Combined antiapoptotic and antioxidant approach to acute neuroprotection for stroke in hypertensive rats

Ord, E. N.J. , Shirley, R., McClure, J. D. , McCabe, C. , Kremer, E. J., Macrae, I. M. and Work, L. M. (2013) Combined antiapoptotic and antioxidant approach to acute neuroprotection for stroke in hypertensive rats. Journal of Cerebral Blood Flow and Metabolism, 33(8), pp. 1215-1224. (doi: 10.1038/jcbfm.2013.70) (PMID:23632970) (PMCID:PMC3734772)

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Publisher's URL: http://dx.doi.org/10.1038/jcbfm.2013.70

Abstract

We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO+control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO+Ngb-expressing CAV-2, CAVNgb; tMCAO+SP600125; tMCAO+CAVNgb+SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression+SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb+SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb+SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ord, Dr Emily and Work, Dr Lorraine and McCabe, Dr Chris and Shirley, Dr Rachel and Macrae, Professor I Mhairi and McClure, Dr John
Authors: Ord, E. N.J., Shirley, R., McClure, J. D., McCabe, C., Kremer, E. J., Macrae, I. M., and Work, L. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Journal of Cerebral Blood Flow and Metabolism
Publisher:Nature Publishing Group
ISSN:0271-678X
ISSN (Online):1559-7016
Copyright Holders:Copyright © 2013 International Society for Cerebral Blood Flow and Metabolism
First Published:First published in Journal of Cerebral Blood Flow and Metabolism
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
418441Capacity Building Award in Integrative Mammalian BiologyMargaret MacleanBiotechnology and Biological Sciences Research Council (BBSRC)BB/E527071/1RI CARDIOVASCULAR & MEDICAL SCIENCES
469451A combined approach targeting oxidative stress and apoptosis in strokeLorraine WorkBritish Heart Foundation (BHF)PG/07/126/24223RI CARDIOVASCULAR & MEDICAL SCIENCES