days post-treatment onset) after 14 days of drug washout. Body weight was monitored, and infarct size was determined by histology.\n\nResultsS44819, administered at 10 mg/kg but not 3 mg/kg significantly improved single pellet reaching performance over 45 days (F(2,96)=22.43, p<0.001). Body weight was not altered. S44819 had no effect on infarct size.\n\nConclusionOur data indicate that post-acute administration of S44819 at 10 mg/kg promotes skilled forelimb movements. The effect was maintained after S44819 wash out.