吡格列酮改善脑室注射链脲霉素诱导的小鼠认知损害及其机制的研究

中国临床药理学与治疗学 ›› 2011, Vol. 16 ›› Issue (9): 986-991.

吡格列酮改善脑室注射链脲霉素诱导的小鼠认知损害及其机制的研究

汪魏平¹, 唐苏苏², 徐文科¹, 张亭亭², 汪平君¹, 洪浩²

¹皖南医学院弋矶山医院药剂科,芜湖 241001,安徽;
²中国药科大学药理教研室,南京 210009,江苏

收稿日期:2011-07-30 修回日期:2011-09-01 出版日期:2011-09-26 发布日期:2011-10-11
通讯作者: 洪浩,男,博士,副教授,硕士生导师,研究方向:神经与内分泌药理。Tel: 025-86185227 E-mail: haohongchina@hotmail.com
作者简介:汪魏平,男,主管药师,研究方向:临床药学。Tel: 13955384001 E-mail: cpyjsyy@126.com

Pioglitazone attenuates cognitive impairment induced by intracerebroventricular streptozotocin injection in mice and underlying mechanisms

WANG Wei-ping¹, TANG Su-su², XU Wen-ke¹, ZHANG Ting-ting², WANG Ping-jun¹, HONG Hao²

¹Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu 241001, Anhui, China;
²Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China

Received:2011-07-30 Revised:2011-09-01 Online:2011-09-26 Published:2011-10-11

摘要/Abstract

摘要： 目的: 研究吡格列酮对脑室注射链脲霉素诱导小鼠认知损害的影响及其作用机制。方法: 采用双侧脑室注射链脲霉素(0.5 mg/kg)制备小鼠认知损害模型,吡格列酮连续灌胃给药 20 d,每天1次,采用Morris水迷宫和Y迷宫试验评价认知功能,并测定脑内乙酰胆碱(Ach)、乙酰胆碱酯酶(AchE)、乙酰胆碱转移酶(ChAT)以及外周血糖水平。结果: 吡格列酮(9 mg·kg^-1·d^-1, 18 mg·kg^-1·d^-1) 能显著缩短小鼠在可见平台试验中寻找平台的潜伏期,增加空间探索试验中平台所在象限停留时间百分率;增加Y迷宫测试中的正确反应次数。吡格列酮还能显著增加小鼠脑组织海马区和皮层区Ach含量,降低AchE活性,并且增加ChAT活性,但对动物外周血糖无明显影响。结论: 吡格列酮可通过降低AchE活性和提高ChAT活性,使小鼠脑内Ach含量增加,从而改善脑室注射链脲霉素所致的小鼠认知损害。

关键词: 吡格列酮, 链脲霉素, 认知损害, 乙酰胆碱, 乙酰胆碱酯酶, 乙酰胆碱转移酶

Abstract: AIM: To investigate the effects of pioglitazone on the cognitive impairment induced by intracerebroventricular streptozotocin injection in mice and underlying mechanisms. METHODS: Streptozotocin (0.5 mg/kg) was intracerebroventricularly injected to induce cognitive impairment in mice. Pioglitazone was administered through a gastric tube every day for consecutive 20 days. The cognition function was evaluated by Morris water maze test and Y maze test. The Ach, AchE and ChAT of the hippocampus and cortex, and the blood glucose level in mice were determined. RESULTS: Pioglitazone (9 mg·kg^-1·d^-1, 18 mg·kg^-1·d^-1) significantly decreased the escape latency in visible platform test, increased the time spent in the platform quadrant in the spatial probe test, and significantly increased the correct number in Y maze test. Pioglitazone also significantly increased Ach levels and ChAT activity, and decreased AchE activity in hippocampus and cortex of mice. The difference in the level of blood glucose was not observed among groups. CONCLUSION: Pioglitazone may improve the cognition impairment induced by intracerebroventricular streptozotocin injection through the elevation of Ach levels that results from the decreased activity of AchE and increased activity of ChAT.

Key words: Pioglitazone, Streptozotocin, Cognitive impairment, Ach, AchE, ChAT

中图分类号:

R965.1

汪魏平, 唐苏苏, 徐文科, 张亭亭, 汪平君, 洪浩. 吡格列酮改善脑室注射链脲霉素诱导的小鼠认知损害及其机制的研究[J]. 中国临床药理学与治疗学, 2011, 16(9): 986-991.

WANG Wei-ping, TANG Su-su, XU Wen-ke, ZHANG Ting-ting, WANG Ping-jun, HONG Hao. Pioglitazone attenuates cognitive impairment induced by intracerebroventricular streptozotocin injection in mice and underlying mechanisms[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2011, 16(9): 986-991.

