Journal Article

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

Fouda, Abdelrahman Y., Pillai, Bindu, Ahmed, Heba A., Ergul, Adviye, Fagan, Susan C., Ishrat, Tauheed, Sayed, Mohammed A., Eldahshan, Wael, Waller, Jennifer L.

2018

Overview

Background With 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. Methods The 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. Results Treatment 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. Conclusion Collectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aging / Alzheimer's disease / Amyloid beta-Peptides - pharmacology / Angiotensin AT1 receptors / Angiotensin AT2 receptors / Angiotensin modulators / Animal cognition / Animals / Antihypertensive Agents - pharmacology / Benzimidazoles - therapeutic use / Biomedical and Life Sciences / Biomedicine / Biphenyl Compounds / Blood pressure / Blood Pressure - drug effects / Cell Hypoxia - drug effects / Cells, Cultured / Cerebral blood flow / Cerebrovascular diseases / Cognition disorders / Cognitive ability / Cognitive Dysfunction - drug therapy / Cognitive Dysfunction - etiology / Cognitive Dysfunction - metabolism / Cognitive-impairment / Complications and side effects / Cytotoxicity / Dementia / Dementia disorders / Disease / Disease Models, Animal / Double-Blind Method / Endothelial Cells - drug effects / Epoetin Alfa / Genotype & phenotype / Hippocampus - drug effects / Humans / Hypertension / Immunology / Infarction, Middle Cerebral Artery - complications / Infarction, Middle Cerebral Artery - pathology / Ischemia / Locomotion - drug effects / Male / Neurobiology / Neurodegeneration / Neurology / Neuromodulation / Neurosciences / Older people / Peptide Fragments - pharmacology / Prevention / Rats / Rats, Inbred SHR / Renin-angiotensin system / Renin-Angiotensin System - drug effects / Renin-Angiotensin System - physiology / Risk factors / Sensorimotor system / Sensory Gating - drug effects / Stroke / Stroke (Disease) / Sulfonamides - therapeutic use / Tetrazoles - therapeutic use / Thiophenes - therapeutic use / Vascular dementia / β-Amyloid