Central and Peripheral Administration of Compound 21 Elicits Cerebroprotective Effects in Ischemic Stroke

Abstract

Studies indicate that angiotensin type 2 receptors (AT2R) in the CNS exert beneficial actions in ischemic stroke. Here we tested the effects of a specific AT2R agonist, Compound 21 (Cp21), on the cerebral deficits produced by endothelin‐1 induced middle cerebral artery occlusion (MCAO). Adult male Sprague Dawley rats were pre‐treated with Cp21 (0.0075μg/h) or artificial cerebrospinal fluid (aCSF) via intracerebroventricular infusion for 7 days prior to ET‐1 induced MCAO. Cp21 treatment reduced neurological deficits and infarct size measured 72 h after MCAO induction. Infarct size was reduced to 28.2±4.0% of ipsilateral gray matter in Cp21‐treated rats (n=16) compared with 54.1±4.7% in aCSF controls (n=21; p=0.0006). Neurological deficits were reduced by Cp21 treatment as indicated by a lower Bederson Exam Score of 0.3±0.1 compared to 1.6±0.2 in control rats (p<0.0001) and a higher Garcia Exam Score of 16.9±0.3 compared to 14.3±0.7 in control rats (p=0.0011). Similar results were obtained with the IP administration of Cp21. Rats received IP injections with Cp21 (0.03 mg) or 0.9% saline at 2 hours prior, and 4, 24, and 48 hours following MCAO induction. Infarct size was reduced to 19.2±3.8% of ipsilateral gray matter in Cp21 treated rats (n=6) compared with 41.5±6.8% in saline controls (n=6; p=0.004). These data are the first demonstration of a non‐peptide AT2R agonist exerting cerebroprotection following MCAO.