交泰丸对糖尿病小鼠认知功能障碍的影响及机制
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摘要
目的:观察交泰丸(Jiaotaiwan,JTW)不同配伍比例对糖尿病胰岛素抵抗、认知功能障碍的作用,并探讨其机制。方法:自发性糖尿病db/db小鼠40只,随机分为模型组,交泰丸1号组(1.68 g·kg-1),交泰丸2号组(3.36 g·kg-1),交泰丸3号组(8.40 g·kg-1),每组8只,另设同周龄C57BL/6J小鼠8只为正常组。干预8周后,检测小鼠学习记忆,空间探索能力;检测空腹血糖(fasting blood glucose,FBG),胰岛素水平(fasting insulin,Fins),计算胰岛素抵抗指数(HOMA-IR),总甘油三酯(total triglyceride,TG),总胆固醇(total cholesterol,TC),游离脂肪酸(free fatty acids,FFA),高密度脂蛋白(high density lipoprotein,HDL),低密度脂蛋白(low density lipoprotein,LDL)等;蛋白免疫印迹法(Western blot)检测tau蛋白p Ser199,p Ser202,p Ser214位点,磷酸化蛋白激酶B (p-Akt),糖原合酶激酶-3β(glycogen synthase kinase-3β,GSK-3β),磷酸化GSK-3β(p-GSK-3β)蛋白表达。结果:与模型组比较,交泰丸2,3号组FBG,Fins和HOMA-IR显著降低(P<0.01); TG,TC,HDL,FFA显著降低(P<0.01);分辨指数、穿越平台次数显著提高(P<0.01);小鼠海马tau蛋白p Ser199,p Ser202,p Ser214位点,GSK-3β蛋白表达明显降低(P<0.05,P<0.01),p-Akt,p-GSK-3β表达显著升高(P<0.01)。结论:交泰丸3号(黄连-肉桂10∶1)具有改善胰岛素抵抗及认知功能障碍的作用,可能与其抑制tau蛋白过度磷酸化,下调GSK-3β蛋白表达和上调p-Akt,p-GSK-3β表达有关。
Objective:To explore effect and mechanism of Jiaotaiwan(JTW) on cognitive impairment in diabetic mice.Method:The 40 db/db mice of spontaneous diabetes were randomly divided into model group,JTW 1 group(1.68 g·kg-1),JTW 2 group(3.36 g·kg-1),and JTW 3 group(8.40 g·kg-1),with 8 mice in each group,and 8 C57 BL/6 J mice were included into normal group.After 8 weeks of treatment,behavioral test,fasting blood glucose(FBG),fasting insulin(Fins),insulin resistance index(HOMA-IR),total triglyceride(TG),total cholesterol(TC),free fatty acids(FFA),high density lipoprotein(HDL),and low density lipoprotein(LDL) were detected.Western blot was used to detect protein expressions of p Ser199,p Ser202,pSer214,p-Akt,glycogen synthase kinase-3β(GSK-3β),phospho-GSK-3β(p-GSK-3β).Result:Compared with model group,FBG,Fins,HOMA-IR,TG,TC,HDL,FFA in JTW group decreased significantly(P<0.01),with a significant improvement in cognitive function(P<0.01),protein expressions of taupSer199,pSer202,pSer214 and GSK-3β in hippocampus of mice decreased significantly(P<0.05,P<0.01),and expressions of p-Akt and p-GSK3 beta significantly increased(P<0.01).Conclusion:JTW 3(Coptidis Rhizoma-Cinnamomi Cortex 10∶1) can alleviate insulin resistance and cognitive impairment.The mechanism may be related to the inhibition of over-phosphorylation of tau protein,the down-regulation of GSK-3β protein expression and the up-regulation of p-Akt and p-GSK-3β expressions.
