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目的:探讨有氧运动激活慢性不可预知应激性刺激(Chronic Unpredictable Stress,CUMS)抑郁小鼠海马BDNF/miR-195/Bcl-2信号通路改善海马功能的作用。方法:8周龄雄性健康KM小鼠,随机数字法分为空白对照组(CG)、CUMS抑郁模型组(MG)和抑郁+有氧运动组(EG),每组12只。13种慢性不可预知应激刺激28天建立CUMS抑郁模型,EG组在建模成功后适应性运动1周后,采用小动物跑台进行8周的有氧运动训练。训练结束后测定各组小鼠的神经行为评分,ELISA法测定血清BDNF,免疫组化法进行海马组织BDNF的定位表达,TUNEL检测海马组织细胞凋亡率,RTPCR检测凋亡相关miRNA与m RNA的表达水平,western blot检测海马BDNF蛋白表达水平。结果:CUMS抑郁小鼠海马功能显著降低,神经行为学评分下降,血清BDNF含量降低,造模效果显著。mRNA与miRNA高度相关的基因涉及到miR-195与BDNF,且两者的差异表达量与有氧运动相关,RT-PCR检测模型组小鼠海马组织Bax、Caspase-3表达上调,Bcl-2表达下降。有氧运动可有效改善抑郁小鼠海马功能,上调海马组织BDNF与Bcl-2的表达水平,下调miR-195和Bax的表达水平,抑制Caspase-3的活化,降低海马细胞凋亡率,且海马miR-195表达水平与BDNF表达呈显著负相关。结论:CUMS抑郁小鼠海马miR-195上调通过靶向抑制Bcl-2的表达水平促进海马细胞凋亡。有氧运动可显著上调抑郁小鼠海马BDNF的表达水平,抑制miR-195在小鼠海马细胞中的促凋亡作用,下调Bax、Caspase-3的表达,发挥抗凋亡作用。这一作用可能与BDNF/miR-195/Bcl-2信号通路的激活有关。
Abstract：Objective:The purpose of this study was to explore the effect of aerobic exercise on hippocampus BDNF,miR-195/Bcl-2 signaling pathway and hippocampus neuronal apoptosis in mice with chronic unpredictable stress depression. Methods:Thirty-six male 8-week old Kunming mice were included in thisstudy,12 of them were in control group(CG),24 were established depression model by CUMS which was used 13 chronic unpredictable stress stimuli for28 days,and then were divided into model group(MG)and model plus exercise group(EG)(n=12).One week after adaptive training,EG group mice performed 8 weeks of aerobic training(Training program:10 m/min,0 slope,60 min/d and 6 times/week.)with a small animal treadmill. Neuroethological assessments wereimplemented on the last day of training. The samples were collected after anesthesia the next day. The level of serum BDNF was assessed by ELISA,TUNEL wasused to detect the apoptosis rate,the expression level of hippocampus BDNF,Bcl-2,Bax,Caspase-3 and miR-195 were examined by RT-PCR,the expressionof hippocampus BDNF were detected by immunohistochemistry,and the expression of hippocampus BDNF was tested by Western blot. Results:The CUMS de-pression mice'function was significantly impaired,the neurobehavioral score was decreased,the expression of serum BDNG was decreased. Aerobic exerciseimproved the hippocampus function of depressed mice,decreased Bax,Caspase-3,increased the level of BDNF,up-regulated the expression of BDNF and Bcl-2,reduced hippocampus cell apoptosis and the expression of miR-195 and Bax,inhibited the expression of Caspase-3.miR-195 expression was negatively cor-related to the expression of BDNF. Conclusions:The up-regulation of miR-195 in the hippocampus of CUMS depression mice promotes apoptosis of hippocampus cells through targeting inhibition of Bcl-2.Aerobic exercise can significantly increase the expression of BDNF in the hippocampus of depression mice,inhib-it the pro-apoptotic effect of mi R-195 in mice hippocampus cells,reduce the expression of Bax,Caspase-3 and inhibit apoptosis of hippocampus,improve hip-pocampus function. The protective effect of aerobic exercise on hippocampus function in CUMS depression mice was related to the activation of the BDNF/miR-195/Bcl-2 signaling pathway.
[1]冯国华.首发抑郁障碍、焦虑障碍、躯体形式障碍的神经内分泌机制研究及治疗前后的比较研究[D].昆明:昆明医科大学,2017:5-8.
