二甲双胍对慢性应激大鼠抑郁行为的影响
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摘要
目的:观察二甲双胍对慢性不可预测性温和应激大鼠抑郁行为的影响。方法:40只雄性SD大鼠随机分为4组(n=10):对照组(CON组)、二甲双胍组(MET组)、模型组(CUMS组)、模型+二甲双胍组(CUMS+MET组),采用慢性不可预测性温和应激(CUMS)方法,用3周时间建立大鼠抑郁模型。造模完成后,两个二甲双胍组腹腔注射二甲双胍(100 mg/kg),对照组和模型组注射等量的生理盐水,每天1次,连续2周。之后检测大鼠体重增长变化、糖水嗜好、强迫游泳和悬尾不动实验、旷场实验等大鼠行为学的改变,采用尼氏染色观察大鼠海马形态结构变化。结果:与对照组比较,CUMS组大鼠体重增长明显减慢(P<0.05),糖水偏爱率明显降低(P<0.05),强迫游泳和悬尾不动实验中不动时间明显延长(P<0.05),旷场实验中自发活动明显减少(P<0.05),大鼠海马的形态结构有所变化,证实CUMS抑郁模型建立成功。与CUMS组比较,二甲双胍处理后对大鼠的体重无明显影响,但能明显改善CUMS抑郁模型大鼠的糖水摄入、不动时间和自发活动(P<0.05),并能修复CUMS大鼠海马的异常形态结构变化。结论:二甲双胍对CUMS诱导的大鼠抑郁行为具有明显的改善作用,为临床糖尿病并发抑郁症的患者提供新的治疗手段。
Objective: To detect the effects of metformin on the depressive-like behaviors in rats. Methods: Forty male SD rats were randomly divided into four groups: control group( CON group),metformin group( MET group),model group( CUMS group),model + metformin group( CUMS + MET group),10 rats in each group. Chronic unpredictable mild stress( CUMS) method was used to establish rat depression model in three weeks. After the model was established successfully,two metformin groups were intraperitoneally injected with metformin( 100 mg/kg),while the control group and the model group were injected with the same amount of saline once a day for two weeks. After that,the changes of weight gain,sucrose water preference experiment,forced swimming test,tail suspension immobility test and open field test were detected. The morphological changes of hippocampus were observed by Nissl staining.Results: Compared with the control group,the weight gain of rats in CUMS group was significantly slowed down( P<0.05),the sucrose preference rate and the spontaneous activity were significantly reduced( P< 0.05),and the immobility time in forced swimming and tail suspension immobility test was significantly prolonged( P < 0. 05),and the morphological structure of hippocampus was changed,which confirmed the success of CUMS depression model. Compared with CUMS group,metformin treatment had no significant effect on body weight of rats,but it could significantly improve sucrose water intake,immobility time and spontaneous activity of CUMS depression model rats( P<0.05),and improve the abnormal morphological changes of hippocampus in CUMS rats. Conclusion: Metformin has a therapeutic benefit against CUMS-induced depression,which provides a new treatment for patients with diabetes mellitus complicated with depression.
Objective: To detect the effects of metformin on the depressive-like behaviors in rats. Methods: Forty male SD rats were randomly divided into four groups: control group( CON group),metformin group( MET group),model group( CUMS group),model + metformin group( CUMS + MET group),10 rats in each group. Chronic unpredictable mild stress( CUMS) method was used to establish rat depression model in three weeks. After the model was established successfully,two metformin groups were intraperitoneally injected with metformin( 100 mg/kg),while the control group and the model group were injected with the same amount of saline once a day for two weeks. After that,the changes of weight gain,sucrose water preference experiment,forced swimming test,tail suspension immobility test and open field test were detected. The morphological changes of hippocampus were observed by Nissl staining.Results: Compared with the control group,the weight gain of rats in CUMS group was significantly slowed down( P<0.05),the sucrose preference rate and the spontaneous activity were significantly reduced( P< 0.05),and the immobility time in forced swimming and tail suspension immobility test was significantly prolonged( P < 0. 05),and the morphological structure of hippocampus was changed,which confirmed the success of CUMS depression model. Compared with CUMS group,metformin treatment had no significant effect on body weight of rats,but it could significantly improve sucrose water intake,immobility time and spontaneous activity of CUMS depression model rats( P<0.05),and improve the abnormal morphological changes of hippocampus in CUMS rats. Conclusion: Metformin has a therapeutic benefit against CUMS-induced depression,which provides a new treatment for patients with diabetes mellitus complicated with depression.