Objective:To explore effect and mechanism of Jiaotaiwan(JTW) on cognitive impairment in diabetic mice.Method:The 40 db/db mice of spontaneous diabetes were randomly divided into model group,JTW 1 group(1.68 g·kg-1),JTW 2 group(3.36 g·kg-1),and JTW 3 group(8.40 g·kg-1),with 8 mice in each group,and 8 C57 BL/6 J mice were included into normal group.After 8 weeks of treatment,behavioral test,fasting blood glucose(FBG),fasting insulin(Fins),insulin resistance index(HOMA-IR),total triglyceride(TG),total cholesterol(TC),free fatty acids(FFA),high density lipoprotein(HDL),and low density lipoprotein(LDL) were detected.Western blot was used to detect protein expressions of p Ser199,p Ser202,pSer214,p-Akt,glycogen synthase kinase-3β(GSK-3β),phospho-GSK-3β(p-GSK-3β).Result:Compared with model group,FBG,Fins,HOMA-IR,TG,TC,HDL,FFA in JTW group decreased significantly(P<0.01),with a significant improvement in cognitive function(P<0.01),protein expressions of taupSer199,pSer202,pSer214 and GSK-3β in hippocampus of mice decreased significantly(P<0.05,P<0.01),and expressions of p-Akt and p-GSK3 beta significantly increased(P<0.01).Conclusion:JTW 3(Coptidis Rhizoma-Cinnamomi Cortex 10∶1) can alleviate insulin resistance and cognitive impairment.The mechanism may be related to the inhibition of over-phosphorylation of tau protein,the down-regulation of GSK-3β protein expression and the up-regulation of p-Akt and p-GSK-3β expressions.
引文
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[7]龚艳琳,陆付耳,董慧,等.交泰丸及其单味药对大鼠2型糖尿病的治疗作用[J].中国医院药学杂志,2010,30(5):356-360.
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[9]胡玉英,胡跃强,张青萍,等.交泰丸联合盐酸多奈哌齐治疗血管性痴呆45例临床研究[J].中国医药导报,2013,10(4):101-102,105.
[10]于春泉,王怡,高杉,等.交泰丸不同配比抗抑郁作用的实验研究[J].中国实验方剂学杂志,2012,18(6):225-228.
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[13]钱俊青,范菁,童君,等.多不饱和脂肪酸微胶囊改善小鼠学习记忆能力研究[J].浙江工业大学学报,2018,46(1):114-118.
[14]Steen E,Terry B M,Rivera E J,et al.Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3diabetes?[J].J Alzheimers Dis,2005,7(1):63-80.
[15]Jung H J,Park S S,Mok J O,et al.Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes[J].Exp Neurol,2011,228(2):232-241.
[16]Biessels G J,Staekenborg S,Brunner E,et al.Risk of dementia in diabetes mellitus:a systematic review[J].Lancet Neurol,2006,5(1):64-74.
[17]彭怀仁.中医方剂大辞典[M].北京:人民卫生出版社,1995:669-670.
[18]全世建,黑赏燕,钱莉莉.加味交泰丸治疗2型糖尿病伴失眠70例临床观察[J].新中医,2012,44(12):85-86.
[19]DONG H,WANG J H,LU F E,et al.Jiaotai pill enhances insulin signaling through phosphatidylinositol3-kinase pathway in skeletal muscle of diabetic rats[J].Chin J Integr Med,2013,19(9):668-674.
[20]李杰,李东华,涂正伟,等.番石榴叶总黄酮促进糖尿病模型小鼠胰岛再生机制[J].中国实验方剂学杂志,2017,23(10):116-121.
[21]胡玉英,刘泰,张青萍.交泰丸对血管性痴呆模型大鼠学习记忆能力及脑组织胆碱能机制的影响[J].重庆医学,2012,41(1):209-210.
[22]王秋,方志军.不同比例交泰丸镇静催眠作用的药效学研究[J].中医临床研究,2011,3(11):16-17.
[23]张潇,高耀,向欢,等.基于网络药理学的交泰丸治疗抑郁症作用机制研究[J].中草药,2017,48(8):1584-1590.
