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.
Highlights
Depression is one of the most prevalent neuropsychiatric disorders in modern society
By assessing the phosphorylation level of threonine 172 (T172) in AMPK, we found that various doses of metformin induced a robust increase in the pT172 level as compared to that induced by the vehicle (F (4, 20) = 33.94, P < 0.001; Fig. 1F, G), but there was no obvious alteration in the total AMPKα level in the hippocampus after various doses of metformin treatment (F (4, 20) = 0.4209, P = 0.7917; Fig. 1F, G)
We have demonstrated that metformin, a widely used anti-diabetes drug, provides antidepressant-like effects in naïve mice as well as stressed mice
Summary
Depression is one of the most prevalent neuropsychiatric disorders in modern society Traditional drugs, such as monoaminergic agents, have defect showing lag response requiring several weeks to months. These drugs have limited efficacy and high resistance rates in patients with depression. Our results suggest that metformin may be a viable therapeutic drug for the treatment of stress-induced depression via activation of AMPK. Chronic stress causes pathophysiological and psychological alterations associated with mental illness, leading to neuropsychiatric disorders including depression [1-3]. Antidepressant-like effect of metformin symptoms associated with the application of ketamine hinder its clinical use [11], thereby strengthening the demanding need to develop alternative fast-acting antidepressants for depression. Given that metformin is a Food and Drug Administrationapproved drug in clinical use for several decades, it would be of great interest to explore the effects of metformin on depressive-like behavior
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