罗格列酮改善链脲霉素诱导的糖尿病小鼠认知障碍及机制研究

摘要/Abstract

摘要：目的：研究罗格列酮（rosiglitazone）对链脲霉素诱导的 1 型糖尿病小鼠认知功能的影响及其作用机制。方法：单剂量尾静脉注射（iv）链脲霉素（150 mg• kg^-1）诱导小鼠 1 型糖尿病模型，将造模成功（空腹血糖>11.1 mmol• L^-1）的小鼠随机分为3 组：模型组，罗格列酮 3.2,1.6 mg• kg^-1• d^-1剂量组；另设正常对照组，每组 10～12只，连续灌胃（ig）给药 6 周。第 6 周采用 Morris 水迷宫和 Y 迷宫实验评价认知功能，并检测空腹血糖、血清胰岛素、海马和皮层区 Aβ₄₀,Aβ₄₂糖尿病动物脑内β分泌酶（β-site amyloid precursor protein cleaving enzyme,BACE1）含量。结果：与模型组相比，罗格列酮 3.2 mg• kg^-1剂量组能显著缩短糖尿病小鼠定位航行试验的潜伏期（P<0.05），增加空间探索实验中平台所在象限的停留时间百分率（P<0.05），并增加糖尿病小鼠在 Y 迷宫测试中的正确反应次数（P<0.05）；罗格列酮对 1 型糖尿病小鼠空腹血糖和胰岛素水平无显著影响；罗格列酮 3.2 mg• kg^-1剂量显著降低糖尿病小鼠脑内海马和皮层区 Aβ₄₀（P<0.05,P<0.05）和 Aβ₄₂（P<0.05,P<0.05）的水平而对海马和皮层区 BACE1 水平无显著影响。结论：罗格列酮 3.2 mg• kg^-1剂量可通过降低脑内 Aβ水平而改善 1 型糖尿病小鼠认知障碍。

关键词:糖尿病,认知障碍,罗格列酮,&,beta,淀粉样蛋白

Abstract:Objective: To investigate the effects of rosiglitazone on cognitive function in streptozotocin-induced diabetic mice and the underlying mechanisms.Methods: Diabetic mice induced by a single intravenous injection of streptozotocin（150 mg• kg^-1body weigh）were used as animal model of type 1 diabetes. Diabetic mice with hyperglycemia（>11.1 mmol•L^-1）were randomly divided into three groups,including untreated diabetes group, rosiglitazone( 3.2 mg•kg^-1and 1.6 mg•kg^-1)treated groups（10~12 mice/group）. After orally administration of rosiglitazone for 6 w, rosiglitazone-treated diabetic mice, untreated diabetic mice and non-diabetic controls were tested in the Morris water maze and Y maze. The serum insulin，the levels of Aβ₄₀，Aβ₄₂and BACE1 in hippocampus and cortex were determined by ELISA assays，and the blood glucose was measured by the glucose oxidase method.Results: Both water maze and Y maze learning were impaired in diabetic mice. In Morris water maze, rosiglitazone（3.2 mg• kg^-1）significantly decreased the escape latency（P<0.05）and increased the time spent in the platform quadran（P<0.05）compared with the vehicle diabetic group. Rosiglitazone（3.2 mg• kg^-1）also significantly increased the number of correct（P<0.05）in Y maze test. Rosiglitazone treatment did not decrease the blood glucose and serum insulin of diabetic mice. Rosiglitazone（3.2 mg• kg^-1）significantly decreased the Aβ₄₀（P<0.05,P<0.05）and Aβ₄₂（P<0.05,P<0.05）levels in both hippocampus and cerebral cortex of diabetic mice, without reducing the increased BACE1 level.Conclusion: Rosiglitazone at the dosage of 3.2 mg• kg^-1improves cognitive impairments in streptozotocin-induced diabetic mice via the alleviation of the Aβ burden in the brain.

Key words:diabetes mellitus,cognitive impairment,rosiglitazone,&,beta,-amyloid protein（A&,beta,）

中图分类号:

R971

张亭亭，刘丽萍，姜荔莹，胡伟，龙燕，洪浩. 罗格列酮改善链脲霉素诱导的糖尿病小鼠认知障碍及机制研究[J]. 神经药理学报, 2011, 1(2): 1-6.

ZHANG Ting-ting，LIU Li-ping，JIANG Li-ying，HU Wei，LONG Yan，HONG Hao. Rosiglitazone Improves Cognitive Impairment in Streptozotocin-induced Diabetic Mice and its Mechanisms[J]. Acta Neuropharmacologica, 2011, 1(2): 1-6.

参考文献

[1] van den Berg E, Kessels R.P, Kappelle L.J,et al. Type 2 diabetes, cognitive function and dementia: vascularand metabolic determinants [J]. Drugs Today (Barc), 2006, 42(11):741–754.
[2] Christopher T.Kodl，Elizabeth R.Seaquist. Cognitive dysfunction and diabetes mellitus[J]. Endocr Rev, 2008, 29(4):494 -511.
[3] Rodney A.Velliquette , Tracy O’ Connor, Robert Vassar. Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer’s disease pathogenesis[J]. J Neurosci,2005, 25(47): 10874-10883.
[4] Kamal A, Biessels GJ, Gispen WH,et al. Synaptic transmission changes in the pyramidal cells of the hippocampus in streptozotocin-induced diabetes mellitus in rats [J]. Brain Res, 2006, 1073-1074:276-280.
[5] Liu Liping, Hong Hao, Liao Jianming,et al. Upregulation of RAGE at the blood-brain barrier in streptozotocin-induced diabetic mice [J]. Synapse, 2009, 63(8):636-642.
[6] Watson G.Stennis, Cholerton Brenna A, Reger Mark A,et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study [J]. Am J Geriatr Psychiatry, 2005,13(11):950-958.
[7] Risner ME, Saunders AM, Altman JF,et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease [J]. Pharmacogenomics J,2006,6(4):246-254.
[8] Brands AM, Kessels RP, de Haan EH,et al. Cerebral dysfunction in type1 diabetes: effects of insulin, vascular risk factors and blood glucose levels [J]. Eur J Pharm acol,2004,490(123):159-168.
[9] Alexis M Stranahan, Thiruma V Arumguam, Roy G Cutler,et al. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons [J]. Nat Neurosci, 2008,11(3):309-317.
[10] Huang Weichan, Shiow-Wen Juang, I.Min Liu,et al. Changes of superoxide dismutase gene expression and activity in the brain of streptozotocin-induced diabetic rats [J]. Neurosci Lett,1999,275(1):25-28.
[11] 曲忠森, 赵永波, 刘文文,等. 胰岛素降低糖尿病大鼠大脑皮层β淀粉样蛋白含量的可能机制[J].中华神经科杂志,2006,39(6):392-395.
[12] Han Weiping, Cai Li. Linking type 2 diabetes and Alzheimer's disease [J]. Proc Natl Acad Sci USA,2010,107(15):6557-6558.
[13] Sakurai T. Targets of the peroxisome proliferator-activated receptor γ agonist trials for the prevention of Alzheimer disease [J]. Arch Neurol,2011, 68(1):542-543.
[14] Ward A Pedersen, Pamela J.McMillan, J.Jacob Kulstad,et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice [J].Exp Neurol,2006,199(2):265-273.
[15] Asif R. Pathan, Anil Bhanudas Gaikwad, Bhoomi Viswanad,et al. Rosiglitazone attenuates the cognitive deficits induced by high fat diet feeding in rats [J]. European J Pharmacol, 2008, 589(1-3):176–179.