缬沙坦改善糖尿病小鼠认知损害及其机制的研究  

Valsartan improves the cognition impairment in diabetic mice and underlying mechanism

作　　者：刘丽萍[1] 唐苏苏[2] 王建青[1] 姜荔莹[2] 张茜[1] 王肖雲[2] 王伟[1] 洪浩[2] 

机构地区：[1]安徽医科大学第二附属医院药剂科,安徽合肥230031 [2]中国药科大学药理学教研室,江苏南京210009

出　　处：《中国药理学通报》2011年第3期405-409,共5页Chinese Pharmacological Bulletin

基　　金：安徽省卫生厅医学科学研究计划课题(No09C154)

摘　　要：目的研究缬沙坦对糖尿病小鼠认知功能的影响及其作用机制。方法给小鼠静脉注射链脲佐菌素(150 mg.kg-1)诱导1型糖尿病模型,挑选空腹血糖>11.1 mmol.L-1小鼠随机分为3组,即模型组、缬沙坦高剂量组(40 mg.kg-1.d-1)及低剂量组(10 mg.kg-1.d-1),并设正常对照组。每组动物10～14只,灌胃给药,4周后用Morris水迷宫试验评价认知功能,用ELISA分析血清胰岛素水平、海马和皮层区Aβ40、Aβ42及BACE1含量,并采用葡萄糖氧化酶法测定血糖。结果缬沙坦(40 mg.kg-1.d-1,10 mg.kg-1.d-1)可以缩短糖尿病小鼠定位导航试验的潜伏期(P<0.05),增加空间探索试验中平台所在象限停留时间百分率(P<0.05);降低糖尿病小鼠海马区Aβ40、Aβ42以及BACE1水平(P<0.05或P<0.01),明显降低糖尿病小鼠皮层Aβ40(P<0.05),而对皮层Aβ42以及BACE1水平无明显影响(P>0.05),对糖尿病小鼠血糖和胰岛素水平也无影响(P>0.05)。结论缬沙坦可以通过抑制糖尿病小鼠脑海马区BACE1而减少Aβ生成,改善认知功能。Aim To investigate the effects of valsartan on the cognitive function in diabetic mice and underlying mechanism.Methods Streptozocin-induced hyperglycemic state was used as an animal model of type 1 diabetes by a single intravenous injection of streptozocin（150 mg·kg-1 body weight）.Diabetic mice were confirmed by the presence of hyperglycemia（11.1 mmol·L-1）,and randomly divided into three groups including vehicle,valsartanⅠ（40 mg·kg-1·d-1）and valsartanⅡ（10 mg·kg-1·d-1） groups,accompanied by age-matched control mice.Valsartan was administered through a gastric tube every day.The cognitive function was evaluated by Morris water maze test after 4 weeks administration of valsartan.The serum insulin,Aβ40,Aβ42 and BACE1 in the hippocampus and cortex of the mice were determined by ELISA assays,and the blood glucose was measured by the glucose oxidase method.Results Valsartan（40 mg·kg-1·d-1,10 mg·kg-1·d-1） decreased the escape latency in place navigation test（P0.05）,and increased the time spent in the platform quadrant in the spatial probe test in diabetic mice（P0.05）in comparison with control mice.Valsartan also decreased the levels of Aβ40,Aβ42 and BACE1 in the hippocampus of diabetic mice（P0.05 or P0.01）and the levels of Aβ40 of the cortex in the diabetic mice（P0.05 or P0.01）,but didn＇t significantly decreased the levels of Aβ42 and BACE1 of the cortex in the diabetic mice.Effects of valsartan on the fasting blood glucose and the serum insulin were not observed in diabetic mice.Conclusion Valsartan may improve the cognition impairment through the decrease of intracerebral Aβ formation in diabetic mice,which results from the inhibition of BACE1.

关 键 词：缬沙坦 糖尿病 认知损害 Aβ40 AΒ42 BACE1 

分 类 号：R-332[医药卫生] R322.81