[2]傅红梅,贺娜英,徐洪敏,等.经一年治疗无效的晚发抑郁症认知功能及海马局部一致性研究[J].老龄化研究,2018,5(1):1-8.
[3] ZHU Z,WANG G,MA K,et al.GABAergic neurons in nucleus accumbens are correlated to resilience and vulnerability to chronic stress for major depression[J].Oncotarget,2017,8(22):35933-35945.
[4] SAPOLSKY RM.Depression,antidepressants,and the shrinking hippocampus[J].Proceedings of the National Academy of Sciences of the United States of America,2001,98(22):12320-12322.
[5] WEI D,YING GE.Hippocampal activation of c-Jun N-terminal kinase,protein kinase B,and p38 mitogen-activated protein kinase in a chronic stress rat model of depression[J].Neural Regeneration Research,2010,5(19):1486-1490.
[6] CASTA?EDA P,MU?OZ M,GARCIA-ROJO G,et al.Association of Ncadherin levels and downstream effectors of Rho GTPases with dendritic spine loss induced by chronic stress in rat hippocampal neurons[J].Journal of Neuroscience Research,2015,93(10):1476-1491.
[7] GARZA JC,GUO M,ZHANG W,et al.Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling[J].Molecular Psychiatry,2012,17(8):790-808.
[8]刘聪,韩金红,王长虹.海马神经元突触可塑性在抑郁症发病机制中的研究[J].中华行为医学与脑科学杂志,2015,24(5):423-426.
[9]曹衍淼,王美萍,曹丛,等.抑郁的多基因遗传基础[J].心理科学进展,2016,24(4):525-535.
[10]李玥,贺敏,张磊阳,等.抑郁症神经解剖及其病理机制的研究进展[J].安徽医药,2017,21(10):1751-1759.
[11]周艳华.槲皮素对力竭运动大鼠肝组织自由基代谢及Bcl-2、Bax mRNA表达的影响[J].现代预防医学,2014,41(4):693-397.
[12]胡莹.泻火化瘀通窍法对耳蜗IRI模型大鼠Caspase-9/6及Bax/Bcl-2影响的实验研究[D].沈阳:辽宁中医药大学,2016:126-128.
[13]杜蓓.冬眠不同时期达乌尔黄鼠腓肠肌单根肌纤维钙离子浓度及Bax和Bcl-2 m RNA表达水平的变化[D].陕西:西北大学,2014:7-8.
[14] ZHOU Y,ZHOU Y,YU SS,et a.Sulfiredoxin-1 exerts anti-apoptotic and neuroprotective effects against oxidative stress-induced injury in rat cortical astrocytes following exposure to oxygen-glucose deprivation and hydrogen peroxide[J].International Journal of Molecular Medicine,2015,36(1):43-52.
[15]王平.乌司他丁对氧化应激损伤海马神经元线粒体膜电位及凋亡相关蛋白Bcl-2、MCU的影响[D].泸州:西南医科大学,2017:16-18.
[16]毕苗苗.CLC-2氯离子通道在RGC-5细胞凋亡中的作用研究[D].长春:吉林大学,2014:12-15.
[17] VERVLIET T,PARYS JB,BULTYNCK G.Bcl-2 and FKBP12 bind to IP3 and ryanodine receptors at overlapping sites:the complexity of protein-protein interactions for channel regulation[J].Biochemical Society Transactions,2015,43(3):396-404.
[18]张天艺,李云涛,刘屏.抑郁平胶囊对CUMS模型大鼠海马神经元细胞凋亡和BDNF表达的影响[J].解放军药学学报,2018,34(2):105-109、11.
[19]汤光花,陈永新,张瑞岭.舒肝颗粒对抑郁大鼠海马神经元凋亡、脑组织Caspase-3蛋白及外周血中细胞因子水平的影响[J].中国老年学杂志,2018,22(1):52-54.
[20]戈含笑,魏宏文,张有志,等.有氧运动对慢性应激大鼠脑海马区神经可塑性的影响[J].北京体育大学学报,2017,40(5):39-45.
[21]褚阳,张玉瑶,王旭,等.microRNA-195的研究进展[J].国际遗传学杂志,2015,38(4):209-213.
[22]王新星.MicroRNA-195对人脑胶质瘤细胞增殖和凋亡的影响[D].太原:山西医科大学,2013:6-8.
