Quantitative tractography of fibers crossing white matter hyperintensities

Abstract

Background: Angiotensin II type 2 (AT 2) receptor activation has been reported to play a role in the cognitive function, although its detailed mechanisms are not fully understood. Compound 21 (C21) has become available to use as a direct AT 2 receptor agonist. Therefore, we examined the possibility that direct AT 2 receptor stimulation by C21 could prevent cognitive decline associated with hypo-perfusion in the brain. Methods:We employed bilateral common carotid artery stenosis model (BCAS) in mice by micro coil technique as model of vascular dementia. The Morris water maze task was performed 6 weeks after BCAS operation. C21 (10 m g/kg/day) was administrated daily by intraperitoneal injection 1 week before BCAS until Morris water maze task.C erebral blood flow (CBF) was analyzed by laser speckle flowmetry and i nflammatory cytokine levels were assessed by quantitative RT-PCR. Total protein was prepared from hippocampus and cortex, and phosphorylation of NMDA receptor (Ty 1472) was determined by immunoblot analysis. Results: The mice showed a significant impairment of spatial learning activity after BCAS and this impairment was significantly attenuated by C21 treatment without influencing blood pressure. Spatial learning ability was severely impaired in AT 2 receptor deficient mice and preventive effect of C21 on cognitive decline was not observed in this mouse strain. CBF in BCAS-treated group was significantly decreased and this decrease was blunted by the treatment with C21. TNFa and MCP-1 mRNA expressions were significantly increased after BCAS, but attenuated by treatment with C21. To further examine the role of direct stimulation of AT2 receptor in cognitive function, we focused on NMDA receptor, which would be influenced by AT 2 receptor activation. After BCAS, phosphorylation of NMDA receptor with water maze task was impaired and the administration of C21 attenuated the decrease in NMDA receptor phosphorylation in BCAS-treated mice. Conclusions: These findings indicate that direct AT 2 stimulation by C21 prevents ischemic vascular dementia induced by hypoperfusion at least in part due to increase in CBF, reduction of inflammation and activation of NMDA receptor. This study principally could offer the possibility to use direct AT 2 receptor stimulation by C21 as a therapeutic tool.