Angiotensin Type 2 Receptor Stimulation With Compound 21 Improves Stroke Outcome In Female Rats: Possible Role For Peroxisome Proliferator-Activated Receptor Gamma

Introduction: The angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neuro-protective, pro-angiogenic and anti-inflammatory after stroke in male rats. Here we aimed to study the effect of C21 treatment on ovary-intact female rats after stroke. Methods: Female Wistar rats were subjected to 3 h middle cerebral artery occlusion (MCAO) using a silicone-coated monofilament and treated at reperfusion with IP C21 0.03 mg/kg. Rats were sacrificed at 24 h and brains collected for infarct analysis. Another cohort of female rats were subjected to MCAO and treated at reperfusion with C21 for 2 days. Animals were followed up and sacrificed at 72 h. Behavioral tests (Bederson, Paw grasp, Beam walk and Rotarod) were performed at 24 h and 72 h, and whole brains were collected for western blotting. Results (mean±SEM): C21 treatment in females resulted in a decrease in infarct size, improvement in Bederson, Paw grasp and rotarod scores. Interestingly, C21 treatment showed a trend toward increased expression of the transcription factor PPARγ at 72 h in sham and stroked animals suggesting a novel crosstalk between the AT2R and PPARγ after ischemic stroke. In addition, stroke surgery resulted in a decrease in the AT2R expression. However, sham treated animals had an increase in the AT2R expression. Conclusions: AT2R stimulation using C21 improves stroke outcome in ovary-intact female rats.