title: Neuroprotection of neurotrophin-3 against focal cerebral ischemia/reperfusion injury is regulated by hypoxia-responsive element in rats.
abstract: Exogenous delivery of the neurotrophin-3 (NT-3) gene may provide a potential therapeutic strategy for ischemic stroke. To investigate the neuroprotective effects of NT-3 expression controlled by 5HRE after focal cerebral ischemia, we constructed a recombinant retrovirus vector (RV) with five copies of hypoxia-responsive elements (5HRE or 5H) and NT-3 and delivered it to the rat brain. Three groups of rats received RV-5H-NT3, RV-5H-EGFP or saline injection. Three days after gene transfer, the rats underwent 90min of transient middle cerebral artery occlusion (tMCAO), followed by 1-28days of reperfusion. Three days after tMCAO, brain NT-3 expression was significantly increased in the RV-5H-NT3-transduced animals compared with the RV-5H-EGFP or saline group, and brain infarct volume was smaller in the RV-5H-NT3-transduced group than the RV-5H-EGFP or saline group. The percentage of TUNEL-positive cells was reduced in RV-5H-NT3-transduced brains compared with the RV-5H-EGFP or saline group 3 and 7days after tMCAO. Furthermore, the neurological status of RV-5H-NT3-transduced rats was better than that of RV-5H-EGFP- or saline-transduced animals from 1day to 4weeks after tMCAO. Our results demonstrated that 5HRE could modulate NT-3 expression in the ischemic brain environment and that the up-regulated NT-3 could effectively improve neurological status following tMCAO due to decreased initial damage. To avoid unexpected side effects, 5HRE-controlled gene expression might be a useful tool for gene therapy of ischemic disorders in the central nervous system.
authors: Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China.
authors: J
authors: J
authors: Zhang
authors: Q
authors: Q
authors: Shi
authors: P
authors: P
authors: Yang
authors: X
authors: X
authors: Xu
authors: X
authors: X
authors: Chen
authors: C
authors: C
authors: Qi
authors: J
authors: J
authors: Zhang
authors: H
authors: H
authors: Lu
authors: B
authors: B
authors: Zhao
authors: P
authors: P
authors: Zheng
authors: P
authors: P
authors: Zhang
authors: Y
authors: Y
authors: Liu
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D004247:DNA / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D009460:Neurologic Examination; D018696:Neuroprotective Agents; D020933:Neurotrophin 3 / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy*; D020218:Response Elements / Q000235:genetics* / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D042461:Vascular Endothelial Growth Factor A; D004247:DNA