参考文献

[1] Ballard C, Gauthier S, Corbett A, et al. Alzheimer's disease[J]. Lancet,2011,377(9770):1019-1031.
[2] Liu Y, Liu F, Grundke-Iqbal I, et al. Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes[J]. J Pathol, 2011, 225(1):54-62.
[3] Mandrekar-Colucci S, Landreth GE. Nuclear receptors as therapeutic targets for Alzheimer's disease[J]. Expert Opin Ther Targets, 2011,15(9):1085-1097.
[4] Heneka MT, Sastre M, Dumitrescu-Ozimek L,et al. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta 1-42 levels in APPV717I transgenic mice[J]. Brain, 2005,128(Pt6):1442-1453.
[5] Hanyu H, Sato T, Kiuchi A, et al. Pioglitazone improved cognition in a pilot study on patients with Alzheimer's disease and mild cognitive impairment with diabetes mellitus[J]. J Am Geriatr Soc, 2009,57(1):177-179.
[6] Sato T, Hanyu H, Hirao K, et al. Efficacy of PPAR γ agonist pioglitazone in mild Alzheimer disease[J]. Neurobiol Aging, 2011,32(9):1626-1633.
[7] Geldmacher DS, Fritsch T, McClendon MJ, et al. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease[J]. Arch Neurol,2011,68(1):45-50.
[8] Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease[J]. Eur J Pharmacol, 2004,490(1/2/3):115-125.
[9] Tota S, Kamat PK, Awasthi H,et al. Candesartan improves memory decline in mice: involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin[J].Behav Brain Res,2009,199(2):235-240.
[10] Pathan AR,Viswanad B,Sonkusare SK,et al. Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats[J].Life Sci,2006,79(23):2209-2216.
[11] Sonkusare S, Srinivasan K, Kaul C, et al. Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats[J]. Life Sci, 2005,77(1):1-14.
[12] Landreth G, Jiang Q, Mandrekar S, et al. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease[J]. Neurotherapeutics, 2008,5(3):481-489.

[1]	施晴，薛锦慧，刘彦君，李娟. 基于AChE双位点抑制的新型多靶向配基抗阿尔茨海默病研究进展[J]. 中国临床药理学与治疗学, 2016, 21(8): 943-949.
[2]	陈永荣, 钟凯龙, 洪浩. 补气活血颗粒对链脲霉素诱导的1型糖尿病小鼠糖脂代谢的影响[J]. 中国临床药理学与治疗学, 2015, 20(4): 409-413.
[3]	徐文科, 李庆, 汪魏平, 唐苏苏, 汪平君, 洪浩, 张婷婷. 长春西汀改善东莨菪碱诱导的小鼠学习记忆障碍及其机制的研究[J]. 中国临床药理学与治疗学, 2014, 19(7): 756-760.
[4]	李娟, 钟正灵, 储冀汝, 赖金娥, 徐文科, 洪浩, 谢海棠. 孟鲁司特对东莨菪碱模型小鼠学习记忆及脑内胆碱能神经的影响[J]. 中国临床药理学与治疗学, 2014, 19(5): 512-516.
[5]	曹迎亚, 鲁卫华, 姜小敢, 鲁美静, 吴敬医, 秦雪梅, 姚卫东. 血清乙酰胆碱受体抗体阳性和阴性重症肌无力患者罗库溴铵肌松时效的比较[J]. 中国临床药理学与治疗学, 2014, 19(10): 1153-1157.
[6]	张妍, 袁鹤鸣, 韩真. 吡格列酮改善代谢综合征大鼠肝脏氧化和硝化应激[J]. 中国临床药理学与治疗学, 2013, 18(9): 988-992.
[7]	何春玲, 邢文, 鲁柯兵, 夏礼斌, 王安才. 吡格列酮联用阿托伐他汀对2型糖尿病患者血脂及血管内皮功能的影响[J]. 中国临床药理学与治疗学, 2013, 18(2): 198-201.
[8]	朱广球, 尤匡掌, 周纲. 盐酸多奈哌齐对老年人术后认知功能的影响[J]. 中国临床药理学与治疗学, 2011, 16(8): 903-907.
[9]	张成密, 沈浩, 徐子锋, 王莹恬, 俞卫锋, 郑吉建. 咪达唑仑对大鼠颈上交感神经节细胞乙酰胆碱受体通道的影响[J]. 中国临床药理学与治疗学, 2011, 16(7): 749-753.
[10]	徐桂中, 刘向文, 侯一平. A型肉毒毒素抑制乙酰胆碱诱发的大鼠离体幽门平滑肌的收缩[J]. 中国临床药理学与治疗学, 2010, 15(12): 1383-1387.
[11]	应卫星, 朱畴文, 李荣洲. 大黄酸和吡格列酮对实验性大鼠非酒精性脂肪性肝炎治疗作用的比较[J]. 中国临床药理学与治疗学, 2009, 14(4): 397-400.
[12]	汪辉, 戴泽平, 朱美芳, 杨定东, 王海. 海马乙酰胆碱酯酶活性与氯胺酮对幼龄大鼠空间学习记忆功能影响的关系[J]. 中国临床药理学与治疗学, 2007, 12(6): 672-675.
[13]	陈新梅, 朱家壁. 人参皂苷Rg1脂质体对东莨菪碱诱导大鼠学习记忆障碍的改善及其作用机制[J]. 中国临床药理学与治疗学, 2005, 10(8): 898-902.
[14]	高敏, 王玉, 汪海. 埃他卡林等三种结构类型的钾通道开放剂对非血管平滑肌舒张作用的选择性[J]. 中国临床药理学与治疗学, 2005, 10(6): 633-636.
[15]	陈鹭颖, 徐江平, 庞建新, 史道华. 一氧化氮部分介导吡格列酮抑制培养兔胸主动脉平滑肌细胞增殖[J]. 中国临床药理学与治疗学, 2005, 10(6): 642-645.