Angiotensin Type 2 Receptor Stimulation With Compound 21 Prevents Delayed Cognitive Impairment In Hypertensive, Ovariectomized Female Rats After Ischemic Stroke: A Randomized, Blinded, Preclinical Study

Introduction: The angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neuroprotective and neurorestorative after stroke in male rats. Here, we aim to determine the long-term impact of C21 treatment on hypertensive female rats after stroke. Methods: Twenty female ovariectomized spontaneously hypertensive rats (SHRs), 16 weeks of age, were subjected to 1h MCAO and randomized at 24h to receive either vehicle or IP C21 0.03 mg/kg for 5 days followed by oral C21 (0.12mg/kg/day) for 5 weeks in drinking water. Sensorimotor behavior tests (modified Bederson, 0-8, where 8 is normal) were performed at 24h and weekly, while cognitive assessments (Passive Avoidance and Novel Object Recognition) were performed at weeks 5 and 6. Results: (mean±SEM) All stroked animals survived and showed improved motor performance at 6 weeks, with no effect of C21. However, C21 treatment significantly improved non-spatial working memory and reference memory without an effect on anxiety level at 6 weeks post-stroke. Conclusions: AT2R stimulation using C21 improves sensorimotor function and prevents the development of cognitive impairment in ovariectomized female rats, even when initiated at 24 hours after stroke.