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Aging and disease    2020, Vol. 11 Issue (1) : 31-43     DOI: 10.14336/AD.2019.0403
Orginal Article |
Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase
Heng Ai1, Weiqing Fang2, Hanyi Hu3, Xupang Hu4, Wen Lu5,*
1Department of Physiology, Hangzhou Medical College, Hangzhou, Zhejiang, China
2Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Zhejiang, China
3Department of Ophthalmology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
4Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang University School of Medicine, Zhejiang, China
5Department of Biochemistry and Molecular Biology, Hainan Medical University, Haikou, Hainan, China
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Abstract  

Depression is one of the most prevalent neuropsychiatric disorders in modern society. However, traditional drugs, such as monoaminergic agents, have defect showing lag response requiring several weeks to months. Additionally, these drugs have limited efficacy and high resistance rates in patients with depression. Thus, there is an urgent need to develop novel drugs or approaches for the treatment of depression. Here, using biochemical, pharmacological, genetic and behavioral methods, we demonstrate that metformin imparts a fast-acting antidepressant-like effect in naïve mice as well as stressed mice subjected to chronic restraint stress model. Moreover, inhibition of AMP-activated protein kinase (AMPK) activity by compound C or knock down of hippocampal AMPKα occluded the antidepressant-like effect induced by metformin. Our results suggest that metformin may be a viable therapeutic drug for the treatment of stress-induced depression via activation of AMPK.

Keywords depression      metformin      chronic restraint stress      AMP-activated protein kinase      Compound C      antidepressant     
Corresponding Authors: Wen Lu   
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These authors contributed equally to this work.

Just Accepted Date: 07 April 2019   Issue Date: 15 January 2020
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Heng Ai
Weiqing Fang
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Wen Lu
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Heng Ai,Weiqing Fang,Hanyi Hu, et al. Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase[J]. Aging and disease, 2020, 11(1): 31-43.
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http://www.aginganddisease.org/EN/10.14336/AD.2019.0403     OR     http://www.aginganddisease.org/EN/Y2020/V11/I1/31
Figure 1.  Dose-dependent antidepressant-like effect of metformin in mice. (A) Schematic illustration of the experimental set up. (B-C) Immobility time of mice after acute treatment of various doses of metformin (intraperitoneal injection) in FST (B) and TST (C), respectively. Data are shown as the mean immobility time ± SEM. Independent groups of mice were used for each behavioral test (n = 8 mice per group). (D-E) Mice receiving different doses of metformin were subjected to the open field test (OFT). The mean distance travelled (D) and the velocity (E) were recorded (n = 8 mice per group). (F) Immunoblots of hippocampal lysate from mice treated with various doses of metformin without behavioral test. The relative levels of p-AMPK (pT172) and AMPKα were analyzed, β-actin served as a loading control. (G-H) Quantification of fold changes in pT172 (G) and AMPKα (H) levels in the hippocampus, n = 5 mice per group. One-way analysis of variance (ANOVA) with Bonferroni post-hoc analysis. *P < 0.05, **P < 0.01, #P < 0.001, n.s. represents not significant. Data are presented as mean ± SEM.
Figure 2.  Time course of metformin-mediated antidepressant-like behavioral effects. After treatment with metformin (50 mg/kg, intraperitoneal injection), the immobility time of C57BL/6 mice in FST (A) and TST (B) at different time points was analyzed, respectively. Independent groups of mice were used for each behavioral test and each time point to avoid behavioral habituation (n = 7 mice per group). One-way analysis of variance (ANOVA) with Bonferroni post-hoc analysis. *P < 0.05, **P < 0.01, n.s. represents not significant. Data are presented as mean ± SEM.
Figure 3.  Metformin produced rapid antidepressant-like effects and diminished the chronic restraint stress (CRS)-induced reduction of p-AMPK in the hippocampus. (A) Timeline of CRS exposure, metformin administration and behavioral test (n = 8 mice per group). (B-C) Mean immobility time ± SEM in non-stressed and stressed mice in FST (B) and TST (C). (D) Metformin prevented the decrease on the sucrose preference test (SPT) in stressed mice. E. Representative western blot of hippocampal proteins. (F-G) Statistical analysis of pT172 (F) and AMPKα (G) levels in the hippocampus, n = 5 mice per group. One-way analysis of variance (ANOVA) with Bonferroni post-hoc analysis. *P < 0.05, **P < 0.01, n.s. represents not significant. Data are presented as mean ± SEM.
