Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation.

Abstract

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.

• Authors: Wenting Fang, Jing Zhang, Luyan Hong, Weibin Huang, Xiaoman Dai, Qinyong Ye, Xiaochun Chen
• Journal: Journal of affective disorders (J Affect Disord) Vol. 260 Pg. 302-313 (01 01 2020) ISSN: 1573-2517 [Electronic] Netherlands
• PMID: 31521867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• Antidepressive Agents
• Brain-Derived Neurotrophic Factor
• Cyclic AMP Response Element-Binding Protein
• Histones
• Fluoxetine
• Metformin
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Acetylation (drug effects)
• Animals
• Antidepressive Agents (pharmacology)
• Brain-Derived Neurotrophic Factor (drug effects)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Depression (chemically induced, drug therapy)
• Diabetes Mellitus, Type 2 (drug therapy, psychology)
• Disease Models, Animal
• Fluoxetine (pharmacology)
• Hippocampus (metabolism)
• Histones (metabolism)
• Male
• Metformin (pharmacology)
• Mice
• Mice, Inbred C57BL
• Stress, Psychological (chemically induced, drug therapy)
• Swimming