毛蕊异黄酮-7-O-β-D-葡萄糖苷调节一氧化氮/小窝蛋白-1/基质金属蛋白酶通路并保护实验性脑缺血再灌注损伤中的血脑屏障完整性。
Calycosin-7-O-β-D-glucoside regulates nitric oxide /caveolin-1/matrix metalloproteinases pathway and protects blood-brain barrier integrity in experimental cerebral ischemia-reperfusion injury.
作者信息
Fu Shuping, Gu Yong, Jiang Jian-Qin, Chen Xi, Xu Mingjing, Chen Xingmiao, Shen Jiangang
机构信息
School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China.
Department of Phytochemistry, China Pharmacology University, 24 Tongjia Alley, Gulou, Nanjing, Jiangsu, 210009, China.
出版信息
J Ethnopharmacol. 2014 Aug 8;155(1):692-701. doi: 10.1016/j.jep.2014.06.015. Epub 2014 Jun 12.
ETHNOPHARMACOLOGY RELEVANCE
Astragali Radix (AR) has been used for thousands years to treat ischemic stroke. Calycosin and its glycoside form calycosin-7-O-β-D-glucoside (CG) are two representative isoflavones in Astragali Radix. However, its neurological effects and related molecular mechanisms are largely unknown. The present study aims to evaluate the neuroprotective effects of CG on blood-brain barrier (BBB) integrity of ischemic brain tissue and explore the relevant signaling mechanisms.
MATERIAL AND METHOD
Male adult Sprague-Daweley rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus 24 h or 14 days of reperfusion. CG (26.8 mg/kg) was intraperitoneally administered into the rats at 15 min before onset of ischemia. The neuroprotective effects of CG were evaluated by measuring infarct volume, histological damage and BBB permeability. Furthermore, the effects of CG on scavenging nitric oxide (NO), and modulating matrix metalloproteinases (MMPs) and caveolin-1 (cav-1) were investigated with in vitro cultured brain microvascular endothelial cells treated with NO donor or oxygen-glucose deprivation (OGD) and/or in vivo rat model of MCAO cerebral ischemia-reperfusion injury.
RESULTS
CG treatment significantly reduced infarct volume, histological damage and BBB permeability in the in vivo MCAO ischemia-reperfusion rat model. CG treatment remarkably inhibited the expression and activities of MMPs, and secured the expression of cav-1 and tight junction proteins in the microvessels isolated from ischemic rat cortex. Furthermore, CG was revealed to scavenge NO, inhibit the activities of MMP-2 and MMP-9, and attenuate cell death in the in vitro cultured brain microvascular endothelial cells under OGD condition.
CONCLUSION
CG could protect BBB integrity in experimental cerebral ischemia-reperfusion injury via regulating NO/cav-1/MMPs pathway.
民族药理学相关性
黄芪已被用于治疗缺血性中风数千年。毛蕊异黄酮及其糖苷形式毛蕊异黄酮-7-O-β-D-葡萄糖苷（CG）是黄芪中的两种代表性异黄酮。然而，其神经学作用及相关分子机制尚不清楚。本研究旨在评估CG对缺血脑组织血脑屏障（BBB）完整性的神经保护作用，并探索相关信号机制。
材料与方法
成年雄性Sprague-Dawley大鼠接受2小时大脑中动脉闭塞（MCAO）加24小时或14天再灌注。在缺血发作前15分钟，将CG（26.8mg/kg）腹腔注射给大鼠。通过测量梗死体积、组织学损伤和BBB通透性来评估CG的神经保护作用。此外，在用NO供体或氧-葡萄糖剥夺（OGD）处理的体外培养脑微血管内皮细胞和/或MCAO脑缺血再灌注损伤的体内大鼠模型中，研究了CG对清除一氧化氮（NO）、调节基质金属蛋白酶（MMPs）和小窝蛋白-1（cav-1）的影响。
结果
在体内MCAO缺血再灌注大鼠模型中，CG治疗显著减少了梗死体积、组织学损伤和BBB通透性。CG治疗显著抑制了MMPs的表达和活性，并确保了从缺血大鼠皮层分离的微血管中cav-1和紧密连接蛋白的表达。此外，在OGD条件下，体外培养的脑微血管内皮细胞中，CG显示出清除NO、抑制MMP-2和MMP-9的活性并减轻细胞死亡的作用。
结论
CG可通过调节NO/cav-1/MMPs途径保护实验性脑缺血再灌注损伤中的BBB完整性。
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