Neuropharmacology

Biography

Biography: Sigal Fleisher-Berkovich

Abstract

The circulating renin-angiotensin system (RAS) is a fundamental regulatory mechanism of blood pressure conserved through evolution. Apart from periphery, an intrinsic RAS was also identified in the brain in which the bioactive hormone, angiotensin II, plays multiple roles. Angiotensin II (Ang II), is formed from angiotensin I by angiotensin converting enzyme (ACE). It acts mainly through angiotensin type 1 receptors (AT1Rs) and can influence brain inflammation expressed in Alzheimer’s disease (AD) models. Although increased levels of brain AT₁Rs, Ang II and ACE were reported in AD models, the role of RAS in brain inflammation remains unclear. Telmisartan, a well-known anti-hypertensive drug and an AT₁R blocker, was suggested to serve as a potential treatment for brain inflammation and AD. The present study shows that intranasally given telmisartan (1mg/kg/day) for 3.5 weeks to 2 month significantly reduced amyloid burden and microglial activation by up to 50% in the cortex of five familial AD (5XFAD) mice. Hippocampal amyloid plaques and microglial activation in 5XFAD were also reduced following 2 months treatment with telmisartan by approximately 50% and 25%, respectively. Short term effects of telmisartn in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor) which exhibited a similar inhibitory effect on the expression of these associated AD markers. In vitro studies including LPS-induced BV2 microglia cells treated with telmisartan resulted in a significant attenuation of inflammatory mediators' production including tumor necrosis factor-α (~ 50% reduction), interleukin 1-β (~30% reduction) and nitric oxide (~60% reduction). Telmisartan effect on NO production in LPS-induced BV2 cells was confirmed in primary neonatal rat microglial cells as well. In LPS-induced primary microglial cells telmisartan reduced the NO production levels by up to 70% and in mixed glial cells by 60 %. Our data may envision potential intervention with the progression of glial activation and AD with both telmisartan and perindopril. Moreover, the non-invasive intranasal delivery may serve as an efficient alternative for systemic administration to modulate the brain RAS.