Abstract 32: Direct Angiotensin II Type 2 Receptor Stimulation by Compound 21 Prevents Vascular Dementia

Abstract

Objectives: Recent clinical evidence demonstrated that angiotensin II type 1 receptor blockers (ARBs) were associated with a significant reduction in the incidence and progression of dementia compared with angiotensin converting enzyme inhibitor. Therefore, we examined the possibility that direct angiotensin II type 2 (AT2) receptor stimulation by AT2 receptor agonist, compound 21 (C21), could prevent cognitive decline associated with hypoperfusion in the brain. Methods: We employed a bilateral common carotid artery stenosis (BCAS) model in mice as a model of vascular dementia. The Morris water maze task was performed 6 weeks after BCAS operation. ARB, azilsartan (0.1 mg/kg/day) or C21 (10 μg/kg/day) was administered from 1 week before BCAS. Cerebral blood flow (CBF) was measured by laser speckle flowmetry and inflammatory cytokine levels were determined by real-time RT-PCR. Results: Wild-type (WT) mice showed the significant prolongation of escape latency after BCAS and this cognitive impairment was attenuated by the pretreatment of azilsartan. Cognitive impairment was more marked in AT2 receptor knockout (AT2KO) mice, and preventive effect of azilsartan on cognitive decline was weaker in AT2KO mice than in WT mice, suggesting that improvement of cognitive decline by azilsartan may involve the stimulation of AT2 receptor. The significant impairment of spatial learning after BCAS in WT mice was attenuated by C21 treatment. CBF in the whole brain in the BCAS-treated group was significantly decreased compared with that in the sham group at 6 weeks after BCAS operation. This decrease was increased by treatment with C21. We assessed expression of inflammatory cytokines such as TNF-[[Unable to Display Character: ]]α and MCP-1 in the cerebral cortex. TNF-α and MCP-1 mRNA expression were significantly increased after BCAS operation, but significantly attenuated by treatment with C21. Azilsartan or C21 at these doses did not affect systolic blood pressure. Conclusions: These findings indicate that direct AT2 stimulation prevents ischemic vascular dementia induced by hypoperfusion at least in part through an increase in CBF, and reduction of inflammation. We expect that direct AT2 receptor stimulation could be a new therapeutic strategy for preventing and treating vascular dementia.