Abstract WP113: Administration of Direct Angiotensin II Type-2 Receptor Agonist, Compound 21, Even After Stroke Prevents Ischemic Brain Damage

Abstract

Objectives: Previous our studies showed that angiotensin II type-2 (AT 2 ) receptor stimulation protects neurons after brain ischemic damage using AT 2 receptor-deficient mice. Recently, Compound 21 (C21) is available to use as a direct AT 2 receptor agonist. We reported that administration of C21 induces vascular dilatation via bradykinin-nitric oxide pathway and maintains cerebral blood flow, resulting in prevention of cognitive impairment. These results inspired us the possibility that administration of C21 could protect ischemic brain damage; therefore, we assessed the effect of C21 on stroke expansion by not only pre-treatment, but also a treatment immediately after stroke. Methods: 10 week-old wild-type male C57BL6 mice were subjected to the middle cerebral artery occlusion (MCAO) by electrocoagulation using a subtemporal approach. Ischemic area after stroke was evaluated by time-course analysis by magnetic resonance imaging (MRI) of the brain. C21 was administrated to mice 2 weeks before MCAO or immediately after MCAO treatment by intraperitoneal injection. Cerebral blood flow was evaluated by using 2D-laser speckle blood flow imaging system. Results: No significant remarkable change was observed in blood pressure in mice with or without C21 treatment. Pretreatment of C21 prevented ischemic brain damage 1 day after MCAO. In contrast, such preventive effect by C21 was not observed in AT 2 receptor-deficient mice. On the other hand, C21 treatment immediately after MCAO did not reduce ischemic area 1 day after MCAO, but remarkably reduced this 3 days after MCAO. Treatment with C21 prevented the reduced cerebral blood flow after MCAO. Conclusions: These findings indicate that AT 2 receptor stimulation by C21 prevents ischemic brain damage at least in part via maintaining cerebral blood flow even after stroke. Therefore, administration of C21 could work as a new therapeutical option in patients with stroke even in acute phase.