[23]赵志强,阴彬,彭小忠.miR-195过表达促进人神经胶质瘤细胞T98G凋亡[J].基础医学与临床,2012,32(7):783-787.
[24]杨源.MircroRNA-195调控LATS2对BEL-7402/5-Fu细胞凋亡的影响[D].衡阳:南华大学,2011:5-6.
[25]张娜娜.miR-103/195/15b调控SALL4抑制脑胶质瘤细胞增殖及侵袭作用的研究[D].哈尔滨:哈尔滨工业大学,2015:13-15.
[26] MELLIOS N,HUANG HS,GRIGORENKO A,et al.A set of differentially expressed miRNAs,including miR-30a-5p,act as posttranscriptional inhibitors of BDNF in prefrontal cortex[J].Human Molecular Genetics,2008,17(19):3030-3042.
[27]瞿准,赵建华,王超,等.脑源性神经生长因子/microRNA-195在创伤性脑损伤中的作用研究[J].海军医学杂志,2018,39(2):113-116、120.
[28] SINGH R,SAINI N.Downregulation of Bcl-2 by miRNAs augments drug-induced apoptosis-a combined computational and experimental approach[J].Journal of Cell Science,2012,125(Pt6):1568-1578.
[29] CHEN YQ,WANG XX,YAO XM,et al.MicroRNA-195 promotes apoptosis in mouse podocytes via enhanced caspase activity driven by Bcl-2 insufficiency[J].American Journal of Nephrology,2011,34(6):549-559.
[30] ZHU H,YANG Y,WANG Y,et al.MicroRNA-195 promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating Sirt1[J].Cardiovascular Research,2011,92(1):75-84.
[31]潘莹,曾宪钦,段雯,等.microRNA-195与Bcl-2/Bax在钙化大鼠主动脉中的表达及其相互作用[J].心脏杂志,2016,28(1):20-24.
[32]陈凌红,楼忠泽,周文华.快速起效抗抑郁药的神经可塑性机制研究进展[J].中国药理学与毒理学杂志,2014,28(4):580-586.
[33] ZHAO J,BAO AM,QI XR,et al.Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients[J].Journal of Affective Disorders,2012,138(3):494-502.
[34] DI PRISCO GV,HUANG W,BUFFINGTON SA,et al.Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α[J].Nature Neuroscience,2014,17(8):1073-1082.
[35]马柯.抑郁症前额叶皮层GABA能神经元功能失调分子机制研究[D].青岛:青岛大学,2017:7-8.
[36]信欣,韦彩川,毕文鹏,等.慢性应激刺激对抑郁模型小鼠构建的行为学研究[J].延边大学医学学报,2017,40(2):92-96.
[37] BEDFORD TG,TIPTON CM,WILLSON NC,et al.Maximum oxygen consumption of rats and its changes with various ex-perimental procedures[J].Journal of Applied Physiology.1979,47(6):1278-1283.
[38]肖雪,李霞,张绍军.microRNA层面上癌症的公共机制[J].生物物理学报,2009,25(1):43-40.
[39] PILLAI RS,BHATTACHARYYA SN,FILIPOWICZ W.Repression of protein synthesis by miRNAs:how many mechanisms?[J].Trends in Cell Biology,2007,17(3):118-126.
[40]王文峰,罗玉梅,万新红.miRNA-195的作用机制与心血管疾病的关系[J].中国医学指南,2013,11(4):69-73.
[41] LEE ST,CHU K,JUNG KII,et al.miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease mode[J].Annals of Neurology,2012,72(2):269-277.
[42]钟晓明,毛庆秋,黄真,等.苏郁胶囊对慢性应激抑郁模型大鼠海马神经细胞凋亡的影响[J].中国现代应用药学杂志,2006,23(8):733-737.
[43]刘聪,韩金红,王长虹.海马神经元突触可塑性在抑郁症发病机制中的研究[J].中华行为医学与脑科学杂志,2015,24(5):423-426.
[44]孟盼,朱青,赵洪庆,等.甘麦大枣汤对慢性应激抑郁大鼠HPA轴及海马现为结构的影响[J].湖南中医药大学学报,2017,37(6):581-585.
[45]宋美卿,马澜,贾力莉,等.对药香橼佛手对抑郁大鼠HPT轴和HPA轴功能的影响[J].中华中医药杂志,2017,(10):4633-4636.