引文
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[11]QIAO H,Li MX,Xu C,et al.Dendritic spines in depression:what we learned from animal models[J].Neural Plast,2016,2016:1-26.
[12]杜青,王宇红,赵洪庆,等.糖尿病并发抑郁症大鼠海马血脑屏障结构的损伤及其机制[J].中国应用生理学杂志,2016,32(6):558-562.
[13]Karki R,Kodamullil AT,Hofmann-Apitius M.Comorbidity analysis between Alzheimer’s disease and type 2diabetes mellitus(T2DM)based on shared pathways and the role of T2DM drugs[J].J Alzheimers Dis,2017,60(2):721-731.
[14]Katila N,Bhurtel S,Shadfar S,et al.Metformin lowersα-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson's disease[J].Neuropharmacology,2017,125:396-407.
[15]Ould-Brahim F,Sarma SN,Syal C,et al.Metformin preconditioning of human induced pluripotent stem cell-derived neural stem cells promotes their engraftment and improves post-stroke regeneration and recovery[J].Stem Cells Dev,2018,27(16):1085-1096.
[2]Zhu XH,Yan HC,Zhang J,et al.Intermittent hypoxia promotes hippocampal neurogenesis and produces antidepressant-like effects in adultrats[J].J Neurosci,2010,30(38):12653-12663.
[3]许玲,王德全,任建民,等.2型糖尿病患者抑郁的患病率及其危险因素[J].中国糖尿病杂志,2003,11(1):46-50.
[4]Su WJ,Peng W,Gong H,et al.Antidiabetic drug glyburide modulates depressive-like behavior comorbid with insulin resistance[J].J Neuroinflammation,2017,14:210-212.
[5]Wang YW,He SJ,Feng X,et al.Metformin:a review of its potential indications.[J].Drug Des Devel Ther,2017,11:2421-2429.
[6]Shivavedi N,Kumar M,Tej GNVC,et al.Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats[J].Brain Res,2017,1674:1-9.
[7]Keshavarzi S,Kermanshahi S,Karami L,et al.Protective role of metformin against methamphetamine induced anxiety,depression,cognition impairment and neurodegeneration in rat:The role of CREB/BDNF and Akt/GSK3 signaling pathways[J].Neurotoxicology,2019,72:74-84.
[8]Khedr SA,Elmelgy AA,El-Kharashi OA,et al.Metformin potentiates cognitive and antidepressant effects of fluoxetine in rats exposed to chronic restraint stress and high fat diet:potential involvement of hipp℃ampal c-Jun repression[J].Naunyn Schmiedebergs Arch Pharmacol,2018,391(4):407-422.
[9]林霄.二甲双胍对高原低氧认知损伤的保护效应及其作用机制的研究[D].合肥:安徽医科大学,2017.
[10]赵燕,付玉.慢性应激抑郁状态对大鼠外周神经内分泌因子生物节律的影响[J].中国应用生理学杂志,2017,33(5):398-402.
[11]QIAO H,Li MX,Xu C,et al.Dendritic spines in depression:what we learned from animal models[J].Neural Plast,2016,2016:1-26.
[12]杜青,王宇红,赵洪庆,等.糖尿病并发抑郁症大鼠海马血脑屏障结构的损伤及其机制[J].中国应用生理学杂志,2016,32(6):558-562.
[13]Karki R,Kodamullil AT,Hofmann-Apitius M.Comorbidity analysis between Alzheimer’s disease and type 2diabetes mellitus(T2DM)based on shared pathways and the role of T2DM drugs[J].J Alzheimers Dis,2017,60(2):721-731.
[14]Katila N,Bhurtel S,Shadfar S,et al.Metformin lowersα-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson's disease[J].Neuropharmacology,2017,125:396-407.
[15]Ould-Brahim F,Sarma SN,Syal C,et al.Metformin preconditioning of human induced pluripotent stem cell-derived neural stem cells promotes their engraftment and improves post-stroke regeneration and recovery[J].Stem Cells Dev,2018,27(16):1085-1096.