RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial

Abstract

BackgroundWith the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown. Moreover, these agents reduce BP, which is undesirable in the acute stroke period, so we believe that giving C21 in this acute phase or delaying ARB administration would enable us to achieve the neurovascular benefits without the risk of unintended and potentially dangerous, acute BP lowering.MethodsThe aim of our study was to determine the impact of candesartan (ARB) or compound-21 (an angiotensin type 2 receptor––AT2R––agonist) on long-term cognitive function post-stroke, in spontaneously hypertensive rats (SHRs). We hypothesized that AT2R stimulation, either directly with C21, or indirectly by blocking the angiotensin type 1 receptor (AT1R) with candesartan, initiated after stroke, would reduce cognitive impairment. Animals were subjected to a 60-min transient middle cerebral artery occlusion and randomly assigned to either saline/C21 monotherapy, for the full study duration (30 days), or given sequential therapy starting with saline/C21 (7 days) followed by candesartan for the remainder of the study (21 days). Outcome measures included sensorimotor/cognitive-function, amyloid-β determination, and histopathologic analyses.ResultsTreatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, post-stroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation.ConclusionCollectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1262-x) contains supplementary material, which is available to authorized users.

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

“…Moreover, modulation of Ang II receptors had protective effects in a mouse cerebral malaria model as evidenced by reduced cerebral hemorrhages and increased survival, whereas AT2R-deficient mice were found to be more susceptible to cerebral malaria. Similarly, spontaneously hypertensive rats prone to middle cerebral artery occlusion (MCAO) and reperfusion showed decreased cognitive dysfunction, Aβ 1–42 cellular accumulation, and chronic-reactive microgliosis in brain tissue in the presence of continuous administration of AT2R agonist and AT1R blocker [ 62 ]. When treated with AT2R agonist at the time of reperfusion, MCAO rats showed preserved neurological function 24 h later [ 63 ].…”

Neurovascular and Cognitive Dysfunction in Hypertension

“…Intervention trials in spontaneously hypertensive rats have shown reduced post-stroke cognitive impairment in rodents treated with RAS modifiers (specifically candesartan, an AT1R blocker). 192 The ongoing HEART phase 1B randomized controlled trial will evaluate the RAS system specifically, in nondemented adults at risk for AD, in which participants will be randomized to placebo vs one of two doses of telmisartan. 193 The optimal treatment regimen to prevent future cognitive impairment or dementia is difficult to ascertain, since nearly all antihypertensives have studies supporting their potential benefit.…”

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

“…Studies have since had conflicting results with regard to the effect of C21 on CBF with some demonstrating no effect [ 193 , 264 ] while others suggest improvement [ 194 ], but BDNF mRNA and protein levels have been shown to be increased with C21 treatment post-stroke and this effect is absent with AT 2 R KO [ 193 ]. Further studies demonstrated that IP delivery of C21 after stroke induction, whether permanent or transient, improved outcome after stroke including in co-morbid animals with hypertension or advanced age [ 193 , 195 , [265] , [266] , [267] , [268] ] ( Table 2 ). Additionally, AT 2 R signalling with C21 has demonstrated further translational potential with promising results achieved with post-stroke oral delivery in female rats [ 269 ] or in a type 2 diabetes animal model [ 270 ], or with an intranasal delivery approach resulting in high levels detectable in the cortex and striatum, and improved outcome following stroke [ 271 ].…”

“…Mechanisms behind the beneficial effects observed with C21 induced AT 2 R signalling in experimental stroke have been attributed to reduced proinflammatory cytokines [ 262 , 264 ], reduced apoptosis [ 193 , 265 , 267 ], reduced ROS and oxidative stress [ 194 , 262 , 267 ], increased VEGF production [ 266 ], increased BDNF production [ 193 , 267 ], a switch from the M1 to M2 microglia phenotype [ 270 ], BBB stabilisation [ 194 , 262 ], and increased angiogenesis [ 267 ] ( Table 2 ). Some of these effects have been demonstrated to be dependent on IL-10 [ 195 ] or peroxisome proliferator-activated receptor-gamma (PPARγ) activation [ 194 ] ( Table 2 ).…”