[46] ANACKER C,CATTANEO A,MUSACLYAN K,et al.Role for the kinase SGK1 in stress,depression,and glucocorticoid effects on hippocampal neurogenesis[J].Proc Natl Acad Sci USA,2013,110(21):8708-8713.
[47] FOURNIER NM,DUMAN RS.Role of vascular endothelial growth factor in adult hippocampal neurogenesis:implications for the pathophysiology and treatment of depression[J].Behavioural Brain Research,2012,227(2):440-449.
[48] MAO HF,XIE J,CHEN JQ,et al.Aerobic exercise combined with huwentoxin-I mitigates chronic cerebral ischemia injury[J].Neural Regeneration research,2017,12(4):596-602.
[49]丁一,张仲文,谢岚,等.过度运动导致海马神经细胞损伤与凋亡研究进展[J].中国运动医学杂志,2016,35(2):176-180.
[50]刘涛.运动对内质网应激诱导阿尔茨海默病模型大鼠海马细胞凋亡的影响[J].体育科学,2012,32(4):72-76.
[51]林喜秀,瞿树林,周桔,等.低氧训练对大鼠心、肝、肾、海马组组细胞凋亡的影响及其机制研究[J].中国运动医学杂志,2012,31(2):146-156.
[52]刘红军,吕毓虎.有氧运动通过上调IGF1改善抑郁症大鼠的学习记忆能力[J].广州体育学院学报,2014,34(3):101-106.
[53]张艳.有氧运动改善慢性应激诱发抑郁大鼠空间学习的脑机制[D].天津:天津体育学院,2014:6-8.
[54]杨建星.有氧运动改善CUMS诱发抑郁大鼠焦虑样行为的脑机制[D].天津:天津体育学院,2014:12-16.
[55] YAO XH,WANG M,HE XN,et al.Electrical coupling regulates layer1 interneuron microcircuit formation in the neocortex[J].Science Foundation in China,2016,7(4):12229.
[56] KONDO M,NAKAMURA Y,ISHIDA Y,et al.The 5-HT3 receptor is essential for exercise-induced hippocampal neurogenesis and antidepressant effects[J].Molecular Psychiatry,2015,20(11):1428-1437.
[57] KIM YH,SUNG YH,LEE HH,et al.Postnatal treadmill exercise alleviates short-term memory impairment by enhancing cell proliferation and suppressing apoptosis in the hippocampus of rat pups born to diabetic rats[J].Journal of Exercise Rehabilitation,2014,10(4):209-217.
[58] KIM SH,KIM HB,JANG MH,et al.Treadmill exercise increase cell proliferation without altering of apoptosis in dentate gyrus of spraguedawiey tats[J].Life Sci,2002,71(11):1331-1340.
[59] KIM SE,KO IG,KIM BK,et al.Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus[J].Experimental gerontology.2010,45(5):357-365.
[60] NI H,LI CL.Physical exercise improves learning by modulating hippocampal mossy fiber sprouting and related gene expression in a developmental rat model of penicillin-induced recurrent epilepticus[J].Toxicology Letters,2009,191(1):26-32.
[61] GRIESBACH GS,HOVDA DA,PINILLA FG,et al.Volumtary exercise or amphetamine treatment but not the combination increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion in injury in rats[J].Neuoscience,2008,154(2):530-540.
[62] HWANG IK,YI SS,SONG W,et al.Effects of age and treadmill exercise in chronic diabetic stages on neuroblast differentiation in a rat model of type 2 diabetes[J].Brain Research,2010,1341(6):63-71.
[63]杨舸.microRNA-195调控RAF1蛋白的表达增强乳腺癌细胞对阿霉素杨武的敏感性的机制研究[D].重庆:重庆医科大学,2013:26-28.
[64] Zhu J,Ye Q,Chang L,et al.Upregulation of miR-195 enhances the radiosensitivity of breast cancer cells through the inhibition of BCL-2[J].International Journal of Pharmaceutics,2017,523(1):300-309.
[65]赵海波,吴永定,梁宇翔,等.miR-195调控NEK2对前列腺癌细胞增殖的影响[J].广东医学,2017,38(7):1002-1005.
[66]郭佳.microRNA-195下调BCOX1在前列腺癌中的表达后抑制前列腺肿瘤增殖和转移的实验研究[D].武汉:武汉大学,2015:1-3.
[67] WANG Y,CHEN H,FU Y,et al.MiR-195 inhibits proliferation and growth and induces apoptosis of endometrial stromal cells by targeting FKN[J].International Journal of Clinical&Experimental Pathology,2013,6(12):2824-2834.
