罗格列酮通过IRS-1/Akt信号通路改善ob/ob小鼠的认知功能障碍  

Rosiglitazone attenuates cognitive function via altering hippocampal IRS-1/Akt signaling pathways in ob/ob mouse

作　　者：柴水琴 李继斌[2] 王宏英[3] 宋晔[3] 刘丹[3] 肖晓秋[1,3] 

机构地区：[1]重庆医科大学附属第一医院脂糖代谢实验室,重庆400016 [2]重庆医科大学公共卫生与管理学院营养与卫生学教研室,重庆400016 [3]重庆医科大学附属儿童医院儿童发育疾病研究省部共建教育部重点实验室,重庆400014

出　　处：《中国药理学通报》2015年第6期785-789,共5页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金面上资助项目(No 81270947);教育部高等学校博士学科点专项科研基金资助项目(No20115503110008)

摘　　要：目的本研究旨在对ob/ob小鼠腹腔注射罗格列酮,观测小鼠空间学习记忆能力及大脑海马组织中与认知功能相关的蛋白表达变化,进而探讨引起这些变化的机制。方法C57BL/6J♂ob/ob小鼠分两组,一组腹腔注射罗格列酮(RSG),即罗格列酮组(ob/ob-RSG),一组注射同等体积的生理盐水,即生理盐水组(ob/ob-Saline),同鼠龄正常C57BL/6J(WT)♂小鼠为同型对照,即正常组(WT)。饲养7个月后注射药物并连续检测随机血糖10 d,新事物探索实验检测空间学习记忆能力。Western blot方法检测海马中BACE1、磷酸化Tau、磷酸化IRS1及IRS1、磷酸化Akt及Akt等蛋白的表达水平,ELISA的方法检测Aβ1-40的水平。结果罗格列酮组小鼠随机血糖水平明显低于生理盐水组,并趋于正常组。新事物探索实验结果显示罗格列酮组的空间学习记忆能力相对于生理盐水组有所改善。罗格列酮组小鼠海马组织中BACE1及磷酸化Tau的表达水平相对于生理盐水组明显下降,并趋于正常组。类似的,海马组织中Aβ水平在罗格列酮处理后明显下降。罗格列酮组小鼠大脑海马组织中胰岛素信号通路相关蛋白IRS1以及下游Akt的磷酸化水平相对于生理盐水组均明显增高,并趋于正常组。结论ob/ob小鼠在注射罗格列酮后,海马组织中IRS1/Akt胰岛素信号通路被激活进而改善肥胖导致的认知功能障碍。Aim To identify alteration in key molecular components related to memory formation and insulin signaling in the hippocampus after rosiglitazone was in-jected into the ob/ob mice to test whether cognitive dysfunction was pharmacologically reversed by regula-tion of rosiglitazone. Methods The age-matched mice were divided into three groups （ n=18 ）： Saline-trea-ted WT mice （ WT-Saline）;Saline-treated ob/ob mice （ ob/ob-Saline） and RSG-treated ob/ob mice （ ob/ob-RSG） through intraperitoneal injection of rosiglitazone （ RSG） . The random glucose levels were measured for 10 days during the intraperitoneal injection period. No-vel object recognition was performed before mice were sacrificed. Western blot was implemented to evaluate the following proteins： BACE1, p-Tau, p-IRS1,IRS1, p-Akt and Akt in hippocampal tissues. The Aβ1-40 levels were detected by ELISA Kit. Results The random blood glucose levels were significantly re-duced in ob/ob-RSG compared with ob/ob-saline. RSG treatment led to an increase in hippocampus-de-pendent cognition of ob/ob mice according to the novel object recognition. The proteins levels of BACE1, p-Tau and Aβ were lowered in RSG-treated ob/ob mice. Furthermore, RSG treatment up-regulated hippocampal p-IRS1/IRS1 and p-Akt/Akt ratio. Conclusion Ros-iglitazone ameliorates cognitive deficits in ob/ob mice through up-regulating insulin signaling pathways in the hippocampus.

关 键 词：罗格列酮 OB/OB小鼠 胰岛素抵抗 IRS1/Akt BACE1 认知障碍 

分 类 号：R-332[医药卫生] R322.81