背景:PPAR的激活剂,特别是PPARγ,可能是对抗脑缺血再灌注损伤炎症反应的有效神经保护药物。熊果酸(UA)可充当PPARγ激动剂并充当抗炎剂。在这项研究中,我们使用大鼠大脑中动脉闭塞和再灌注模型,研究UA作为神经保护剂如何调节金属蛋白酶/抗金属蛋白酶平衡.
方法:在雄性SD大鼠中建立大脑中动脉闭塞再灌注模型(闭塞2小时,再灌注48小时)。再灌注后0.5、24和47小时胃内给予UA。再灌注后1、24.5和47.5小时腹膜内施用双酚A二缩水甘油醚(PPARγ拮抗剂)。再灌注48小时后,估计神经功能缺损和梗死体积.通过蛋白质印迹和免疫组织化学检查PPARγ水平和金属蛋白酶/抗金属蛋白酶平衡。还评估了MAPK信号传导途径的激活。
结果:UA治疗(5、10或20mg/kg)的大鼠表现出神经功能缺损评分的显着改善,梗死体积,完整神经元数量与对照大鼠比较(P<0.01)。UA处理组的PPARγ蛋白水平和PPARγ阳性细胞百分比均升高(P<0.01)。与对照组相比,UA处理组显示MMP2,MMP9和活化MAPKs的蛋白质水平降低(P<0.01),但TIMP1水平升高(P<0.01)。UA以剂量依赖性方式发挥其保护作用。与UA和双酚A二缩水甘油醚共同治疗完全消除了UA诱导的PPARγ表达变化;然而,UA继续发挥显着但部分的神经保护作用。
结论:UA可作为PPARγ激动剂改善金属蛋白酶/抗金属蛋白酶平衡,可能通过抑制MAPK信号通路的激活,从而减轻脑缺血和再灌注损伤。因此,UA可以作为一种新型的神经保护性治疗剂。
BACKGROUND: Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance.
METHODS: The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed.
RESULTS: UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect.
CONCLUSIONS: UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway, thereby attenuating cerebral ischemia and reperfusion injury. Therefore, UA may serve as a novel neuroprotective therapeutic agent.