Ginsenoside Rgl attenuates structural disruption of the blood-brain barrier to protect the central nervous system in ischemia/reperfusion

目的:尽管人参皂甙Rg1有较强的神经保护作用,但前期研究表明Rg1难以透过血脑屏障到达脑实质。血脑屏障能维持中枢神经系统内环境的稳定,对中枢神经系统至关重要。本研究旨在验证Rg1是通过保护血脑屏障而发挥神经保护作用的观点。方法:雄性SD大鼠才用大脑中动脉闭塞(MCAO)2h后再灌22h。Rg1(45mg.kg1)于缺血后1h和再灌注3h通关尾静脉给药。动物模型测定血脑屏障的致密性,体外测定MDA和SOD。同时在体内外试验中测定基质金属蛋白酶的表达量和活性以及基质金属蛋白酶组织抑制剂mRNA的表达量以评估Rg1对血脑屏障结构的保护作用。结果:在缺血/再灌注模型大鼠中,依文思蓝的渗透率、基质金属蛋白酶的表达量和活性明显升高,而给以Rg1的模型鼠中这种升高得到明显抑制。缺血/再灌注模型大鼠中TIMP-2mRNA的表达降低,而给以Rg1的模型鼠中这种降低明显减轻。体外模型的结果与整体动物试验结果一致。结论:人参皂苷Rg1可能是通过保护脑微血管内皮细胞和减少病理条件下基质金属蛋白酶的表达量和活性、降低细胞外基质的水解,达到保护血脑屏障结构完整的作用,从而间接发挥了中枢神经系统保护作用。

AIM： Although ginsenoside Rgl possesses potent neuroprotective effects, it cannot easily be transported to brain parenchyma because of the blood-brain barrier （BBB）. This study was aimed to verify the hypothesis that the ginsenoside Rgl neuro- protective effect might be mainly derived from its direct protective effects on BBB. METHODS： Male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion （MCAO） by using the suture insertion method followed by 22 h of reperfusion. In the Rgl-treated group, Rgl （45 mg.kg^-1） was administrated via tail venous （i.v.） 1 h before focal ischemia and 3 h after reperfusion. The integrity of the BBB was measured in vivo, MDA and SOD were estimated in vitro. The expression and activity of matrix metallo- proteinases （MMPs）, and the expression of tissue inhibitor of matrix metalloproteinases （TIMPs） mRNA, were determined to evaluate the protective effect of Rgl on BBB structure both in vivo and in vitro. RESULTS： In ischemiaJreperfusion rats, using the EB dye extravasation, the expression and activity of MMPs were increased as compared to sham rats, while in Rgl-treated rats, these increases were inhibited. The expression of TIMP-2 mRNA in the ischemia/reperfusion rats was decreased as compared to sham rats, while in Rgl-treated rats, these decreases were ameliorated. The results of in vitro models were consistent with those of in vivo models. CONCLUSION： Ginsenoside Rgl may exert its protective effect of CNS indirectly by protecting the structure of the BBB, through protecting BMECs and reducing the expression and activity of MMPs in pathological conditions.