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Ginsenoside-Rg1 Rescues Stress-Induced Depression-Like Behaviors via Suppression of Oxidative Stress and Neural Inflammation in Rats.

ABSTRACT: Depression is an inflammatory-related condition, with the progression in neuronal damage resulting in major depression disorder. Ginsenoside-Rg1, a sterol extract from the herb Panax ginseng, has been shown to exert neuroprotective effects upon neurodegeneration disorders. However, whether ginsenoside-Rg1 confers antidepressant-like effects on neuroinflammation as associated with depression, as well as the possible mechanism involved in these neuroprotective effects, is currently unclear. In the present report, we show that treatment with ginsenoside-Rg1 (40?mg/kg, i.p.) significantly ameliorated depressive-like behaviors as induced by chronic unpredictable mild stress (CUMS) in a rat model of depression. Moreover, these CUMS rats treated with ginsenoside-Rg1 showed reductions in the levels of the oxidative stress products and the activity in the antioxidant stress kinase. Furthermore, CUMS rats treated with ginsenoside-Rg1 showed ameliorated neuroinflammation and associated neuronal apoptosis along with a reduction in dendritic spine atrophy and display of depressive behaviors. Taken together, the results of this study suggest that ginsenoside-Rg1 produces antidepressant-like effects in CUMS-exposed rats; and one of the mechanisms for these antidepressant-like effects of ginsenoside-Rg1 appears to involve protection against oxidative stress and thus the neuronal deterioration resulting from inflammatory responses. These findings provide evidence for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related depression.

SUBMITTER: Li Y

PROVIDER: S-EPMC7125461 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Ginsenoside-Rg1 Rescues Stress-Induced Depression-Like Behaviors via Suppression of Oxidative Stress and Neural Inflammation in Rats.

Li Ye Y Wang Liyan L Wang Peng P Fan Cuiqin C Zhang Ping P Shen Jie J Yu Shu Yan SY

Oxidative medicine and cellular longevity 20200318

Depression is an inflammatory-related condition, with the progression in neuronal damage resulting in major depression disorder. Ginsenoside-Rg1, a sterol extract from the herb <i>Panax ginseng</i>, has been shown to exert neuroprotective effects upon neurodegeneration disorders. However, whether ginsenoside-Rg1 confers antidepressant-like effects on neuroinflammation as associated with depression, as well as the possible mechanism involved in these neuroprotective effects, is currently unclear. ...[more]

PMID: 32273940

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Project description: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.

Project description:Oxidative stress-induced cytoskeletal dysfunction of neurons has been implicated as a crucial cause of cell apoptosis or death in the central nervous system (CNS) diseases, such as neurodegenerative and psychiatric diseases. The application of neuroprotectants rescuing the neurons from cytoskeletal damage and apoptosis can be a potential treatment for these CNS diseases. Ginsenoside Rg1 (Rg1), one of the major active components of ginseng, has been reported possessing notable neuroprotective activities. However, there is rare report about its effect on cytoskeleton and its undergoing mechanism. The current study is to reveal the regulatory effects of Rg1 on cytoskeletal and morphological lesion in oxidative stress-induced neuronal apoptosis. The results demonstrated that pre-treatment with Rg1 (0.1-10 μM) attenuated hydrogen peroxide (H2O2)-induced neuronal apoptosis and oxidative stress through reducing the intracellular reactive oxygen species (ROS) production and methane dicarboxylic aldehyde (MDA) level. The Rg1 treatment also abolished H2O2-induced morphological changes, including cell rounding, membrane blebbing, neurite retraction and nuclei condensation, which were generated by myosin IIA-actin interaction. These effects were mediated via the down-regulation of caspase-3, ROCK1 (Rho-associated kinase1) activation and myosin light chain (MLC, Ser-19) phosphorylation. Furthermore, inhibiting myosin II activity with blebbistatin partly blocked the neuroprotective effects of Rg1. The computer-aided homology modelling revealed that Rg1 preferentially positioned in the actin binding cleft of myosin IIA and might block the binding of myosin IIA to actin filaments. Accordingly, the neuroprotective mechanism of Rg1 is related to the activity that inhibits myosin IIA-actin interaction and the caspase-3/ROCK1/MLC signaling pathway. These findings put some insights into the unique neuroprotective properties of Rg1 associated with the regulation of myosin IIA-actin cytoskeletal structure under oxidative stress and provide experimental evidence for Rg1 in CNS diseases.

Project description:Background Agomelatine has been shown to be effective in the treatment of depression, but the molecular mechanisms underlying its antidepressant effects have yet to be elucidated. Identification of these molecular mechanisms would not only offer new insights into the basis for depression but also provide the foundation for the development of novel treatments for this disorder. Methods Intraperitoneal injection of LPS was used to induce depression-like behaviors in rats. The interactions of the 5-HT2C reporter and Gαi-2 were verified by immunoprecipitation or immunofluorescence assay. Inflammatory related proteins, autophagy related proteins and apoptosis markers were verified by immunoblotting or immunofluorescence assay. