Abstract
Various studies on focal cerebral ischemic models have implicated the direct activation and expression of matrix metalloproteinases (MMPs), especially MMP-9, as a key orchestrator of blood-brain barrier (BBB) disruption. Moreover, studies have shown that MMP-9 siRNA can protect the BBB from ischemia/reperfusion injury. In the present study, we investigated the neuroprotective role of a lentivirus vector-mediated mmp-9shRNA following focal cerebral ischemia-specifically assessing whether LV-mmp9shRNA silencing of MMP-9 mRNA could ameliorate BBB disruption and in turn reduce vascular permeability, neuronal cell death, and neurobehavioral deficits. Treatment was given 2 weeks prior to surgery using a lentivirus-mediated vector. Surgery was conducted using the established middle cerebral artery occlusion (MCAO) model in rats, while outcomes were measured 24 h after injury. Our results demonstrated a significant reduction in brain infarction volume, brain water content, and neurobehavioral deficits following LV-mmp9shRNA treatment. Additionally, Evans blue and IgG extravasation were reduced, MMP-9 mRNA expression was silenced, and Western blot analysis revealed a decreased expression of MMP-9 and VEGF with an increased expression of occludin and collagen IV in brain tissues. This suggests that successful delivery of LV-mmp9shRNA may ameliorate ischemic brain injury by preserving structural integrity and improving functional outcome. © 2010 Elsevier B.V. All rights reserved.
Original language | English |
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Pages (from-to) | 347-359 |
Number of pages | 13 |
Journal | Brain Research |
Volume | 1367 |
DOIs | |
State | Published - Jan 7 2011 |
ASJC Scopus Subject Areas
- General Neuroscience
- Molecular Biology
- Clinical Neurology
- Developmental Biology
Keywords
- Blood-brain barrier (BBB)
- Brain edema
- Lentivirus
- MMP-9
- Middle cerebral artery occlusion (MCAO)
- shRNA
- Single-Blind Method
- RNA, Small Interfering/genetics
- Male
- Tetrazolium Salts
- Matrix Metalloproteinase 9/genetics
- Gene Expression Regulation/genetics
- Disease Models, Animal
- Gene Transfer Techniques
- Cells, Cultured
- Rats
- Blood-Brain Barrier/metabolism
- Trauma Severity Indices
- Rats, Sprague-Dawley
- RNA, Messenger/metabolism
- Infarction, Middle Cerebral Artery/prevention & control
- Animals
- Evans Blue
- Analysis of Variance
- Cell Line, Transformed
- Lentivirus/genetics