Abstract

Hypertension is one of the major risk factors for central nervous system (CNS) disorders like stroke and Alzheimer's disease (AD). On the other hand, CNS diseases like AD have been associated with gliosis and impaired neurogenesis. Further, renin angiotensin system (RAS) is intricately associated with hypertension; however, the accumulating evidences suggest that over-activity of RAS may perpetuate the brain inflammation related with AD. Therefore, in the present study, we examined the effect of hypertension and RAS on glial (astrocytes and microglia) activation and hippocampal neurogenesis in a rat model of chronic hypertension. We used Candesartan [angiotensin type 1 receptor (AT1R) blocker (ARB)] both at a low dose (0.1mg/kg) and anti-hypertensive dose (2mg/kg) to explore whether their effect on astrocyte and microglial activation, neuroinflammation, and neurogenesis is blood pressure (BP) dependent or independent. Our data revealed that hypertension induces robust microglial and astrocyte activation, neuroinflammation, andcripples hippocampal neurogenesis. Importantly, AT1R blockade by Candesartan, even at low dose (0.1mg/kg), prevented astrocyte and microglial activation and neuroinflammation in the brain of hypertensive rats. Mechanistically, AT1R blockade prevented the activation of NADPH oxidase, reactive oxygen species (ROS) generation, suppression of MAP kinase and NFкB signaling. Importantly, we, for the first time to our knowledge, provided the evidence that AT1R blockade by activating Wnt/β-catenin signaling, promotes neurogenesis during hypertensive state. We conclude that AT1R blockade prevents astrocyte and microglial activation and improves hippocampal neurogenesis in hypertensive state, independent of BP lowering action.

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