Figure 4.  Inhibition of AMPK by compound C prevented the metformin-induced antidepressant-like effect in stressed mice. Compound C (CC) attenuated the ability of metformin to reduce the immobility time of mice in FST (A) and TST (B). (C) CC abolished the metformin-induced elevation of sucrose preference in SPT as compared with metformin-treated stressed mice (n = 8 mice per group for all behavioral tests). (D) Representative western blot of hippocampal proteins in non-stressed or stressed mice treated with metformin or CC plus metformin. Quantification of p-AMPK at T172 (E) and AMPK (F), n = 5 mice per group. One-way ANOVA with Bonferroni post-hoc analysis. #P < 0.001, n.s. represents not significant. Data are presented as mean ± SEM.
Figure 5.  Adeno-associated virus (AAV)-mediated knock down (KD) of AMPKα in the hippocampus occluded the antidepressant-like effect in stressed mice. (A) Schematic showing the experimental design and targeting strategy for knock down AMPKα. The eGFP (enhanced green fluorescent protein) was exploited to visualize the infection of the virus and an H1 promoter was used to drive the expression of shRNA. (B) Representative images of coronal slice with intensive GFP signal, indicating successful AAV infection in the hippocampus, scale bar = 300μm. (C-D) KD of AMPKα in the hippocampus hampered the metformin-induced elevation in struggling time in FST (C) and TST (D) of stressed mice, n = 7-8 mice per group. (E) KD of AMPKα in the hippocampus occluded the increased sucrose preference in SPT induced by metformin in stressed mice. (F) Representative blots of hippocampal proteins in AAV-NC- and AAV-shRNA-injected mice after CRS without behavior test. (G-H) Statistical analysis of the pT172 (G) and AMPKα (H) levels in the hippocampus, n = 5 mice per group. The results were analyzed using a two-way ANOVA with Bonferroni post hoc analysis. *P < 0.05, **P < 0.01, n.s. represents not significant. Data are presented as mean ± SEM.
Figure 6.  Summary of our findings. Mice subjected to chronic restraint stress (CRS) that did or did not receive metformin show distinct behavior. Metformin reversed the reduction of p-AMPK (pT172) level in the hippocampus of mice subjected to CRS, thereby alleviating the depressive-like behavior caused by CRS.
[1] Manji HK, Drevets WC, Charney DS (2001). The cellular neurobiology of depression. Nat Med, 7:541-547.
[2] Krishnan V, Nestler EJ (2008). The molecular neurobiology of depression. Nature, 455:894-902.
[3] Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci, 10:434-445.
[4] Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B (2007). Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet, 370:851-858.
[5] Levinstein MR, Samuels BA (2014). Mechanisms underlying the antidepressant response and treatment resistance. Front Behav Neurosci, 8:208.
[6] Gerhard DM, Wohleb ES, Duman RS (2016). Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity. Drug Discov Today, 21:454-464.
[7] Abdallah CG, Sanacora G, Duman RS, Krystal JH (2018). The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacol Ther, 190:148-158.
[8] Abdallah CG, Sanacora G, Duman RS, Krystal JH (2015). Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med, 66:509-523.
[9] Krystal JH, Sanacora G, Duman RS (2013). Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry, 73:1133-1141.
[10] Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. (2000). Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 47:351-354.
[11] Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995). Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology, 13:9-19.
[12] Wiernsperger NF, Bailey CJ (1999). The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs, 58 Suppl 1:31-39; discussion 75-82.
[13] Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. (2009). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 32:193-203.
[14] Halimi S (2006). Metformin: 50 years old, fit as a fiddle, and indispensable for its pivotal role in type 2 diabetes management. Diabetes Metab, 32:555-556.
