吡格列酮对胰岛素抵抗大鼠海马神经元β-淀粉样肽及其相关蛋白的影响研究  

The expressions of β-amyloid or related enzymes in rat brain and the effect of Pioglitazone intervention

作　　者：朱艳利[1] 刘雪平[1] 郑敏[1] 郝跃伟[1] 赵婷婷[1] 卓晶明[1] 

机构地区：[1]山东大学附属省立医院保健病房,山东济南250021

出　　处：《吉林医学》2011年第18期3619-3621,共3页Jilin Medical Journal

摘　　要：目的:观察胰岛素抵抗大鼠海马神经元β-淀粉样肽(β-amyloid,Aβ)生成与其相关蛋白的表达及吡格列酮的干预效果。方法:48只6～8周龄的Wistar大鼠随机分为正常对照组(Control组)、吡格列酮对照组(Pioglitazone,PIO组)、胰岛素抵抗组(Insulin resistance,IR组)、吡格列酮-胰岛素抵抗干预组(Insulin resistance+pioglitazone,IR-PIO组),IR组和IR-PIO组饮用10%果糖水4周建立胰岛素抵抗模型,造模成功后,Pioglitazone组及IR-PIO组给予吡格列酮10 mg/(kg.d)灌胃,同时,IR组和NC组给于相同体积的生理盐水,共12周;免疫组织化学检测大鼠脑皮层Aβ42的蛋白表达;Western blotting检测大鼠脑皮质区APP、β分泌酶1(β-secretase,BACE1)、早老素(Presenilin,PS-1)、脑啡肽酶(Neprilysin,NEP)及胰岛素降解酶(Insulin-degrading enzyme,IDE)的表达。结果:免疫组织化学检测显示IR组和IR-PIO组大鼠脑皮质Aβ42的蛋白表达明显高于NC组及NC-PIO组(P<0.01),而IR-PIO组Aβ42的蛋白表达低于IR组(P<0.05);Western blotting检测IR组和IR-PIO组大鼠脑皮质APP、BACE1、PS-1的蛋白表达明显高于NC组及NC-PIO组(P<0.01),与IR组相比,IR-PIO组以上各指标表达明显减低(P<0.01);各组间NEP表达差异无统计学意义(P>0.05);NC组及NC-PIO组IED的表达明显增强,与NC组相比,IR组IED的蛋白表达明显减弱(P<0.01),而IR-PIO组蛋白的表达明显强于IR组。结论:胰岛素抵抗大鼠脑皮质可能通过上调BACE1,PS-1活性,促进Aβ42生成增加,同时抑制IED的活性减少了Aβ42的降解;吡格列酮能抑制BACE1,PS-1的表达,增强IED的活性,减少Aβ42生成及促进分解增加。Objective This studys aims to detect the expressions of β-amyloid precusorprotein（APP）,β-amyloid（Aβ1～42） or related enzymes,to explore the effect of Pioglitazone intervention in insulin resistance rat brain.Methods Forty-eight Wistar male rats were randomly divided into three groups：the control（NC） group,the Pioglitazone（PIO） group,the insulin resistance（IR） group and the insulin resistance ＋ Pioglitazone（IR-PIO） group.Before making rat modle,the NC,PIO group rats were given with tap water,and the IR,IR-PIO groups were fed with 10% fructose for 4 weeks to establish insulin resistance rat modle.Afer successfully making it,rats in IR-PIO group rats were given with Pioglitazone at the same time,IR and IR-PIO group rats drank the identical volume physiological saline for 12 weeks.Immunohistochemistry were employed to examine the leve of Aβ1～42 in the cortex;western blotting were employed to examine the changes of APP,β-secretase（BACE1）,presenilin（PS-1）,Neprilysin（NEP） and insulin degrading enzyme（IDE）,in brain tissues of rats.Results Immunohistochemistry results indicated that optical densities of Aβ1～42 in the cortex of the IR and IR-PIO group rats were signiflcantly higher than that of control and PIO group animals,and the IR-PIO group was lower than that of the IR group（P0.01）.Western blotting showed that APP,BACE1 and PS-1 levels in the rat cortex were signi？cantly elevated in the IR and IR-PIO group rats compared with nomal controls and PIO group（P0.01）,and the concentration in the IR-PIO group was lower than that of the IR group rat（P0.05）.But,the grayscales of IDE was lower than that in NC group.After treated with pioglitazone,the grayscales of IDE was increased.There was no difference in APP,Aβ1～42,BACE1,PS-1and IDE between NC group and PIO group.Conclusion APP metabolism in the insulin resistance brain may be involved in the pathogenesis of Alzheimer’s disease.Pioglitazone may prevent the cerebral injury induced by insulin resistance

关 键 词：胰岛素抵抗 阿尔茨海默病 Β分泌酶 Γ-分泌酶 吡格列酮 

分 类 号：R965[医药卫生—药理学]