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• W2788878633 abstract "Objective: We hypothesized that blockade of the γ-amino-butyric acid (GABA)A receptor using the selective α5-antagonist S44819 promotes brain remodeling and plasticity in the post-acute stroke phase and enhances neurological recovery. Background: GABA, the predominant inhibitory neurotransmitter in the adult mammalian brain, has a critical role in post-stroke neurological recovery. Tonic GABA activity is increased in peri-infarct cortex, resulting in cerebral hypoexcitability that compromises brain plasticity. Design/Methods: C57BL6/j mice were exposed to transient intraluminal middle cerebral artery occlusion. Starting 72 hours post-stroke, vehicle or S44819 (3 or 10 mg/kg, b.i.d. per os) were administered over 28 days. Neurological recovery was evaluated during S44819 delivery and up to 14 days after completion of S44819 delivery using Rotarod, tight rope, open field and Barnes maze tests (n=18 animals/group). Perilesional tissue remodeling was evaluated by quantifying brain and striatal atrophy (cresyl violet histochemistry), neuronal survival (NeuN immunohistochemistry) and glial scar formation (GFAP immunohistochemistry) at 14, 28 and 42 dpt (n=6 animals per group). Results: S44819, delivered at 10 but not 3 mg/kg, persistently improved motor-coordination skills, examined by Rotarod and tight rope tests, starting at 14 dpt. This effect persisted after completion of S44819 delivery, i.e. up to 42 dpt. Spatial memory, assessed by Barnes maze tests at 8–19 dpt, was enhanced by S44819. Spontaneous motor activity, evaluated in open-field tests, was increased at 7 dpt but not 28 dpt, whereas anxiety, also investigated by open-field tests, was reduced at 7 dpt but not 28 dpt. Delayed atrophy of the striatum, i.e., the core of the middle cerebral artery territory, was reduced by S44819 at 42, but not 14 or 28 dpt, whereas neuronal survival was enhanced at 42 dpt and glial scar formation was reduced at 14, 28 and 42 dpt. Conclusions: Our data provide strong evidence that S44819 enhances neurological recovery in the post-acute stroke phase. Disclosure: Dr. Wang has nothing to disclose. Dr. Sanchez-Mendoza has nothing to disclose. Dr. de Carvalho has nothing to disclose. Dr. Kaltwasser has nothing to disclose. Dr. Machado has received personal compensation as an employee of Servier (France), Dr. Doeppner has nothing to disclose. Dr. Bassetti has received personal compensation for activities with Servier as an Advisory Board Member. Dr. Bassetti has received research support from Servier. Dr. Hermann has received personal compensation for activities with Servier as Advisory board. Dr. Hermann has received research support from Servier." @default.
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• W2788878633 date "2017-04-18" @default.
• W2788878633 modified "2023-09-23" @default.
• W2788878633 title "Post-acute delivery of GABAA receptor alpha5-antagonist S44819 promotes motor-coordination recovery, prevents secondary brain atrophy and reduces astrocytic scar formation after transient middle cerebral artery occlusion in mice (P3.109)" @default.
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