Abstract
Depression is a common mental disorder that presents a considerable challenge for public health. The natural product geniposide has neuroprotective effects on depression, but the underlying mechanism behind these effects had remained undefined. The present study was designed to investigate the role of microRNAs (miRs) in this mechanism. It studied mice with depression-like behavior established by exposure to chronic unpredictable mild stress (CUMS) for 2 months. The CUMS mice were intragastrically fed with geniposide at a dose of 10 ml/kg daily for two consecutive weeks. We monitored the depression-like behaviors of the CUMS mice by the forced swimming test (FST) and tail suspension test (TST). Then, we measured the cerebral expression of miR-298-5p and NADPH oxidase 1 (Nox1) mRNA in the CUMS mice by the RT-qPCR. The targeting relationship between miR-298-5p and Nox1 was evaluated by dual-luciferase reporter gene assay. The concentrations of adenosine triphosphate (ATP) and reactive oxygen species (ROS) were determined by the CellTiter-Glo® and flow cytometry, respectively. The mitochondrial membrane potential (MMP) was detected using JC-1 staining. Moreover, the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and TGF-β) was determined by ELISA, RT-qPCR, and western blot analysis. We found that miR-298-5p was poorly-expressed while Nox1 was highly-expressed in the brain tissues of the CUMS-induced mice. Intriguingly, Geniposide treatment reversed the behavioral abnormalities of CUMS mice, including shortened immobility time. Geniposide inhibited the Nox1 expression by increasing miR-298-5p levels. There were increased ATP content and MMP and reduced contents of ROS and inflammatory cytokines in the CUMS mice receiving geniposide treatment. Hence, this study revealed an antidepressant effect of geniposide on CUMS-induced depression-like behavior in mice by down-regulating the miR-298-5p-targeted Nox1. This highlights a novel candidate target for the treatment of depression.
Highlights
Depression is a heterogeneous psychiatric disorder that poses challenges for clinical treatment due to its systemic complexity and lack of clear therapeutic targets (Wittenborn et al, 2016)
Geniposide Was Capable of Alleviating Depression in chronic unpredictable mild stress (CUMS) Mice
To investigate the therapeutic effect of geniposide on depression, we evaluated the depression-like behaviors of CUMS mice, including immobility time in forced swimming test (FST) and TST
Summary
Depression is a heterogeneous psychiatric disorder that poses challenges for clinical treatment due to its systemic complexity and lack of clear therapeutic targets (Wittenborn et al, 2016). Comorbid depression has been reported to enhance the morbidity rate of stroke, cardiovascular diseases, diabetes, and obesity (Penninx et al, 2013). With the dramatic acceleration in the pace of life in modern society, stress has become one of the most common environmental factors that cause depression (Athira et al, 2019). The optimal choice in the treatment of depression is antidepressants (Kok and Reynolds, 2017). There are great challenges for depression therapeutics (Cuijpers, 2018), meaning studies need to identify novel and more effective therapeutic approaches
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