[15] Kickstein E, Krauss S, Thornhill P, Rutschow D, Zeller R, Sharkey J, et al. (2010). Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci U S A, 107:21830-21835.
[16] Li J, Deng J, Sheng W, Zuo Z (2012). Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav, 101:564-574.
[17] Patrone C, Eriksson O, Lindholm D (2014). Diabetes drugs and neurological disorders: new views and therapeutic possibilities. Lancet Diabetes Endocrinol, 2:256-262.
[18] Ashabi G, Khodagholi F, Khalaj L, Goudarzvand M, Nasiri M (2014). Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats: interference of AMPK/PGC-1alpha pathway. Metab Brain Dis, 29:47-58.
[19] Asadbegi M, Yaghmaei P, Salehi I, Ebrahim-Habibi A, Komaki A (2016). Neuroprotective effects of metformin against Abeta-mediated inhibition of long-term potentiation in rats fed a high-fat diet. Brain Res Bull, 121:178-185.
[20] Guo M, Mi J, Jiang QM, Xu JM, Tang YY, Tian G, et al. (2014). Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharmacol Physiol, 41:650-656.
[21] Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L, et al. (2012). Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell, 11:23-35.
[22] Kim JJ, Diamond DM (2002). The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci, 3:453-462.
[23] Popoli M, Yan Z, McEwen BS, Sanacora G (2011). The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci, 13:22-37.
[24] Jiang S, Li T, Ji T, Yi W, Yang Z, Wang S, et al. (2018). AMPK: Potential Therapeutic Target for Ischemic Stroke. Theranostics, 8:4535-4551.
[25] Hardie DG (2007). AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol, 8:774-785.
[26] Culmsee C, Monnig J, Kemp BE, Mattson MP (2001). AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci, 17:45-58.
[27] Wang BZ, Yang JJ, Zhang H, Smith CA, Jin K (2019). AMPK Signaling Regulates the Age-Related Decline of Hippocampal Neurogenesis. Aging and disease: 0.
[28] Zuccoli GS, Saia-Cereda VM, Nascimento JM, Martins-de-Souza D (2017). The Energy Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence. Front Neurosci, 11:493.
[29] Kim DM, Leem YH (2016). Chronic stress-induced memory deficits are reversed by regular exercise via AMPK-mediated BDNF induction. Neuroscience, 324:271-285.
[30] Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest, 108:1167-1174.
[31] Ai H, Shi XF, Hu XP, Fang WQ, Zhang B, Lu W (2017). Acute stress regulates phosphorylation of N-methyl-d-aspartate receptor GluN2B at S1284 in hippocampus. Neuroscience, 351:24-35.
[32] Can A, Dao DT, Terrillion CE, Piantadosi SC, Bhat S, Gould TD (2012). The tail suspension test. J Vis Exp: e3769.
[33] Cui Y, Yang Y, Ni Z, Dong Y, Cai G, Foncelle A, et al. (2018). Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature, 554:323-327.
[34] Lu W, Fang W, Li J, Zhang B, Yang Q, Yan X, et al. (2015). Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-D-aspartate (NMDA) Receptors. J Biol Chem, 290:22945-22954.
[35] Lu W, Ai H, Peng L, Wang JJ, Zhang B, Liu X, et al. (2015). A novel phosphorylation site of N-methyl-D-aspartate receptor GluN2B at S1284 is regulated by Cdk5 in neuronal ischemia. Exp Neurol, 271:251-258.
[36] Wang SE, Ko SY, Jo S, Choi M, Lee SH, Jo HR, et al. (2017). TRPV1 Regulates Stress Responses through HDAC2. Cell Rep, 19:401-412.
[37] Dalvi A, Lucki I (1999). Murine models of depression. Psychopharmacology (Berl), 147:14-16.
[38] Jiang T, Yu JT, Zhu XC, Wang HF, Tan MS, Cao L, et al. (2014). Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br J Pharmacol, 171:3146-3157.
[39] Gantois I, Khoutorsky A, Popic J, Aguilar-Valles A, Freemantle E, Cao R, et al. (2017). Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med, 23:674-677.
