Abstract
Ginsenoside Rg1 is the principal active ingredient in ginseng. The antidepressant effects of Rg1 have been validated; however, the specific underlying mechanism of this effect needs further research. Rats were subjected to the chronic restraint stress (CRS) depression model. Rg1, or a positive control drug, was administered to the rats. Depression-like behaviours were evaluated through behavioural experiments. Cytokine, mRNA, protein, ATP, and mitochondria DNA levels were detected using the indicated methods. Lentivirus-packaged plasmids were injected into the rat brain for GAS5 overexpression or knockdown. In vitro mitochondrial dysfunction was evaluated by detecting mitochondrial reactive oxygen species and mitochondrial membrane potential. Direct interaction between GAS5 and EZH2 was validated by RNA immunoprecipitation and RNA pull-down assay. The enrichment of EZH2 and H3K27me3 was evaluated through chromatin immunoprecipitation quantitative real-time PCR. Rg1 treatment alleviated depression-like behaviours, microglial activation, and mitochondrial dysfunction in CRS rats. Similarly, GAS5 knockdown revealed a similar protective effect of Rg1 treatment. GAS5 overexpression in the rat brain compromised the protective effect of Rg1 treatment. Moreover, Rg1 treatment or GAS5 knockdown attenuated microglial activation and mitochondrial dysfunction in vitro. Mechanically, GAS5 was suppressed SOCS3 and NRF2 expression by facilitating EZH2-mediated transcriptional repression. Rg1 attenuated microglial activation and improved mitochondrial dysfunction in depression by downregulating GAS5 expression. Mechanically, GAS5 might regulate microglial activation and mitochondrial dysfunction via the epigenetic suppression of NRF2 and SOCS3.
Highlights
Depression is a type of emotional disorder that brings a tremendous burden to society and individuals
J The protein levels of SOCS3, NRF2, and EZH2 in hippocampus were detected by western blots. *P < 0.05; **P < 0.01; ***P < 0.001 of EZH2 on gene transcription [30]
We investigated the effect of growth arresting-specific 5 (GAS5) knockdown on microglial activation and neuronal mitochondrial dysfunction in vitro. qPCR revealed that GAS5 short hairpin RNA (shRNA) sharply diminished the expression of GAS5 upon LSP stimulation (Fig. 7A)
Summary
Depression is a type of emotional disorder that brings a tremendous burden to society and individuals. Depression is characterized by high morbidity, mortality, and disability rates [1]. Typical symptoms of depression include depressed mood, retardation of thought, loss of volitional activity, and cognitive impairment [2]. Psychological, and social environmental factors are associated with the pathogenesis of depression. Biological factors mainly involve heredity, neurobiochemical, neuroendocrine, and nerve regeneration [3]. Most antidepressants in clinical use are synthetic compounds, including selective 5-HT reuptake inhibitors (SSRIs) [4]. The current treatments improve depression, they fail to resolve the symptoms entirely in more than half of the cases. It is urgent to identify novel potential candidates for the treatment of depression
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