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目的探讨新型钙增敏剂盐酸椒苯酮胺(PPTA)对脑缺血再灌注(I/R)损伤的保护作用。方法采用四血管阻断(4-VO)建立全脑I/R损伤模型。造模成功后随机分为假手术组、模型组(I/R)、PPTA 2.5,5和10 mg·kg-1组。Morris水迷宫测定大鼠学习记忆能力;Nissl染色观察海马神经元细胞丢失情况;实时RT-PCR检测海马bax,caspase-3,bcl-2以及iNOS基因表达情况。同时采用PC12细胞建立氧糖剥夺(OGD)损伤模型,进一步探讨PPTA对神经元细胞的保护作用。结果 PPTA 5和10 mg·kg-1组可显著缩短大鼠的逃避潜伏期(P<0.05);以及显著减少术后大鼠海马CA1区神经元细胞丢失情况;PCR检测结果表明,术后给予PPTA,胱天蛋白酶3,bcl-2和bax以及iNOS的表达与I/R组比较均有显著性差异。PPTA对PC12细胞OGD损伤具有明显的保护作用,能够维持受损细胞的活力并减少LDH以及NO的释放;同时能够调节相关凋亡基因的表达,以及降低iNOS的基因表达,呈现出一定的浓度依赖性。结论 PPTA能显著改善术后大鼠的学习记忆能力,减轻海马神经元丢失情况,保护OGD对神经元细胞的损伤,提示可能是通过抗凋亡途径以及抑制iNOS-NO通路的表达来实现。
Objective To investigate the protective effect of a new calcium sensitizer, piperphentonamine hydrochloride (PPTA), on cerebral ischemia-reperfusion (I / R) injury. Methods Whole-brain I / R injury model was established by four-vessel occlusion (4-VO). After successful modeling, they were randomly divided into sham-operation group, model group (I / R), PPTA 2.5, 5 and 10 mg · kg-1 groups. Morris water maze was used to measure the learning and memory abilities of rats. Nissl staining was used to observe the loss of hippocampal neurons. Real-time RT-PCR was used to detect the expression of bax, caspase-3, bcl-2 and iNOS in hippocampus. At the same time, PC12 cells were used to establish the model of oxygen glucose deprivation (OGD) injury and to further explore the protective effect of PPTA on neuronal cells. Results PPTA 5 and 10 mg · kg-1 significantly shortened the escape latency of rats (P <0.05), and significantly reduced the neuronal cell loss in the hippocampal CA1 region of the rats after operation. The results of PCR showed that PPTA , Caspase 3, bcl-2 and bax and iNOS expression compared with the I / R group were significantly different. PPTA has a significant protective effect on OGD injury in PC12 cells, and can maintain the viability of damaged cells and reduce the release of LDH and NO; at the same time, it can regulate the expression of related apoptosis genes and reduce the gene expression of iNOS, showing a certain concentration dependence Sex. Conclusion PPTA can significantly improve the learning and memory ability, reduce the loss of neurons in hippocampus and protect the neurons from damage by OGD, which suggests that PPTA may be through anti-apoptotic pathway and iNOS-NO pathway inhibition.