还脑益聪方靶向HAMP调节铁代谢改善AD模型小鼠认知障碍的机制研究  

Study on the machanism of Huannao Yicong Deoction targeting HAMP to regu|ate iron metabo|ism and improve cognitive impairment in AD model mice

作　　者：孙宁宁 贺小平 刘珊 赵炎 钟健民 郝雅煊 张烨华 董贤慧 SUN Ning-ning;HE Xiao-ping;LIU Shan;ZHAO Yan;ZHONG Jian-min;HAO Ya-xuan;ZHANG Ye-hua;DONG Xian-hui(Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease,Hebei University of Chinese Medicine,Shijiazhuang 050091,China)

机构地区：[1]河北中医药大学,河北省心脑血管病中医药防治研究重点实验室,河北石家庄050091

出　　处：《中国药理学通报》2024年第7期1240-1248,共9页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金(No 81803935);河北省自然科学基金项目(No H2023423009);河北省省级科技计划(No 223777145D);河北省中医药管理局课题(No 2024078);河北省卫健委重点科技研究计划(No 20200129)。

摘　　要：目的探讨还脑益聪方(Huannao Yicong decoction,HYD)对APP/PS1小鼠学习记忆能力与脑铁代谢的影响以及HAMP基因敲除小鼠(HAMP^(-/-)小鼠)和APP/PS1双转基因模型小鼠的相关性。方法实验分5组,HAMP^(-/-)组:6月龄HAMP基因敲除小鼠;APP/PS1组:6月龄APP/PS1双转基因小鼠;HAMP^(-/-)+还脑益聪方组(HAMP^(-/-)+HYD);APP/PS1+还脑益聪方组(APP/PS1+HYD);阴性对照组:6月龄C57BL/6J小鼠,每组6只。还脑益聪方灌胃给药(还脑益聪方13.68 g·kg^(-1)体质量),其余各组给予蒸馏水灌胃,每天1次,给药2个月。给药结束后,Morris水迷宫测试每组小鼠学习记忆能力;生化法检测各小鼠脑组织铁含量;Western blot与RT-qPCR检测各组小鼠海马转铁蛋白(transferrin,TF)、转铁蛋白受体1(transferrin receptor1,TFR1)、膜铁转运蛋白1(ferroportin1,FPN1)蛋白、二价金属离子转运体1(divalent metal transporter1,DMT1)与β淀粉样蛋白(β-amyloid protein,Aβ)及mRNA表达水平。结果与正常组相比,HAMP^(-/-)组小鼠与APP/PS1组小鼠学习记忆能力均降低,脑组织铁含量升高,HAMP^(-/-)组与APP/PS1组小鼠海马中Aβ蛋白表达升高(P<0.01),TF、TFR1、DMT1蛋白及mRNA表达均升高(P<0.01),FPN1蛋白及mRNA表达降低(P<0.01);分别与HAMP^(-/-)组和APP/PS1组相比,HAMP^(-/-)+HYD组与APP/PS1+HYD组小鼠学习记忆能力均提高,脑组织铁含量降低,Aβ蛋白表达下降(P<0.01),TF、TFR1、DMT1蛋白及mRNA表达降低(P<0.01),FPN1蛋白及mRNA表达升高(P<0.01)。结论HAMP^(-/-)小鼠和APP/PS1小鼠之间具有一定关联性,HYD可以改善HAMP^(-/-)与APP/PS1小鼠学习记忆能力,减少Aβ沉积,其机制可能与调节TF、TFR1、DMT1、FPN1的表达,改善脑铁超载有关。Aim To explore the effects of Huannao Yicong decoction(HYD)on the learning and memory ability and brain iron metabolism in APP/PS1 mice and the correlation of HAMP knockout mice and APP/PS1 double transgenic model mice.Methods The experiment was divided into five groups,namely,HAMP^(-/-)group(6-month HAMP gene knockout mice),APP/PS1 group(6-month APP/PS1-double-transgenic mice),HAMP^(-/-)+HYD,APP/PS1+HYD,and negative control group(6-month C57BL/6J mice),with six mice in each group.The dose was administered(13.68 g·kg^(-1)weight),and the other groups received distilled water for gavage once a day for two months.After the administration of the drug,the mice in each group were tested for learning and memory in the Morris water maze;Biochemical detection was performed to detect iron ion content in each mouse brain;Western blot and RT-qPCR were carried out to analyze hippocampal transferrin(TF),transferrin receptor1(TFR1),membrane iron transporter1(FPN1)divalent metal ion transporter1(DMT1)andβ-amyloid protein(Aβ)protein and mRNA expression levels in each group.Results Compared with the normal group,both HAMP^(-/-)mice and APP/PS1 mice had reduced the learning and memory capacity,increased iron content in brain tissue,Aβprotein expression increased in hippocampus of HAMP^(-/-)group and APP/PS1 group mice(P<0.01),the protein and mRNA expression of TF,TFR1 and DMT1 increased in hippocampal tissues of HAMP^(-/-)and APP/PS1 groups(P<0.01),and the FPN1 protein and mRNA expression decreased(P<0.01).Compared with the HAMP^(-/-)and APP/PS1 groups,respectively,HAMP^(-/-)+HYD group and APP/PS1+HYD group had improved learning and memory ability,decreased iron content,decreased Aβprotein expression(P<0.01),decreased TF,TFR1,DMT1 protein and mRNA expression(P<0.01),and increased expression of FPN1 protein and mRNA(P<0.01).Conclusions There is some association between HAMP^(-/-)mice and APP/PS1 mice,HYD can improve the learning and memory ability of HAMP^(-/-)and APP/PS1 mice and reduce the Aβdeposition.The mechanism may be r

关 键 词：还脑益聪方 HAMP基因敲除小鼠 铁代谢 APP/PS1 认知障碍 Β淀粉样蛋白 

分 类 号：R-332[医药卫生] R289.5R338.64R591.1R745.7