title: Different protective and reparative effects of olmesartan in stroke according to time of administration and withdrawal.
abstract: Angiotensin type 1 receptor blockers (ARBs) have induced improved functional recovery and reduced infarct volume in experimental animal models of stroke. Clinical data have indicated a positive correlation between prestroke treatment with ARBs and reduced stroke severity and better outcomes; however, the mechanisms of these beneficial effects are not yet well understood. This study compares the protective and possible reparative effects of continuous oral treatment with olmesartan (OLM) with OLM pretreatment and withdrawal after permanent middle cerebral artery occlusion (pMCAO) in rats. Fifty-two Sprague-Dawley rats were randomly assigned to five groups: MCAO(-/OLM) (OLM 10 mg/kg/day for 14 days after infarct), MCAO(OLM/OLM) (OLM 10 mg/kg/day for 7 days before and 14 days after infarct), MCAO(OLM/-) (OLM 10 mg/kg/day for 7 days before infarct), sham, and control. We analyzed functional recovery; lesion size; cell death; expression of the pro-oxidant enzyme NADPH oxidase 4 (NOX-4); isolectin-B4; and repair markers such as glial fibrillary acidic protein, vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF). All of the OLM-treated groups showed significantly better functional scores and reduced infarct sizes and cell death compared with the control group 14 days after pMCAO. Levels of NOX-4, VEGF, and BDNF were significantly lower in the brains of the MCAO(OLM/OLM) and sham groups compared with the other groups. OLM treatment improved functional recovery and reduced lesion size and cell death after cerebral ischemia. Only the continuous administration of OLM before and after stroke reduced oxidative stress levels, with better tissue preservation, without triggering brain repair marker activation.
authors.affiliation: Department of Neurology and Stroke Centre, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ (Health Research Institute), Autónoma University of Madrid, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gutiérrez-Fernández
authors.forename: Blanca
authors.initials: B
authors.lastname: Fuentes
authors.forename: Berta
authors.initials: B
authors.lastname: Rodríguez-Frutos
authors.forename: Jaime
authors.initials: J
authors.lastname: Ramos-Cejudo
authors.forename: Laura
authors.initials: L
authors.lastname: Otero-Ortega
authors.forename: Exuperio
authors.initials: E
authors.lastname: Díez-Tejedor
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage*; D020287:In Situ Nick-End Labeling; D008279:Magnetic Resonance Imaging; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013777:Tetrazoles / Q000008:administration & dosage*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D007093:Imidazoles; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; C437965:olmesartan; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat
keywords: cerebral infarct; olmesartan; protective and repair markers