纳美芬通过调控Sirt1/TLR4/NF-κB通路改善老年大鼠术后认知功能障碍  

Nalmefene Alleviates Postoperative Cognitive Dysfunction in Aged Rats via the Sirt1/TLR4/NF-κB Pathway

作　　者：张琳 唐富东 刘跃丹 耿红芳 ZHANG Lin;TANG Fudong;LIU Yuedan;GENG Hongfang(Author information-Department of Anesthesiology and Perioperative Medicine,Henan Provincial People's Hospital,Zhengzhou University People's Hospital,Henan University People's Hospital,Zhengzhou 450003,China)

机构地区：[1]河南省人民医院麻醉与围术期医学科,郑州大学人民医院,河南大学人民医院,郑州450003

出　　处：《中国药学杂志》2025年第6期604-611,共8页Chinese Pharmaceutical Journal

基　　金：河南省医学科技攻关联合共建项目资助(LHGJ20220065)。

摘　　要：目的探究纳美芬对老年大鼠术后认知功能障碍(postoperative cognitive dysfunction,POCD)的影响及其分子机制。方法将17月龄的SD大鼠适应饲养一周后,随机分成对照(Control)组、模型(Model)组、模型+纳美芬(Model+Nal)组、模型+纳美芬+EX527(Model+Nal+EX527)组,每组8只。除Control组外,使用七氟烷麻醉和剖腹探查术建立POCD模型。Model+Nal组大鼠在麻醉诱导前30 min皮下注射0.1 mg·kg^(-1)盐酸纳美芬;Model+Nal+EX527组大鼠在麻醉诱导前30 min皮下注射0.1 mg·kg^(-1)盐酸纳美芬,并腹腔注射10 mg·kg^(-1)EX527[沉默信息调节因子1(Sirt1)抑制剂]。Morris水迷宫实验评估大鼠认知能力。术后第3天处死大鼠,苏木素-伊红(HE)染色观察海马组织病理学改变,Tunel染色分析神经元凋亡,酶联免疫吸附测定(ELISA)方法分析肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)含量,蛋白质免疫印迹(Western blot)法检测B-细胞淋巴瘤因子2(Bcl-2)、Bcl-2相关X蛋白(Bax)、Sirt1、Toll样受体4(TLR4)和核因子κB亚基p65(NF-κB p65)蛋白表达水平。结果与Control组相比,Model组大鼠出现认知障碍,海马DG区神经元出现损伤,DG区神经元凋亡比例增多,TNF-α和IL-6含量增加,Bax、TLR4和NF-κB p65蛋白表达增加,Bcl-2和Sirt1表达降低(P<0.001);与Model组相比,Model+Nal组大鼠认知能力增强,海DG区神经元损伤减轻,DG区神经元凋亡比例减少,TNF-α和IL-6含量降低,Bax、TLR4和NF-κB p65蛋白表达减少,Bcl-2和Sirt1表达增加(P<0.001);与Model+Nal组相比,Model+Nal+EX527组大鼠认知能力减弱,海马DG区神经元损伤增加,DG区神经元凋亡比例增多,TNF-α和IL-6含量增加,Bax、TLR4和NF-κB p65蛋白表达增加,Bcl-2和Sirt1表达降低(P<0.001)。结论纳美芬可通过Sirt1/TLR4/NF-κB通路减轻POCD老年大鼠神经炎症和神经元损伤,改善认知功能障碍。OBJECTIVE To explore the effect and molecular mechanism of nalmefene on postoperative cognitive dysfunction(POCD)in aged rats.METHODS Seventeen-month-old SD rats were randomly divided into control group(Control),model group(Model),model+nalmefene group(Model+Nal),model+nalmefene+EX527 group(Model+Nal+EX527)with 8 rats in each group after one week of acclimatization.The POCD animal models(excluding the Control group)were established by sevoflurane anesthesia and exploratory laparotomy.The rats in Model+Nal group were subcutaneously injected with 0.1 mg·kg^(-1)nalmefene hydrochloride 30 min before anesthesia induction.The rats in Model+Nal+EX527 group were injected subcutaneously with 0.1 mg·kg^(-1)nalmefene hydrochloride and intraperitoneally with 10 mg·kg^(-1)EX527(Sirt1 inhibitor)30 min before anesthesia induction.Morris water maze experiment was conducted to analyze the cognitive abilities of rats.Hippocampal tissues were collected 3 d after surgery.The pathological changes of the hippocampus were observed by HE staining.Neuron apoptosis was analyzed by Tunel staining.ELISA method was used to detect the contents of TNF-αand IL-6.The protein expression levels of Bax,Bcl-2,Sirt1,TLR4 and NF-κB p65 were determined by Western blot.RESULTS Compared with the Control group,the cognitive dysfunction was seen,neuronal damage and the proportion of apoptotic neurons in hippocampal DG region were increased,TNF-αand IL-6 contents as well as the expression of Bax,TLR4 and NF-κB p65 were elevated,while the expression of Bcl-2 and Sirt1 was decreased in the Model group(P<0.001).Compared with the Model group,the cognitive ability was enhanced,neuronal damage and the proportion of apoptotic neurons in hippocampal DG region were decreased,TNF-αand IL-6 contents as well as the expression of Bax,TLR4 and NF-κB p65 were reduced,whereas the expression of Bcl-2 and Sirt1 was elevated in the Model+Nal group(P<0.001).Compared with the Model+Nal group,the cognitive ability was suppressed,neuronal damage and the proportion of apo

关 键 词：纳美芬 老年大鼠 术后认知功能障碍 沉默信息调节因子1 Toll样受体4/核因子κB 

分 类 号：R965.1[医药卫生—药理学]