UCF-101, A Novel Omi/HtrA2 Inhibitor, Protects Against Cerebral Ischemia/Reperfusion Injury in Rats
UCF-101, A Novel Omi/HtrA2 Inhibitor, Protects Against Cerebral Ischemia/Reperfusion Injury in Rats
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DOI：
10.1002/ar.20910
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发表时间：
2009-06-01
影响因子：
2
通讯作者：
Ma, Jing
中科院分区：
文献类型：
--
作者：
Su, Danying;Su, Zhiqiang;Ma, Jing
本研究的目的是探讨UCF-101，一种新的Omi/HtrA 2抑制剂，在缺血/再灌注脑损伤后的治疗效果和神经保护机制。雄性Wistar大鼠大脑中动脉闭塞2小时，然后再灌注。将动物分为3组：假手术组、溶剂处理的缺血/再灌注组和UCF-101处理组。在UCF-101治疗组中，在再灌注前10分钟腹膜内给予大鼠UCF-101（1.5 μ mol/kg）。评价大鼠的神经功能缺损，并通过氯化2，3，5-三苯基四氮唑评估脑梗死体积。TUNEL染色检测细胞凋亡。Western blot检测caspase-8、caspase-3、FasL和FLIP蛋白的表达。结果表明，UCF-101治疗显著减少脑梗死面积约16.27%（P < 0.05），并改善神经行为。TUNEL染色显示，UCF-101处理显著减少了大脑皮层中的TUNEL阳性细胞。此外，在用UCF-101处理的小鼠中，由缺血诱导的FasL表达和活性caspase-8和caspase-3的裂解产物的上调减弱，而FLIP水平的上调增加。本研究结果表明，UCF-101对小鼠脑缺血/再灌注损伤具有保护作用。UCF-101在体内提供神经保护，并且这与Fas介导的凋亡蛋白的调节相关。总之，UCF-101的使用是用于治疗局灶性脑缺血的有效的神经保护因子。Anat Rec，292：854-861，2009. (C)2009威利-利斯公司
The aim of this study was to investigate the therapeutic efficacy and neuroprotective mechanisms of UCF-101, a novel Omi/HtrA2 inhibitor, following ischemia/reperfusion brain injury. Male Wistar rats were subjected to 2 hr of middle cerebral artery occlusion followed by reperfusion. Animals were divided into 3 groups: sham, vehicle-treated ischemia/reperfusion, and UCF-101 treatment. In the UCF-101 treatment group, rats were intraperitoneally administered UCF-101 (1.5 mu mol/kg) 10 min prior to reperfusion. The rats were evaluated for neurological deficits, and brain infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride. TUNEL staining was utilized to evaluate the amount of apoptosis. In addition, expressions of protein caspase-8, caspase-3, FasL, and FLIP were examined by Western blot analysis. Results demonstrated that UCF-101 treatment significantly decreased cerebral infarct size by about 16.27% (P < 0.05) and also improved neurological behavior. TUNEL staining revealed that UCF-101 treatment significantly reduced TUNEL-positive cells in the cerebral cortex. Furthermore, the upregulation in the expression of FasL and the cleavage products of active caspase-8 and caspase-3 induced by ischemia was attenuated in mice treated with UCF-101, whereas upregulation of FLIP levels was increased. The present results demonstrated that UCF-101 protects against cerebral ischemia/reperfusion injury in mice. UCF-101 provided neuroprotection in vivo, and this was correlated with regulation of Fas-mediated apoptotic proteins, Taken together, the use of UCF-101 is a potent, neuroprotective factor for the treatment of focal cerebral ischemia. Anat Rec, 292:854-861, 2009. (C) 2009 Wiley-Liss, Inc.