[2]Velayudhan L,Poppe M,Archer N,et al.Risk of developing dementia in people with diabetes and mild cognitive impairment[J].Br J Psychiatry,2010,196(1):36-40.
[3]de la Monte S M,Wands J R.Alzheimer's disease is type 3 diabetes-evidence reviewed[J].J Diabetes Sci Technol,2009,2(6):1101-1113.
[4]Craft S.Insulin resistance and Alzheimer's disease pathogenesis:potential mechanisms and implications for treatment[J].Curr Alzheimer Res,2007,4(2):147-152.
[5]PEI J J,Tanaka T,Tung Y C,et al.Distribution,levels,and activity of glycogen synthase kinase-3 in the Alzheimer disease brain[J].J Neuropathol Exp Neurol,1997,56(1):70-78.
[6]袁琳,李慧姣,胡娜,等.交泰丸不同配比组方降糖作用及相关机制探讨[J].中国实验方剂学杂志,2017,23(8):130-137.
[7]龚艳琳,陆付耳,董慧,等.交泰丸及其单味药对大鼠2型糖尿病的治疗作用[J].中国医院药学杂志,2010,30(5):356-360.
[8]李慧姣,袁琳,胡娜,等.不同配伍比例交泰丸对db/db小鼠降糖作用的比较研究[J].中国中医药科技,2017,24(2):153-155,170.
[9]胡玉英,胡跃强,张青萍,等.交泰丸联合盐酸多奈哌齐治疗血管性痴呆45例临床研究[J].中国医药导报,2013,10(4):101-102,105.
[10]于春泉,王怡,高杉,等.交泰丸不同配比抗抑郁作用的实验研究[J].中国实验方剂学杂志,2012,18(6):225-228.
[11]全世建,林杏娥,刘妮.交泰丸不同配伍比例的药效学研究[J].中药材,2006,29(2):164-166.
[12]Bevins R A,Besheer J.Object recognition in rats and mice:a one-trial non-matching-to-sample learning task to study'recognition memory[J].Nat Protoc,2006,1(3):1306-1311.
[13]钱俊青,范菁,童君,等.多不饱和脂肪酸微胶囊改善小鼠学习记忆能力研究[J].浙江工业大学学报,2018,46(1):114-118.
[14]Steen E,Terry B M,Rivera E J,et al.Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3diabetes?[J].J Alzheimers Dis,2005,7(1):63-80.
[15]Jung H J,Park S S,Mok J O,et al.Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes[J].Exp Neurol,2011,228(2):232-241.
[16]Biessels G J,Staekenborg S,Brunner E,et al.Risk of dementia in diabetes mellitus:a systematic review[J].Lancet Neurol,2006,5(1):64-74.
[17]彭怀仁.中医方剂大辞典[M].北京:人民卫生出版社,1995:669-670.
[18]全世建,黑赏燕,钱莉莉.加味交泰丸治疗2型糖尿病伴失眠70例临床观察[J].新中医,2012,44(12):85-86.
[19]DONG H,WANG J H,LU F E,et al.Jiaotai pill enhances insulin signaling through phosphatidylinositol3-kinase pathway in skeletal muscle of diabetic rats[J].Chin J Integr Med,2013,19(9):668-674.
[20]李杰,李东华,涂正伟,等.番石榴叶总黄酮促进糖尿病模型小鼠胰岛再生机制[J].中国实验方剂学杂志,2017,23(10):116-121.
[21]胡玉英,刘泰,张青萍.交泰丸对血管性痴呆模型大鼠学习记忆能力及脑组织胆碱能机制的影响[J].重庆医学,2012,41(1):209-210.
[22]王秋,方志军.不同比例交泰丸镇静催眠作用的药效学研究[J].中医临床研究,2011,3(11):16-17.
[23]张潇,高耀,向欢,等.基于网络药理学的交泰丸治疗抑郁症作用机制研究[J].中草药,2017,48(8):1584-1590.
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