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Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase.

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 AMPK? 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.

SUBMITTER: Ai H

PROVIDER: S-EPMC6961762 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase.

Ai Heng H Fang Weiqing W Hu Hanyi H Hu Xupang X Lu Wen W

Aging and disease 20200201 1

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 demonstr ...[more]

PMID: 32010479

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Project description:BACKGROUND AND PURPOSE:Regulating P2X7 receptor-mediated activation of NLRP3 inflammasomes could be a therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process was modulated by gentiopicroside, the main active secoiridoid glycoside from Gentiana manshurica Kitagawa. EXPERIMENTAL APPROACH:In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administered ethanol or using chronic plus binge ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice. In vitro, HepG2 cells were treated with ethanol. RAW 264.7 macrophages and murine bone marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP. KEY RESULTS:In both the acute and chronic alcohol-induced mouse hepatosteatosis models, gentiopicroside decreased serum aminotransferases and triglyceride accumulation. Up-regulated SREBP1, down-regulated PPAR? and phosphorylated acetyl-CoA carboxylase caused by acute and chronic alcohol feeding were modulated by gentiopicroside, through the elevation of LKB1 and AMPK. Suppression of P2X7 receptor-NLRP3 activation by gentiopicroside inhibited IL-1? production. In ethanol-exposed HepG2 cells, gentiopicroside reduced lipogenesis and promoted lipid oxidation via activation of P2X7 receptor-NLRP3 inflammasomes. Genetic or pharmacological blockade of P2X7 receptors enhanced AMPK activity and reduced SREBP1 expression in ethanol-treated HepG2 cells. Gentiopicroside down-regulated P2X7 receptor-mediated inflammatory responses in LPS/ATP-stimulated RAW 264.7 macrophages and BMDMs. IL-1? from macrophages accelerated lipid accumulation in hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and it was further alleviated by gentiopicroside. CONCLUSIONS AND IMPLICATIONS:Activation of LKB1/AMPK signalling by gentiopicroside was mediated by the P2X7 receptor-NLRP3 inflammasome, suggesting the therapeutic value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis.

Dataset Information

Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase.

Publications

Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase.

Similar Datasets

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