六味地黄丸对老龄小鼠海马突触可塑性的作用  

Effects of Liuwei Dihuang Pills on hippocampal synaptic plasticity of aged mice

作　　者：杨晶[1] 王世界 郝莉[2] 马金莲 宋军营[1] 张紫娟[2] 张振强[1] YANG Jing;WANG Shi-jie;HAO Li;MA Jin-lian;SONG Jun-ying;ZHANG Zi-juan;ZHANG Zhen-qiang(Academy of Chinese Medical Sciences,Henan University of Chinese Medicine,Zhengzhou 450046,China;School of Medicine,Henan University of Chinese Medicine,Zhengzhou 450046,China)

机构地区：[1]河南中医药大学中医药科学院,河南郑州450046 [2]河南中医药大学医学院,河南郑州450046

出　　处：《中成药》2023年第4期1093-1100,共8页Chinese Traditional Patent Medicine

基　　金：国家自然科学基金项目(U1504829);河南省科技攻关项目(212102310314,222102310280);河南省高校科技创新团队支持计划资助项目(21IRTSTHN026)。

摘　　要：目的探讨六味地黄丸对老龄小鼠海马突触可塑性的神经保护作用及其机制。方法将60只20月龄老龄小鼠随机分为模型组、多奈哌齐组和六味地黄丸低、中、高剂量组,每组12只,另取12只3月龄小鼠为正常组,连续灌胃给药60 d,通过行为学测试评估小鼠学习记忆能力,透射电镜和电生理学观察小鼠海马区神经元突触形态和功能,高尔基染色法检测小鼠海马神经元树突棘密度,Western blot法检测小鼠海马PI3K/Akt/CREB通路相关蛋白表达。结果与正常组比较,模型组小鼠学习记忆能力减弱(P<0.01),突触数量减少(P<0.01),突触后膜变薄(P<0.01),突触间隙增宽、分界模糊(P<0.01),树突棘密度降低(P<0.01),突触传递效能减弱,海马SYN、PSD-95、MAP-2、p-Akt、p-CREB、TrkB、BDNF、PI3K、PKA蛋白表达降低(P<0.05,P<0.01);与模型组比较,六味地黄丸中、高剂量组和多奈哌齐组小鼠学习能力提升(P<0.05,P<0.01),突触数量增加(P<0.01),突触后膜变厚(P<0.01),突触间隙缩窄、分界清晰(P<0.01),树突棘密度增加(P<0.01),海马区突触传递的长时程增强(LTP)效应增强,海马SYN、PSD-95、MAP-2、p-Akt、p-CREB、TrkB、BDNF、PI3K、PKA蛋白表达升高(P<0.05,P<0.01)。结论六味地黄丸能够改善老龄小鼠认知功能障碍,其机制可能与调控PI3K/Akt/CREB信号通路以增强海马突触可塑性相关。AIM To investigate the neuroprotective effects of Liuwei Dihuang Pills on hippocampal synaptic plasticity of aged mice and the mechanism.METHODS Sixty 20-month-old mice were randomly divided into the model group,the donepezil group and the low,medium and high dose Liuwei Dihuang Pills groups,with 12 mice in each group,and another 123-month-old mice assigned into the normal group.After 60 days corresponding consecutive administration,the mice were subjected to the evaluation of their learning and memory abilities by the behavioral tests;the observation of the synaptic morphology and function of mouse hippocampal neurons by transmission electron microscopy and electrophysiology;the detection of the density of dendritic spines in mouse hippocampal neurons by Golgi staining;and the detection of hippocampal PI3K/Akt/CREB signaling pathway related protein expression by Western blot.RESULTS Compared with the normal group,the model group displayed weakened learning and memory abilities(P<0.01),decreased number of synapses(P<0.01),thinner postsynaptic membrane(P<0.01),widened synaptic gap and blurred boundary(P<0.01),weakened synaptic transmission efficiency,and decreased protein expressions of hippocampal SYN,PSD-95,MAP-2,p-Akt,p-CREB,TrkB,BDNF,PI3K and PKA(P<0.05,P<0.01).Compared with the model group,the medium and high dose Liuwei Dihuang Pills groups and donepezil group shared improved learning ability(P<0.05,P<0.01),increased number of synapses(P<0.01),thicker postsynaptic membrane(P<0.01),narrowed synaptic gap and clearer boundary(P<0.01),and increased density of dendritic spines(P<0.01);improved long-term enhancement(LTP)effect of hippocampal synaptic transmission,and increased protein expressions of hippocampal SYN,PSD-95,MAP-2,p-Akt,p-CREB,TrkB,BDNF,PI3K and PKA(P<0.05,P<0.01).CONCLUSION Liuwei Dihuang Pills can improve the cognitive dysfunction of aged mice,and its mechanism may be related to the enhancement of hippocampal synaptic plasticity via PI3K/Akt/CREB signaling pathway.

关 键 词：六味地黄丸 脑老化 突触可塑性 PI3K/Akt/CREB信号通路 神经退行性病变 

分 类 号：R285.5[医药卫生—中药学]