Abstract 25: Promoting Recovery After Stroke by Manipulating NMDA Receptor-Associated Signalling in the Early Post Stroke Phase

Abstract

Introduction: According to the World Health Organization (WHO), stroke remains a leading cause of mortality and neurological disability globally. To date, there is no effective pharmacological treatment to promote recovery from stroke. Promoting regenerative repair may improve recovery and it is known that N-methyl-D- aspartate receptors (NMDARs) play important roles in neural circuit rebuilding. Therefore, an appealing strategy to promote stroke recovery is to selectively inhibit cell death mechanisms while promoting pro-survival processes mediated by NMDARs. A promising agent for this purpose is Tat-NR2B9c (NA-1), a clinical-stage agent being tested in Phase 3 trials for acute ischemic stroke. Tat-NR2B9c promotes the activation of pro-survival signaling and is a potent neuroprotector against excitotoxicity. Here we sought to determine whether treatment with Tat-NR2B9c promotes functional recovery in rats subjected to ischemic brain damage during the subacute recovery phase. Methods: Stroke was induced by Pial Vessel Disruption (PVD) in Sprague Dawley rats. Permanent devascularisation was induced by removing all the pia and the attached blood vessels of the left motor cortex. Experimental groups were: PVD + Tat-NR2B9c (n = 12); PVD + Vehicle (n = 11); Sham + Tat-NR2B9c (n = 8); Sham + Vehicle (n = 8). Tat-NR2B9c was injected intravenously (IV) beginning 3 days after stroke and was administered daily for 7 days. A behavioral battery of tests followed, composed of neurological score, cylinder test, horizontal ladder and adhesive removal tests. Brains were stained with H&E and the infarct size was analyzed by ImageJ. Results: Repeated IV injections of Tat-NR2B9c led to a significant improvement in all motor tasks: decreased number in foot slips by 3.6-fold in horizontal ladder (P < 0.0001); improved neurological score by 4.7-fold compared to control (P < 0.0001); improved use of affected limb by 58% in cylinder test (P = 0.0006); reduced adhesive removal test time by 81% (P < 0.0001). There was no difference in infarct sizes between the groups. Conclusion: Treatment with Tat-NR2B9c post stroke improved functional outcome in rats subjected to PVD. Current studies are ongoing to assess the mechanism of action underlying the observed recovery.