Modulation of brain ACE and ACE2 may be a promising protective strategy against cerebral ischemia/reperfusion injury: an experimental trial in rats

Abstract

The brain renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression. We evaluated the protective effects of the angiotensin receptor blocker (ARB) telmisartan and the angiotensin-converting enzyme 2 (ACE2) activator xanthenone on experimental cerebral ischemia/reperfusion (I/R) injury. Rats were divided into a sham control, a cerebral I/R control, a standard treatment (nimodipine, 10 mg/kg/day, 15 days, p.o.), three telmisartan treatments (1, 3, and 10 mg/kg/day, 15 days, p.o.), and three xanthenone treatments (0.5, 1, and 2 mg/kg/day, 15 days, s.c.) groups. One hour after the last dose, all rats except the sham control group were exposed to 30-min cerebral ischemia followed by 24-h reperfusion. Brain ACE and ACE2 activities and the apoptotic marker caspase-3 levels were assessed. Glutathione (GSH), malondialdehyde (MDA), and nitric oxide end products (NOx) as oxidative markers and tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-10 as immunological markers were assessed. Histopathological examination and immunohistochemical evaluation of glial fibrillary acidic protein (GFAP) were performed in cerebral cortex and hippocampus sections. Telmisartan and xanthenone in the higher doses restored MDA, NOx, TNF-α, IL-6, caspase-3, ACE, and GFAP back to normal levels and significantly increased GSH, IL-10, and ACE2 compared to I/R control values. Histopathologically, both agents showed mild degenerative changes and necrosis of neurons in cerebral cortex and hippocampus compared with I/R control group. Modulation of brain RAS, either through suppression of the classic ACE pathway or stimulation of its antagonist pathway ACE2, may be a promising strategy against cerebral I/R damage.

Update on New Aspects of the Renin-Angiotensin System in Hepatic Fibrosis and Portal Hypertension: Implications for Novel Therapeutic Options

“…It was also shown that ACE2 activation by XNT protected experimental pregnant rats against leptin induced hypertension and proteinuria [76] and reduced hypertension-induced cardiac fibrosis in SHR [77]. Moreover, it was also shown to increase brain tissue ACE2 gene expression in cerebral ischemia/reperfusion injury in experimental rats [78].…”

The interaction of RAAS inhibitors with COVID-19: Current progress, perspective and future

“…First, preclinical studies were searched in the PubMed database, and all the related studies [ [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] ] are listed in Table 1 . Kidoguchi et al [ 46 ] analyzed the expression of ACE2 in adenine-induced chronic renal failure model mice, and the results suggested that azilsartan did not increase ACE2 expression in the kidney compared to the control group.…”

“… Source Animal Model Study design Effect of RAAS blockers on ACE2 Kidoguchi [ 46 ]，2019 Mice Adenine-induced chronic renal failure model Azilsartan (ARB); 2 mg/kg/day orally for 4 weeks Compared to the vehicle group, azilsartan didn't increased ACE2 expression in kidney. Abdel-Fattah [ 47 ], 2018 Rat A cerebral ischemia/reperfusion (I/R) injury model Three telmisartan (ARB) treatments: 1, 3, and 10 mg/kg/day; orally for 15 days Telmisartan in the higher doses significantly increased ACE2 expression compared to I/R control values. Wang W [ 48 ], 2018 Mice A chronic intermittent hypoxia model Telmisartan (ARB); 10 mg/kg/d for 4 weeks, intragastrically Telmisartan elevated the expression of cardiac ACE2.…”

Fighting the War Against COVID-19 via Cell-Based Regenerative Medicine: Lessons Learned from 1918 Spanish Flu and Other Previous Pandemics

“…ACE2 is a type 1 integral membrane protein that functions as an extracellular receptor attached to the plasma membrane of cells in the lungs, heart, brain, and other vital organs [ 14 , 15 ]. It is primarily expressed on type 2 pneumocytes in the lungs and on enterocytes in the small intestine.…”