Assessing the effects of Ang-(1-7) therapy following transient middle cerebral artery occlusion

Abstract

The counter-regulatory axis, Angiotensin Converting Enzyme 2, Angiotensin-(1-7), Mas receptor (ACE2/Ang-1-7/MasR), of the renin angiotensin system (RAS) is a potential therapeutic target in stroke, with Ang-(1-7) reported to have neuroprotective effects in pre-clinical stroke models. Here, an extensive investigation of the functional and mechanistic effects of Ang-(1-7) was performed in a rodent model of stroke. Using longitudinal magnetic resonance imaging (MRI) it was observed that central administration of Ang-(1-7) following transient middle cerebral artery occlusion (MCAO) increased the amount of tissue salvage compared to reperfusion alone. This protective effect was not due to early changes in blood brain barrier (BBB) permeability, microglia activation or inflammatory gene expression. However, increases in NADPH oxidase 1 (Nox1) mRNA expression were observed in the treatment group compared to control. In order to determine whether Ang-(1-7) has direct cerebrovascular effects, laser speckle contrast imaging (LSCI) was performed to measure dynamic changes in cortical perfusion following reperfusion. Delivery of Ang-(1-7) did not have any effect on cortical perfusion following reperfusion however; it showed an indication to prevent the ‘steal phenomenon’ within the contralateral hemisphere. The comprehensive series of studies have demonstrated a moderate protective effect of Ang-(1-7) when given alongside reperfusion to increase tissue salvage.

The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential

“…Beneficial effects of delivery of Ang-(1–7), acting via Mas receptor and not AT 2 R, have also been demonstrated post-stroke in experimental models with both delivery prior to stroke induction [ 244 , [246] , [247] , [248] ] and after reperfusion [ 249 , 250 ] ( Table 1 ). Time of delivery varied from 48 h [ 246 ], 7 days [ 244 , 248 ] to 4 weeks [ 247 ] prior to stroke, and continued to the study endpoint, typically 24 h [ [246] , [247] , [248] ] out to 3 days [ 244 ].…”

Cyclic angiotensin-(1-7) contributes to rehabilitation of animal performance in a rat model of cerebral stroke

“…(1-7) (899 Da) have been clearly demonstrated in many studies [1,18,19,33,39,40]. Cerebral stroke may initially cause BBB dysfunction (20).…”

“…In this study, cAng-(1-7) clearly and significantly improved motor functions evaluated by neuroscore, stepping test and body swing test. Sensory motor functions were also sensitive to the treatment with cAng- (1)(2)(3)(4)(5)(6)(7) witnessed by the forelimb placement test. The effect of cAng-(1-7) reached its highest significance in the period of day 29 to 50.…”

“…Therefore it can not be excluded that cAng-(1-7) passes the BBB early after the stroke induction. Intracerebrally administered Ang- (1)(2)(3)(4)(5)(6)(7) exerts protective effects on the BBB integrity, which may contribute to recovery after cerebral stroke, by regulating the tight junction protein expression [30,48]. Restoration of BBB integrity importantly contributes to reducing stroke-related neurological damage [2].…”

“…Consistent with difficult delivery across the BBB, natural Ang-(1-7) has been administered by intracerebral infusion in many studies [1,18,19,30,33,39,40,48]. In essence, the efficient delivery of peptides across the intact BBB to the brain requires invasive techniques.…”