Direct angiotensin II type 2 receptor stimulation by compound 21 prevents vascular dementia

• Cognitive decline by cerebral hypoperfusion was more marked in AT2KO mice than in WT.
• Preventive effect of ARB on cognitive decline was weaker in AT2KO mice than in WT.
• C21 treatment attenuated cognitive decline induced by chronic cerebral hypoperfusion.
• Reduction of cerebral blood flow in hypoperfusion model was attenuated by C21.
• The increase in inflammation in hypoperfusion model was attenuated by C21 treatment.

Angiotensin II type 2 (AT2) receptor activation has been reported to play a role in cognitive function, although its detailed mechanisms and pathologic significance are not fully understood. We examined the possibility that direct AT2 receptor stimulation by compound 21 (C21) could prevent cognitive decline associated with hypoperfusion in the brain.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. Azilsartan (0.1 mg/kg/day) or C21 (10 μg/kg/day) was administered from 1 week before BCAS. Cerebral blood flow (CBF) and inflammatory cytokine levels were also determined. Wild–type (WT) mice showed significant prolongation of escape latency after BCAS, and this cognitive impairment was attenuated by pretreatment with azilsartan. Cognitive impairment was more marked in AT2 receptor knockout (AT2KO) mice, and the preventive effect of azilsartan on cognitive decline was weaker in AT2KO mice than in WT mice, suggesting that the improvement of cognitive decline by azilsartan may involve stimulation of the AT2 receptor. The significant impairment of spatial learning after BCAS in WT mice was attenuated by C21 treatment. The decrease in CBF in the BCAS–treated group was blunted by C21 treatment, and the increase in TNF–α and MCP–1 mRNA expression after BCAS was attenuated by C21 treatment. These findings indicate that direct AT2 receptor stimulation attenuates ischemic vascular dementia induced by hypoperfusion at least in part through an increase in CBF, and a reduction of inflammation.