Abstract 43: Endovascular Delivery of Low Dose Compound 21 is Neuroprotective Independent of Reperfusion in Ischemic Stroke

Abstract

Background: Intracerebroventricular (ICV) injection of angiotensin type 2 receptor (AT2R) agonists is neuroprotective in stroke. However, ICV delivery of a blood brain barrier impermeable AT2R agonists has limited utility in clinical stroke treatment. We investigated whether low dose endovascular (EV) delivery of a selective AT2R agonist, Compound 21 (C21), after stroke confers neuroprotection under various states of reperfusion. Methods: Aged male mice (12 mos) underwent either permanent middle cerebral artery ligation (pMCAL)(n=12) or spontaneously reperfusing embolic clot MCA occlusion (eMCAo)(n=10). Mice were randomized to EV-delivery of either C21 (1 μg/kg) or 10μL saline at the site of occlusion 2h post-stroke. Statistical significance was determined at p<0.05. Results: C21 treatment following pMCAL prevented infarct progression and significantly reduced stroke injury by >30% at 48h post pMCAL (p<0.02). In eMCAo stroke, C21 was effective in reducing both infarction volume and edema by >25% (p<0.01). Conclusions: We demonstrate that EV-delivery of C21 is effective in both non-reperfused and spontaneously reperfusing stroke. This site-specific delivery may have potential benefits as an adjuvant neuroprotectant combined with endovascular thrombectomy, while averting possible blood-pressure lowering risks associated with AT2R agonism. Of additional translational interest, the current COVID19 pandemic and related ongoing recombinant huACE2-trial therapies will eventually affect ATRs physiology. Given the prominence of thrombotic strokes in COVID19 patients, C21 as an AT2R agonist may be a potential therapy to test in COVID19-related thrombotic stroke models.