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

Rosiglitazone Improves Cognitive Impairment in Streptozotocin-induced Diabetic Mice and its Mechanisms

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。

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-1 body weight） 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^-1·d^-1 and 1.6 mg·kg^-1·d^-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,Aβ42 and 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 quadrant（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-1 improves cognitive impairments in streptozotocin-induced diabetic mice via the alleviation of the Aβ burden in the brain.