Lentivirus-mediated transfer of MMP-9 shRNA provides neuroprotection following focal ischemic brain injury in rats
Lentivirus-mediated transfer of MMP-9 shRNA provides neuroprotection following focal ischemic brain injury in rats
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DOI：
10.1016/j.brainres.2010.10.002
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发表时间：
2011-01-07
期刊：
影响因子：
2.9
通讯作者：
Zhou, Changman
中科院分区：
文献类型：
--
作者：
Hu, Qin;Chen, Chunhua;Zhou, Changman
对局灶性脑缺血模型的各种研究表明，基质金属蛋白酶（MMP），特别是MMP-9的直接激活和表达，是血脑屏障（BBB）破坏的关键协调者。此外，研究表明MMP-9 siRNA可以保护血脑屏障免受缺血/再灌注损伤。在本研究中，我们研究了局灶性脑缺血后慢病毒载体介导的MMP-9 shRNA的神经保护作用，特别是评估MMP-9 mRNA的LV-mmp 9 shRNA沉默是否可以改善BBB破坏，从而减少血管通透性，神经元细胞死亡和神经行为缺陷。在手术前2周使用慢病毒介导的载体给予治疗。使用建立的大鼠大脑中动脉闭塞（MCAO）模型进行手术，并在损伤后24 h测量结果。我们的研究结果表明，LV-mmp 9 shRNA治疗后，脑梗死体积，脑含水量和神经行为缺陷显着减少。此外，伊文思蓝和IgG外渗减少，MMP-9 mRNA表达沉默，Western blot分析显示MMP-9和VEGF表达减少，occludin和胶原IV表达增加。这表明成功递送LV-mmp 9 shRNA可以通过保持结构完整性和改善功能结果来改善缺血性脑损伤。(C)2010 Elsevier BV保留所有权利。
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. (C) 2010 Elsevier B.V. All rights reserved.