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Background: With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as will the number of individuals with post-stroke cognitive impairment (PSCI). Unfortunately, no specific FDA approved treatments for PSCI exist. Although clinical trial evidence supports that renin angiotensin system (RAS) modulation by angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults. The aim of our study was to determine the impact of the ARB candesartan or the AT2R agonist, C21, after stroke, on long-term cognitive function in spontaneously hypertensive rats (SHRs).Methods: Thirty three SHRs were subjected to a 60 minute transient middle cerebral artery occlusion (MCAO) and randomly assigned to either Saline/ C21 (0.3 mg/kg, IP) only or Saline/ C21 (7 days) followed by candesartan (0.3 mg/kg) IP for the remainder of the study. Outcome measures included sensorimotor and cognitive function, performed using a sequence of blinded tests, and assessed at baseline and up to 28 days post-stroke. Animals were sacrificed at 30 days and their brains collected for amyloid-β protein determination and histopathologic analyses.Results: Chronic administration of C21, or candesartan prevented PSCI, even when treatment was initiated at 7 days after the ischemic insult. The groups treated with C21 and candesartan demonstrated superior performance on the novel NOR test, compared to saline treated animals. C21 (first 7 days) only or C2 and candesartan treatments had markedly lower hippocampal concentrations of Aβ1-42 at 30 days post-stroke than those treated with saline. Sensorimotor deficits (Bederson and beam walk scores) were pronounced at 24 h post-stroke and all treatment groups showed similar recovery at 28 days post stroke. C21 had no effect on BP compared to saline-treated controls.Conclusion: Collectively, our findings demonstrate that RAS modulators effectively prevent PSCI, even when treatment is delayed.