[68]吴巍芸.miR-195表达调控对大肠癌细胞HT-29增殖和凋亡的影响及其机制探讨[J].中国医学创新,2015,12(35):25-28.
[69] QU J,ZHAO L,ZHANG P,et al.MicroRNA-195 chemosensitizes colon cancer cells to the chemotherapeutic drug doxorubicin by targeting the first binding site of BCL2L2 mRNA[J].Journal of Cellular Physiology,2015,230(3);535-545.
[70]孙丽华,谢海龙,赵洪霞,等.miR-195保护大鼠慢性脑低灌注诱发痴呆的作用与APLP2的关系[J].哈尔滨医科大学学报,2015,49(1):13-17.
[71]阿库布千,李祥龙,罗鑫,等.microRNA-195在脑膜瘤中的表达及其功能研究[J].国际神经病学神经外科学杂志,2017,44(6):638-641.
[72] XU F,ZHU Y,HE Q,et al.Identification of microRNA-regulated pathways using an integration of microRNA-mRNA microarray and bioinformatics analysis in CD34+cells of myelodysplastic syndromes[J].Scientific Reports,2016,6(1):32232.
[73] LI Y,WU D,WANG P,et al.miR-195 Regulates Proliferation and Apoptosis through Inhibiting the mTOR/p70s6k Signaling Pathway by Targeting HMGA2 in Esophageal Carcinoma Cells[J].Disease Markers,2017,(2):1-9.
[74]幕伟,苗旺,刘晓东,等.miR-195对人脑胶质瘤细胞U251和SHG-44增殖的抑制作用[J].中华临床医师杂志,2013,7(12):5374-5377.
[75]张娴,谢连红,朱旭婷,等.microRNA-195在心力衰竭的表达及其对心肌细胞增殖的影响[J].中国循证心血管医学杂志,2017,9(1):37-41.
[76] SHUANG Y,LI C,ZHOU X,et al.Expression of miR-195 in laryngeal squamous cell carcinoma and its effect on proliferation and apoptosis of Hep-2[J].European Review for Medical and Pharmacological Sciences,2017,21(14):3232-3238.
[77]谢皇,刘怿敏.miR-195靶向抑制S6K1基因对前列腺癌侵袭和转移的影响[J].实用医学杂志,2017,33(22):3698-3701.
[78] HANG P,SUN C,GUO J,et al.BDNF-mediates Down-regulation of MicroRNA-195 Inhibits Ischemic Cardiac Apoptosisn in Rats[J].International Journal of Biological Sciences,2016,12(8):979-989.
[79] ZHU H,YANG Y,WANG Y,et al.MicroRNA-195 promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating Sirt1[J].Cardiovascular Research,2011,92(1);75-84.
[80] GAO CK,LIU H,CUI CJ,et al.Roles of MicroRNA-195 in cardiomyocyte apoptosis induced by myocardial ischemia-reperfusion injury[J].Journal of Genetics,2016,95(1):99-108.
[81]张帅,孙丽华,艾静.microRNA-195在长期低灌注诱发认知功能障碍中的作用及其分支机制[J].神经药理学报,2016,6(6):1-22.
[82]王昉,梅蕊,彭樊,等.miRNA-195在小鼠早发精神分裂症发病机制中的作用[J].中国老年学杂志,2017,37(7):3411-3412.
[83] BEVERIDGE NJ,GARDINER E,CARROL AP,et al.Schizophrenia is associated with an increase in cortical microRNA biogenesis[J].Molecular Psychiatry,2010,15(12):1176-1189.
基本信息:
DOI：10.13297/j.cnki.issn1005-0000.2018.02.008
中图分类号:R749.4
引用信息:
[1]屈红林,谢军,陈嘉勤,等.有氧运动激活BDNF/miR-195/Bcl-2信号通路抑制CUMS抑郁小鼠海马神经细胞凋亡[J].天津体育学院学报,2018,33(02):148-155+176.DOI:10.13297/j.cnki.issn1005-0000.2018.02.008.
基金信息:
湖南省教育厅科技重点项目(项目编号:2016-1293);; 江西省卫生计生委科技计划项目(项目编号:20183019);; 江西省教育厅科学技术研究重点项目(项目编号:GJJ161006)
2018-03-25
2018-03-25