目的 探讨五味子甲素对血管性痴呆（VD）大鼠沉默信息调节因子1/过氧化物酶体增殖物激活受体γ辅助激活因子-1α（SIRT1/PGC-1α）通路及海马神经元凋亡的影响。方法 50只大鼠双侧颈总动脉永久性结扎法制备VD模型，造模大鼠按照随机数字表法分为模型组、五味子甲素（20、40、80 mg/kg）组、阳性对照组，每组10只；另取10只大鼠不结扎左右颈总动脉近端、远端，其余处理相同，为假手术组。五味子甲素（低、中、高）剂量组分别ip 20、40、80 mg/kg五味子甲素，阳性对照组ig 0.54 g/kg甲磺酸双氢麦角毒碱片，假手术组和模型组ip等体积溶媒，1次/d，连续21 d。Morris水迷宫实验评估大鼠空间探索能力；苏木精-伊红（HE）染色观察海马区神经元形态；脱氧核糖核苷酸末端转移酶介导的缺口末端标记法（TUNEL）检测海马区神经元凋亡情况；蛋白免疫印迹检测大鼠海马区B淋巴细胞瘤-2基因（Bcl-2）、Bcl-2相关X蛋白（Bax）、半胱氨酸天冬氨酸蛋白酶-3（Caspase-3）、活化的Caspase-3（cleaved Caspase-3）、SIRT1、PGC-1α蛋白表达水平。结果 模型组大鼠海马区细胞形态不规则或纺锤形，胞质和核浓缩、出现神经元凋亡情况；五味子甲素（低、中、高）剂量组随着剂量的增加，神经元凋亡情况逐渐缓解，且高剂量组几乎观察不到凋亡神经元。与假手术组相比，模型组大鼠海马区神经元凋亡比例、海马区Bax、cleaved Caspase-3/Caspase-3蛋白水平升高，平台象限停留时间、穿越平台次数减少，海马区Bcl-2、SIRT1、PGC-1α蛋白水平降低（P<0.05）。与模型组相比，五味子甲素（中、高）剂量组大鼠海马区神经元凋亡比例、海马区Bax、cleaved Caspase-3/Caspase-3蛋白水平降低，平台象限停留时间、穿越平台次数增加，海马区Bcl-2、SIRT1、PGC-1α蛋白水平升高（P<0.05）；五味子甲素低剂量组平台象限停留时间增加，海马区神经元凋亡比例、Bax、cleaved Caspase-3/Caspase-3蛋白水平降低，Bcl-2蛋白水平升高（P<0.05）。结论 五味子甲素可以抑制VD大鼠海马神经元凋亡情况，可能是通过激活SIRT1/PGC-1α通路实现的。

Objective To investigate the effects of schisandrin A on silent mating type information regulation 2 homolog 1/peroxisome proliferator-activated receptor γ coactivator-1α (SIRT1/PGC-1α) pathway and apoptosis of hippocampal neurons in vascular dementia (VD) rats.Methods The VD model was established by permanent ligation of bilateral common carotid arteries in 50 rats, the model rats were divided into model group, schisandrin A (low, medium and high) dose groups and positive control group according to the random number table, with 10 rats in each group. Another 10 rats were given the same treatment as the sham operation group, except that the proximal and distal ends of the left and right common carotid arteries were not ligated. schisandrin A (low, medium and high) dose groups were intraperitoneally injected with 20, 40, 80 mg/kg schisandrin A respectively, and the positive control group was intragastrically administered with 0.54 g/kg dihydroergotoxine mesylate tablets, and the sham operation group and model group were intraperitoneally injected with the same volume of solvent, once a day for 21 days. Morris water maze test was used to evaluate space exploration, the hippocampal neurons were detected by hematoxylin eosin (HE), the apoptosis of hippocampal neurons was detected by terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), Western blotting was used to detect the levels of B-lymphoma-2 gene (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, activated Caspase-3 (cleaved Caspase-3), SIRT1, PGC-1α protein.Results In the model group, the morphology of the hippocampal neurons were irregular or spindle shaped, the cytoplasm and nucleus were concentrated, and neuron apoptosis was observed, with the increase of schisandrin A (low, medium, and high) dose groups, the apoptosis of neurons gradually alleviated, and almost no apoptotic neurons were observed in the high dose group. Compared with those in the sham operation group, the apoptosis ratio of hippocampal neurons and the levels of Bax and cleaved Caspase3/Caspase-3 protein in the model group were higher, the time to stay on the platform quadrant and the time of crossing the platform were more, and the protein levels of Bcl-2, SIRT1 and PGC-1α in hippocampus were lower (P<0.05). Compared with those in the model group, the apoptosis ratio of hippocampal neurons and the levels of Bax and cleaved Caspase3/Caspase-3 protein in the schisandrin A (medium and high) dose groups were lower, the time to stay on the platform quadrant and the times of crossing the platform were less, and the protein levels of Bcl-2, SIRT1 and PGC-1α in hippocampus were higher (P<0.05), the time spent on the platform in the schisandrin A low dose groups was less, the apoptosis ratio of hippocampal neurons and the levels of Bax and cleaved-caspase3/caspase3 protein were lower, and the protein level of Bcl-2 was higher (P<0.05).Conclusion Schisandrin A can inhibit the apoptosis of hippocampal neurons in VD rats, which may be realized by activating SIRT1/PGC-1α pathway.

R285.5

国家自然科学青年科学基金资助项目（81904264）