Lentivirus-mediated transfer of MMP-9 shRNA provides neuroprotection following focal ischemic brain injury in rats.
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.
Department of Anatomy and Embryology, Peking University Health Science Center, Beijing 100191, China.
Qin
Q
Hu
Chunhua
C
Chen
Nikan H
NH
Khatibi
Li
L
Li
Lei
L
Yang
Ke
K
Wang
Jingyan
J
Han
Weiming
W
Duan
John H
JH
Zhang
Changman
C
Zhou
D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005070:Evans Blue; D005786:Gene Expression Regulation / Q000235:genetics; D018014:Gene Transfer Techniques; D020244:Infarction, Middle Cerebral Artery / Q000517:prevention & control*; D016086:Lentivirus / Q000235:genetics / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016037:Single-Blind Method; D013778:Tetrazolium Salts; D015599:Trauma Severity Indices
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D005070:Evans Blue; C009591:triphenyltetrazolium; D020780:Matrix Metalloproteinase 9