[40] Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H (2012). Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry, 39:112-119.
[41] Christiansen SH, Olesen MV, Wortwein G, Woldbye DP (2011). Fluoxetine reverts chronic restraint stress-induced depression-like behaviour and increases neuropeptide Y and galanin expression in mice. Behav Brain Res, 216:585-591.
[42] Liang S, Wang T, Hu X, Luo J, Li W, Wu X, et al. (2015). Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience, 310:561-577.
[43] Emerling BM, Viollet B, Tormos KV, Chandel NS (2007). Compound C inhibits hypoxic activation of HIF-1 independent of AMPK. FEBS Lett, 581:5727-5731.
[44] Covington HE3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. (2010). Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci, 30:16082-16090.
[45] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 329:959-964.
[46] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002). Neurobiology of depression. Neuron, 34:13-25.
[47] Willner P (1997). Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl), 134:319-329.
[48] Willner P (2005). Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology, 52:90-110.
[49] Mineur YS, Belzung C, Crusio WE (2006). Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice. Behav Brain Res, 175:43-50.
[50] Blanchard RJ, McKittrick CR, Blanchard DC (2001). Animal models of social stress: effects on behavior and brain neurochemical systems. Physiol Behav, 73:261-271.
[51] Golden SA, Covington HE3rd, Berton O, Russo SJ (2011). A standardized protocol for repeated social defeat stress in mice. Nat Protoc, 6:1183-1191.
[52] Li SX, Han Y, Xu LZ, Yuan K, Zhang RX, Sun CY, et al. (2018). Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Mol Psychiatry, 23:597-608.
[53] Kato T, Fogaca MV, Deyama S, Li XY, Fukumoto K, Duman RS (2018). BDNF release and signaling are required for the antidepressant actions of GLYX-13. Mol Psychiatry, 23:2007-2017.
[54] Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. (2011). NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature, 475:91-95.
[55] Doucet MV, Harkin A, Dev KK (2012). The PSD-95/nNOS complex: new drugs for depression? Pharmacol Ther, 133:218-229.
[56] Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, et al. (2013). Metformin improves healthspan and lifespan in mice. Nat Commun, 4:2192.
[57] Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cocheme HM, Noori T, et al. (2013). Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell, 153:228-239.
[58] Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, et al. (2009). Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A, 106:3907-3912.
[59] Li J, McCullough LD (2010). Effects of AMP-activated protein kinase in cerebral ischemia. J Cereb Blood Flow Metab, 30:480-492.
[60] Amato S, Liu X, Zheng B, Cantley L, Rakic P, Man HY (2011). AMP-activated protein kinase regulates neuronal polarization by interfering with PI 3-kinase localization. Science, 332:247-251.
[61] Potter WB, O'Riordan KJ, Barnett D, Osting SM, Wagoner M, Burger C, et al. (2010). Metabolic regulation of neuronal plasticity by the energy sensor AMPK. PLoS One, 5:e8996.
[62] Yu DF, Shen ZC, Wu PF, Guan XL, Chen T, Jin Y, et al. (2016). HFS-Triggered AMPK Activation Phosphorylates GSK3beta and Induces E-LTP in Rat Hippocampus In Vivo. CNS Neurosci Ther, 22:525-531.
[63] Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan J, Lark A, et al. (2011). Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain, 7:70.
[64] Zhu S, Wang J, Zhang Y, Li V, Kong J, He J, et al. (2014). Unpredictable chronic mild stress induces anxiety and depression-like behaviors and inactivates AMP-activated protein kinase in mice. Brain Res, 1576:81-90.
[65] Cao K, Zheng A, Xu J, Li H, Liu J, Peng Y, et al. (2014). AMPK activation prevents prenatal stress-induced cognitive impairment: modulation of mitochondrial content and oxidative stress. Free Radic Biol Med, 75:156-166.
[66] Russell RR3rd, Bergeron R, Shulman GI, Young LH (1999). Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol, 277:H643-649.
[67] Sakamoto K, Goransson O, Hardie DG, Alessi DR (2004). Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am J Physiol Endocrinol Metab, 287:E310-317.
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