Effects of metformin on depressive behavior in chronic stress rats

doi:10.12047/j.cjap.5775.2019.052

Abstract

Abstract: 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.

Key words: metformin, chronic unpredictable mild stress, rat, depressive behavior, hippocampus

LI Gai-fen, ZHAO Ming, ZHAO Tong, CHENG Xiang, FAN Ming, ZHU Ling-ling. Effects of metformin on depressive behavior in chronic stress rats[J]. CJAP, 2019, 35(3): 245-249.

References

[1] Menard C, Pfau ML, Hodes GE, et al. Social stress induces neurovascular pathology promoting depression[J]. Nat Neurosci, 2017, 20(12): 1752-1760.
[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 2 diabetes 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 lowers α-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.