YC-1对肝部分切除术后老年小鼠认知功能及海马神经元凋亡的影响

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摘要目的：观察缺氧诱导因子（HIF-1α）特异性抑制剂（YC-1）对肝部分切除术后老年小鼠认知功能及海马神经元凋亡蛋白Bcl-2、Bax、Caspase-3表达的影响，探讨HIF-1α在术后认知功能障碍（POCD）发病机制中的作用。方法：健康雄性C57BL/6雄性小鼠48只，18个月龄，体质量25～35 g，采用随机数字表法分为3组（每组n=16）：假手术组（Sham组）、手术+0.9%氯化钠溶液组（手术+NS组）和HIF-1α抑制剂YC-1组（手术+YC-1组），根据手术后测试时间点不同分为术后1 d、3 d两个亚组，各亚组8只。建立肝部分切除术作为手术模型组，YC-1组给小鼠腹腔注射YC-1，Sham组在肝部分切除术相同手术部位做切开缝合术。用Morris水迷宫测试小鼠的学习记忆能力，采用Western blot法检测海马HIF-1α、Bcl-2、Bax、Caspase-3表达。结果：与Sham组比较，手术+NS组术后1 d、3 d平均逃避潜伏期的时间明显延长，空间探索跨越平台次数减少，海马HIF-1α、Bax、Caspase-3蛋白表达量增加，Bcl-2蛋白表达量减少（P＜0.01）；与手术+NS组比较，手术+YC-1组逃避潜伏期时间缩短，空间探索跨越平台次数增加（P＜0.05），手术+YC-1组海马HIF-1α、Bax、Caspase-3蛋白表达量减少，Bcl-2蛋白表达量增加（P＜0.05）。结论：YC-1改善肝部分切除术后小鼠认知功能和海马神经元凋亡与抑制HIF-1α蛋白有关，POCD的神经元凋亡机制部分与HIF-1α有关。

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关键词 ： YC-1, 缺氧诱导因子-1&alpha, 肝部分切除术, 认知功能, 细胞凋亡, 海马, 小鼠

Abstract：Objective: To investigate the effect of 3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole (YC-1) on cognitive function and hippocampal neuronal apoptosis in aged mice after partial hepatectomy, and to discuss the role of hypoxia inducible factor-1α (HIF-1α) in the mechanism of post-operative cognitive dysfunction (POCD). Methods: Forty-eight healthy male type C56BL/6 mice, aged 18 months, weighing 25-35 g, were used in the study. The mice of either type were randomly divided into 3 groups (n=16), using a random number table: sham operation group (sham group), operation group (operation+NS group) and HIF-1α inhibitor YC-1 group (operation+YC-1 group). Operation models were established by partial hepatectomy and the YC-1 treatment was given to the operation group. In sham group, the mice were incised and given surgical suture on the same surgical site in partial hepatectomy. Then each group was divided 1 d and 3 d respectively (n=8). Hidden and cued platform Morris water maze training and testing was used to observe spatial memory abilities on 1st or 3rd day. After the Morris water maze test, mice in each group were sacrificed after anesthesia. The hippocampus was separated for detection of the expression of HIF-1α and Bax, Bcl-2, activated caspase-3 by Western blot. Results: Compared with sham group, the latency for mice to find the flat was obviously prolonged and the time taken to cross the flat were decreased in the Morris water maze test. The expression of HIF-1α, Bax, activated caspase-3 were significantly increased and Bcl-2 was decreased at 1 day and 3 days in the operation group (P<0.01). Compared with the operation+NS group, the latency to find the flat was obviously decreased and the times to cross the flat were increased; the expression of HIF-1α, Bax, activated caspase-3 were significantly decreased and Bcl-2 increased at 1 day and 3 days in the operation+YC-1 group. Conclusion: YC-1 can improve the cognitive function and ameliorate the hippocampal neuronal apoptosis after partial hepatectomy. It was induced by down regulation of HIF-1α protein. HIF-1α is partially involved in the mechanism of POCD induced hippocampal neuronal apoptosis in mice.

Key words： YC-1 hypoxia inducible factor-1α partial hepatectomy cognitive function;apoptosis hippocampus mice

收稿日期: 2018-06-28

基金资助:宁波市自然科学基金资助项目（201701HJ-B01471）。

作者简介: 葛叶盈（1973-），女，浙江宁波人，主任医师，硕士。

链接本文:

https://xb.wmu.edu.cn/CN/ 或 https://xb.wmu.edu.cn/CN/Y2018/V48/I12/888

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