慢性应激-糖皮质激素-组蛋白脱乙酰酶功能轴在慢性应激术后认知障碍中的作用  

Role of chronic stress-glucocorticoid-histone deacetylase axis in postopera-tive cognitive dysfunction induced by chronic stress

作　　者：郑智滢 宫祥丹 夏天娇[2] 陈超超 顾小萍[1] ZHENG Zhiying;GONG Xiangdan;XIA Tianjiao;CHEN Chaochao;GU Xiaoping(Department of Anesthesiology,Affiliated Drum Tower Hospital,Medical School of Nanjing University,Nanjing 210008,China;Medical School,Nanjing University,Nanjing 210093,China)

机构地区：[1]南京大学医学院附属鼓楼医院麻醉科,江苏南京210008 [2]南京大学医学院,江苏南京210093

出　　处：《中国病理生理杂志》2025年第2期268-276,共9页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.82171193);“十四五”江苏省医学重点学科(麻醉学)(No.ZDXK202232)。

摘　　要：目的:探讨小鼠慢性应激状态在术后认知功能障碍的作用,以及组蛋白脱乙酰酶2(histone deacetylase 2,HDAC2)在其中的机制联系。方法:建立重复社交失败应激模型以及长时程异氟醚麻醉模型小鼠,动物实验分为对照(Ctrl)组、异氟醚麻醉(Iso)组、慢性社交失败应激(RSDS)组和慢性社交失败应激联合异氟醚麻醉(RSDS+Iso)组;通过社交逃避实验和新环境抑制进食实验测试焦虑情绪行为改变;通过新物体识别实验和Morris水迷宫实验测试小鼠认知功能水平改变;利用ELISA实验检测小鼠血浆皮质酮水平;从胎鼠海马提取原代海马神经元,将神经元细胞分组为对照(Ctrl)组,慢性应激复合长时程异氟醚麻醉(Cort+Iso)组,单纯CAY-10683干预(CAY)组和CAY-10683治疗(CAY+Cort+Iso)组;采用CCK-8方法检测细胞活力变化;采用Western blot方法检测脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)和HDAC2蛋白的表达变化。结果:(1)RSDS模型小鼠成功建立,且ELISA实验结果提示慢性应激复合长时程异氟醚麻醉的小鼠血浆皮质酮水平明显升高。(2)认知行为学实验和Western blot结果显示慢性应激状态的小鼠在接受长时程异氟醚麻醉后其认知水平和海马组织BDNF蛋白表达水平明显下降。(3)Western blot结果显示慢性应激显著提高了长时程异氟醚麻醉的小鼠海马组织HADC2蛋白表达水平,利用HDAC2抑制剂可降低慢性应激复合长时程异氟醚麻醉的原代海马神经元HDAC2蛋白表达量,同时增加BDNF的蛋白表达水平。结论:(1)慢性应激可显著加重长时程异氟醚麻醉介导的术后认知功能障碍,同时伴有海马HDAC2蛋白表达水平的增加。(2)抑制HDAC2可有效改善慢性应激复合长时程异氟醚麻醉所导致的认知相关蛋白BDNF的蛋白表达下降。AIM:To explore the impact of chronic stress on postoperative cognitive dysfunction in rats and to elucidate the mechanistic link to histone deacetylase 2(HDAC2).METHODS:A repeated social defeat stress model and a prolonged isoflurane anesthesia model were established in mice.The rats were randomly assigned to four groups:control(Ctrl)group,isoflurane anesthesia(Iso)group,chronic social defeat stress(RSDS)group,and chronic social defeat stress combined with isoflurane anesthesia(RSDS+Iso)group.Anxiety-like behaviors were evaluated using the social avoidance test and the novelty-suppressed feeding test.Cognitive function was assessed through the novel object recognition test and the Morris water maze.Plasma corticosterone levels were measured via enzyme-linked immunosorbent assay(ELISA).Primary hippocampal neurons were isolated from fetal mouse hippocampi and classified into four groups:control group,chronic stress combined with prolonged isoflurane anesthesia(Cort+Iso)group,CAY-10683 intervention(CAY),and CAY-10683 treatment(CAY+Cort+Iso)group.Cell viability was determined using CCK-8 assay,and protein expression levels of brain-derived neurotrophic factor(BDNF)and HDAC2 were analyzed by Western blot.RESULTS:The RSDS mouse model was successfully established,with ELISA results indicating a significant increase in plasma corticosterone levels in mice subjected to chronic stress combined with prolonged isoflurane anesthesia.Behavioral assessments and Western blot analyses revealed that mice exposed to prolonged isoflurane anesthesia following chronic stress showed marked declines in cognitive function and hippocampal BDNF protein expression levels.Additionally,chronic stress significantly elevated HDAC2 protein expression in the hippocampi of mice undergoing prolonged isoflurane anesthesia.Treatment with an HDAC2 inhibitor reduced HDAC2 protein expression in primary hippocampal neurons sub-jected to chronic stress combined with prolonged isoflurane anesthesia,concurrently increasing BDNF protein expression levels.CON

关 键 词：术后认知功能障碍 慢性应激 组蛋白乙酰化 组蛋白脱乙酰酶2 

分 类 号：R363.2[医药卫生—病理学] R619[医药卫生—基础医学] R741