Document Detail


Combined antiapoptotic and antioxidant approach to acute neuroprotection for stroke in hypertensive rats.
MedLine Citation:
PMID:  23632970     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Emily N J Ord; Rachel Shirley; John D McClure; Christopher McCabe; Eric J Kremer; I Mhairi Macrae; Lorraine M Work
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-05-01
Journal Detail:
Title:  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism     Volume:  33     ISSN:  1559-7016     ISO Abbreviation:  J. Cereb. Blood Flow Metab.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-08-01     Completed Date:  2013-10-22     Revised Date:  2014-08-03    
Medline Journal Info:
Nlm Unique ID:  8112566     Medline TA:  J Cereb Blood Flow Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1215-24     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anthracenes / pharmacology
Antioxidants / pharmacology*
Apoptosis / drug effects*
Dependovirus / genetics
Enzyme Inhibitors / pharmacology
Genetic Vectors
Globins / biosynthesis,  genetics
Green Fluorescent Proteins / metabolism
Hypertension / complications,  drug therapy*
Hypoxia, Brain / pathology
Immunohistochemistry
Infarction, Middle Cerebral Artery / pathology
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
Lentivirus / genetics
Male
Nerve Tissue Proteins / biosynthesis,  genetics
Neuroprotective Agents / pharmacology*
Oxidative Stress / drug effects
Plethysmography
Rats
Rats, Inbred SHR
Real-Time Polymerase Chain Reaction
Stroke / etiology,  prevention & control*
Transduction, Genetic
Grant Support
ID/Acronym/Agency:
PG/07/126/24223//British Heart Foundation; //Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
0/Anthracenes; 0/Antioxidants; 0/Enzyme Inhibitors; 0/Nerve Tissue Proteins; 0/Neuroprotective Agents; 0/anthra(1,9-cd)pyrazol-6(2H)-one; 0/neuroglobin; 147336-22-9/Green Fluorescent Proteins; 9004-22-2/Globins; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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