PMID- 31521867 OWN - NLM STAT- MEDLINE DCOM- 20201116 LR - 20201116 IS - 1573-2517 (Electronic) IS - 0165-0327 (Linking) VI - 260 DP - 2020 Jan 1 TI - Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. PG - 302-313 LID - S0165-0327(19)31272-8 [pii] LID - 10.1016/j.jad.2019.09.013 [doi] AB - BACKGROUND: Metformin, a first-line antiglycemic drug, has been reported to have anti-depressant effects in patients with type 2 diabetes; however, its exact role and underlying mechanism still need to be investigated. METHOD: C57BL/6J mice were subjected to the Chronic social defeat stress (SDS) and drug administration (Control + Vehicle, SDS + Vehicle, SDS + MET (200 mg kg(-1)), SDS + FLUOX (3 mg kg(-1)), SDS + MET + FLUOX). And the depression phenotypes were evaluated by the sucrose preference test, social interaction, tail suspension test and forced swimming test. The potential mechanisms underlying the effects of metformin on depression was discussed by using Chromatin immunoprecipitation, Quantitative real-time PCR mRNA expression analysis and Western blot in vivo and in primary cultured hippocampal neurons. RESULT: The metformin treatment counteracted the development of depression-like behaviors in mice suffering SDS when administered alone and enhanced the anti-depressant effect of fluoxetine when combined with fluoxetine. Further RNA sequencing analysis revealed that metformin treatment prevented the transcriptional changes in the medial prefrontal cortex (mPFC) of the animals and Golgi staining indicated favorable morphological changes in the neurite plasticity of CA1 pyramidal neurons, which approximated to those found in unstressed mice. At a molecular level, metformin significantly upregulated the expression of the brain-derived neurotrophic factor (BDNF) by increasing the histone acetylation along with the BDNF promoter, which was attributed to the activation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB). CONCLUSION: Our findings suggest that metformin can produce antidepressant effects, which provides empirical insights into the clinical value of metformin in the prevention and therapy of depression. CI - Copyright (c) 2019. Published by Elsevier B.V. FAU - Fang, Wenting AU - Fang W AD - Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350001, China. FAU - Zhang, Jing AU - Zhang J AD - Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350001, China. Electronic address: drzj@163.com. FAU - Hong, Luyan AU - Hong L AD - Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China. FAU - Huang, Weibin AU - Huang W AD - Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China. FAU - Dai, Xiaoman AU - Dai X AD - Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350001, China. FAU - Ye, Qinyong AU - Ye Q AD - Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350001, China. FAU - Chen, Xiaochun AU - Chen X AD - Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350001, China. Electronic address: chenxc998@fjmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190903 PL - Netherlands TA - J Affect Disord JT - Journal of affective disorders JID - 7906073 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Histones) RN - 01K63SUP8D (Fluoxetine) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Acetylation/*drug effects MH - Animals MH - Antidepressive Agents/*pharmacology MH - Brain-Derived Neurotrophic Factor/*drug effects MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Depression/chemically induced/*drug therapy MH - Diabetes Mellitus, Type 2/drug therapy/psychology MH - Disease Models, Animal MH - Fluoxetine/pharmacology MH - Hippocampus/metabolism MH - Histones/metabolism MH - Male MH - Metformin/*pharmacology MH - Mice MH - Mice, Inbred C57BL MH - Stress, Psychological/chemically induced/drug therapy MH - Swimming OTO - NOTNLM OT - AMPK OT - Histone acetylation OT - Major depressive disorder OT - Metformin OT - Social defeat stress OT - Synaptic plasticity EDAT- 2019/09/16 06:00 MHDA- 2020/11/18 06:00 CRDT- 2019/09/16 06:00 PHST- 2019/05/19 00:00 [received] PHST- 2019/07/22 00:00 [revised] PHST- 2019/09/02 00:00 [accepted] PHST- 2019/09/16 06:00 [pubmed] PHST- 2020/11/18 06:00 [medline] PHST- 2019/09/16 06:00 [entrez] AID - S0165-0327(19)31272-8 [pii] AID - 10.1016/j.jad.2019.09.013 [doi] PST - ppublish SO - J Affect Disord. 2020 Jan 1;260:302-313. doi: 10.1016/j.jad.2019.09.013. Epub 2019 Sep 3.