PMID- 30599373 OWN - NLM STAT- MEDLINE DCOM- 20190401 LR - 20190401 IS - 1573-2517 (Electronic) IS - 0165-0327 (Linking) VI - 246 DP - 2019 Mar 1 TI - Possible role of GLP-1 in antidepressant effects of metformin and exercise in CUMS mice. PG - 486-497 LID - S0165-0327(18)31413-7 [pii] LID - 10.1016/j.jad.2018.12.112 [doi] AB - BACKGROUND: Both depression itself and antidepressant medication have been reported to be significantly related to the risk of type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a treatment target for T2DM, has a neuroprotective effect. As an enhancer and sensitiser of GLP-1, metformin has been reported to be safe for the neurodevelopment. The present study aimed to determine whether and how GLP-1 mediates antidepressant effects of metformin and exercise in mice. METHODS: Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 8 weeks. From the 4th week, CUMS mice were subjected to oral metformin treatment and/or treadmill running. A videocomputerized tracking system was used to record behaviors of mice for a 5-min session. ELISA, western blotting and immunohistochemistry were used to examine serum protein concentrations, protein levels in whole hippocampus, protein distribution and expression in dorsal and ventral hippocampus, respectively. RESULTS: Our results supported the validity of metformin as a useful antidepressant; moreover, treadmill running favored metformin effects on exploratory behaviors and serum corticosterone levels. CUMS reduced GLP-1 protein levels and phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), but increased protein levels of B-cell lymphoma 2-associated X-protein (BAX) in mice hippocampus. All these changes were restored by both single and combined treatment with metformin and exercise. LIMITATIONS: We did not establish a causal relationship between GLP-1 expression and related signaling, using GLP-1 agonist and antagonist or knockout techniques. CONCLUSIONS: Our findings have demonstrated that protein levels of pERK and BAX may be relevant to the role of GLP-1 in antidepressant effects of metformin and exercise, which may provide a novel topic for future clinical research. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Liu, Weina AU - Liu W AD - Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China. Electronic address: weina1978@126.com. FAU - Liu, Jiatong AU - Liu J AD - Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China. FAU - Huang, Zhuochun AU - Huang Z AD - Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China. FAU - Cui, Zhiming AU - Cui Z AD - Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China. FAU - Li, Lingxia AU - Li L AD - Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China. FAU - Liu, Wenbin AU - Liu W AD - Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China. FAU - Qi, Zhengtang AU - Qi Z AD - Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China. Electronic address: qzht79@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181226 PL - Netherlands TA - J Affect Disord JT - Journal of affective disorders JID - 7906073 RN - 0 (Antidepressive Agents) RN - 0 (Bax protein, mouse) RN - 0 (Hypoglycemic Agents) RN - 0 (Neuroprotective Agents) RN - 0 (bcl-2-Associated X Protein) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9100L32L2N (Metformin) RN - W980KJ009P (Corticosterone) SB - IM MH - Animals MH - Antidepressive Agents/*therapeutic use MH - Corticosterone/blood MH - Depression/metabolism/*therapy MH - Depressive Disorder/drug therapy MH - Diabetes Mellitus, Type 2/metabolism MH - *Exercise Therapy MH - Exploratory Behavior MH - Glucagon-Like Peptide 1/*physiology MH - Hippocampus/metabolism MH - Hypoglycemic Agents/*therapeutic use MH - MAP Kinase Signaling System/physiology MH - Male MH - Metformin/*therapeutic use MH - Mice MH - Mice, Inbred C57BL MH - Neuroprotective Agents/pharmacology MH - Signal Transduction/drug effects MH - Stress, Psychological/metabolism/*therapy MH - bcl-2-Associated X Protein/metabolism EDAT- 2019/01/02 06:00 MHDA- 2019/04/02 06:00 CRDT- 2019/01/02 06:00 PHST- 2018/06/29 00:00 [received] PHST- 2018/12/18 00:00 [revised] PHST- 2018/12/24 00:00 [accepted] PHST- 2019/01/02 06:00 [pubmed] PHST- 2019/04/02 06:00 [medline] PHST- 2019/01/02 06:00 [entrez] AID - S0165-0327(18)31413-7 [pii] AID - 10.1016/j.jad.2018.12.112 [doi] PST - ppublish SO - J Affect Disord. 2019 Mar 1;246:486-497. doi: 10.1016/j.jad.2018.12.112. Epub 2018 Dec 26.