Abstract
Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders.
Highlights
Depression is considered a critical psychiatric disorder associated with neuronal dysfunction in specific brain regions that usually result from stress stimuli [1,2,3]
VmPFC 4-HNE levels were significantly increased in chronic unpredictable mild stress (CUMS) exposed rats (Figures 4B,D), while ginsenoside-Rg1 pre-treatment displayed evidence of reducing this oxidative stress as indicated by decreased 4-HNE staining relative to that observed in CUMSexposed rats (P < 0.05)
Our findings demonstrate that ginsenoside-Rg1 ameliorated behavioral dysfunctions induced by chronic stress via attenuating activation of microglia and astrocytes as well as by decreasing the overexpression in a series of pro-inflammatory cytokines, decreasing structural deficits in dendritic spines and synapses and ameliorating neuronal apoptosis within the ventral medial prefrontal cortex (vmPFC)
Summary
Depression is considered a critical psychiatric disorder associated with neuronal dysfunction in specific brain regions that usually result from stress stimuli [1,2,3]. Results from previous studies have indicated that increased levels of pro-inflammatory factors including interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and reactive oxygen species (ROS) are present in patients with major depressive disorder (MDD) [8, 9]. These results suggest that activation of inflammatory pathways may represent a significant component in the pathophysiology of MDD [10, 11]. A detailed characterization of the molecular mechanisms underlying these inflammatory processes in depression phenotypes can provide promising insights into therapeutic approaches that targeting specific deficits resulting in depression
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