title: Low-dose candesartan enhances molecular mediators of neuroplasticity and subsequent functional recovery after ischemic stroke in rats.
abstract: We have previously reported that angiotensin type 1 receptor (AT1R) blockade with candesartan exerts neurovascular protection after experimental cerebral ischemia. Here, we tested the hypothesis that a low, subhypotensive dose of candesartan enhances neuroplasticity and subsequent functional recovery through enhanced neurotrophic factor expression in rats subjected to ischemia reperfusion injury. Male Wistar rats (290-300 g) underwent 90 min of middle cerebral artery occlusion (MCAO) and received candesartan (0.3 mg/kg) or saline at reperfusion and then once every 24 h for 7 days. Functional deficits were assessed in a blinded manner at 1, 3, 7, and 14 days after MCAO. Animals were sacrificed 14-day post-stroke and the brains perfused for infarct size by cresyl violet. Western blot and immunohistochemistry were used to assess the expression of growth factors and synaptic proteins. Candesartan-treated animals showed a significant reduction in the infarct size [t (13) = -5.5, P = 0.0001] accompanied by functional recovery in Bederson [F (1, 13) = 7.9, P = 0.015], beam walk [F (1, 13) = 6.7, P = 0.023], grip strength [F (1, 13) = 15.2, P = 0.0031], and rotarod performance [F (1, 14) = 29.8, P < 0.0001]. In addition, candesartan-treated animals showed significantly higher expression of active metalloproteinase-3 (MMP-3), laminin, and angiopoietin-1 (Ang-1). The expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) and its receptor was significantly increased in the animals treated with candesartan. Also, we observed significant increases in neuroplasticity markers, synaptophysin, and PSD-95. These results indicate that low-dose candesartan had a large and enduring effect on measures of plasticity, and this accompanied the functional recovery after ischemic stroke.
authors.affiliation: Charlie Norwood VA Medical Center, Augusta, GA, USA, tauheedarshi@gmail.com.
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Bindu
authors.initials: B
authors.lastname: Pillai
authors.forename: Sahar
authors.initials: S
authors.lastname: Soliman
authors.forename: Abdelrahman Y
authors.initials: AY
authors.lastname: Fouda
authors.forename: Anna
authors.initials: A
authors.lastname: Kozak
authors.forename: Maribeth H
authors.initials: MH
authors.lastname: Johnson
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D020521:Stroke / Q000188:drug therapy*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; C081643:candesartan
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