ZLN005改善老年小鼠术后认知功能障碍与突触损伤  

ZLN005 improves postoperative cognitive dysfunction and synaptic damage of the elderly mice

作　　者：吴旭阳 黄永鑫 陈安迪 陈晓辉 郑晓春 Wu Xuyang;Huang Yongxin;Chen Andi;Chen Xiaohui;Zheng Xiaochun(Academy of Integrative Medicine,Fujian University of Traditional Chinese Medicine,Fujian,Fuzhou 350001,China;Anesthesia Medical Center,Fuzhou University Affiliated Provincial Hospital,Fujian,Fuzhou 350001,China)

机构地区：[1]福建中医药大学中西医结合学院,福建福州350122 [2]福州大学附属省立医院麻醉医学中心,福建福州350001

出　　处：《创伤与急诊电子杂志》2024年第4期225-236,共12页Journal of Trauma and Emergency(Electronic Version)

基　　金：福建省科技创新联合基金(2023Y96030113)。

摘　　要：目的探讨ZLN005是否可以通过提高海马组织中过氧化物酶体增殖物激活受体γ辅助活化因子1α(peroxisome proliferators activated receptorγcoactivator-1α,PGC-1α)表达水平,从而改善吸入性麻醉药异氟烷与腹部开放手术后发生的海马突触损伤引起的老年小鼠术后认知功能障碍(postoperative cognitive dysfunction,POCD)。方法18月龄的SPF级老年C57BL/6J小鼠45只,采用随机数字表法分为Sham组(实施假手术,n=15)、Sur组(进行麻醉与手术,n=15)、ZLN005组(应用ZLN005后进行麻醉与手术,n=15)。Sham组小鼠仅吸入空气3h,Sur组小鼠使用1.5%异氟烷吸入麻醉3h并进行肝叶部分切除术,ZLN005组在手术前1h腹腔注射PGC-1α转录激动剂ZLN00515mg/kg,随后再吸入1.5%异氟烷麻醉3h并进行肝叶部分切除术。于麻醉与手术结束后72h检测3组老年小鼠海马组织PGC-1α、核呼吸因子1(nuclear respiratory factor-1,NRF-1)与线粒体转录因子A(mitochondrial transcription factor A,mTFA)蛋白表达水平;评估线粒体代谢标志物细胞色素c氧化酶Ⅳ亚型(cytochrome c oxidaseⅣ,COXⅣ)与三磷酸腺苷合酶5亚基1(adenosine triphosphate synthase 5 subunit alpha 1,ATP5A1)蛋白表达水平;评估突触后密度蛋白95(postsynaptic density protein 95,PSD-95)与突触素(synaptophysin,SYP)蛋白表达水平;运用高尔基染色法评估神经元树突棘缺失与突触损伤程度;通过Sholl分析法确定神经突触状态;通过透射电镜观察突触后致密物厚度与突触囊泡数量;使用水迷宫实验检测小鼠学习记忆能力用以评估认知功能。结果与Sham组相比,Sur组小鼠海马中PGC-1α、NRF-1、mTFA、COXⅣ、ATP5A1、PSD-95与SYP蛋白表达量降低(P<0.05),高尔基染色显示树突棘减少,电镜下突触后致密物厚度变薄,突触囊泡数量减少。ZLN005组海马PGC-1α、NRF-1、mTFA、COXⅣ、ATP5A1、PSD-95、SYP蛋白表达水平比Sur组高,树突棘数量与突触囊泡数量多于Sur组,突触后致密物厚度大于Objective To investigate whether ZLN005 can improve hippocampal synaptic damage-induced postoperative cognitive dysfunction(POCD)in elderly mice following exposure to inhalational anesthetic isoflurane and abdominal open surgery by increasing the expression level of peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α)in hippocampal tissues.Method Forty-five SPF-grade elderly C57BL/6J mice,aged 18 months,were randomly divided into Sham group undergoing sham operation(n=15),Sur group receiving anesthesia and surgery(n=15),and ZLN005 group treated with ZLN005 prior to anesthesia and surgery(n=15)using a random number table method.The mice in the Sham group inhaled only air for 3 hours;the Sur group mice received 1.5%isoflurane inhalational anesthesia for 3 hours followed by partial hepatectomy;the ZLN005 group received an intraperitoneal injection of the PGC-1αtranscriptional activator ZLN005 at 15 mg/kg one hour before surgery,followed by 1.5%isoflurane inhalational anesthesia for 3 hours and partial hepatectomy.Seventy-two hours after the anesthesia and surgery,we measured the protein expression levels of PGC-1α,nuclear respiratory factor-1(NRF-1),and mitochondrial transcription factor A(mTFA)in hippocampal tissues of the three groups.Additionally,we assessed mitochondrial respiration biomarkers cytochrome c oxidase IV subunit(COXⅣ)and adenosine triphosphate synthase 5 alpha subunit 1(ATP5A1)protein levels,and evaluated postsynaptic density protein 95(PSD-95)and synaptophysin(SYP)protein expression levels.We employed Golgi staining to assess the loss of neuronal dendritic spines and synaptic damage severity;determined neuronal synaptic states using Sholl analysis,and observed the thickness of postsynaptic densities and the number of synaptic vesicles through transmission electron microscopy.Finally,we evaluated cognitive function using the Morris water maze for behavioral assessment of learning and memory.Result Compared to the Sham group,the Sur group exhibited decreased expression levels of P

关 键 词：术后认知功能障碍 过氧化物酶体增殖物激活受体γ辅助活化因子1α 突触 线粒体 麻醉 老年 海马 

分 类 号：R73[医药卫生—肿瘤]