Abstract WP113: Dose-response and Therapeutic Time-window of Compound 21: a Randomized Preclinical Trial in Rat Model of Thromboembolic Stroke

Abstract

Background: We and others have previously shown promising results with the use of the angiotensin type 2 receptor agonist, compound 21 (C21), in experimental stroke. Here we aimed to determine the best dose and time window for C21 in a clinically relevant embolic stroke model. Methods: This study was conducted as a translational, randomized, controlled, blinded preclinical trial with the guidance of our biostatistician. Male Wistar rats (8-9 weeks old) were subjected to embolic middle cerebral artery occlusion (eMCAO). For the dose-response study, animals received C21 (0.01, 0.03 and 0.06 mg/kg/d) or saline (orally) for 5 days, with the first dose given IV at 3 h post-eMCAO. For the time-window study, the optimal dose of C21 was initiated at 3, 6 or 24 h post-eMCAO and daily thereafter, for 5 days. Behavioral outcomes (Bederson, paw grasp and grip strength) were blindly assessed at days, 1, 3, 5 and 7. Rats were then sacrificed and their brains collected for infarct size and vascular density analyses. Results (Table): In the dose-response study, repeated-measures ANOVA showed significant (p < 0.05) behavioral improvement with the low dose (0.01 mg/kg). This dose was associated with higher vascularity in the ischemic penumbra, detected by laminin staining, compared to saline treated controls (65±6 vs 46±7 p < 0.05). In the time-window study, the 0.01 mg/kg dose displayed non-statistically significant improvements when given 3 h and 6 h after eMCAO. There were no differences between doses or time-windows for either % infarct size or tissue loss. Conclusions: C21 given at 0.01 mg/kg/d was effective in improving behavioral dysfunction after embolic stroke when administered within 6 h. Compound C21 shows promise as a potential therapeutic agent and should be examined for safety and efficacy in clinical trials for ischemic stroke.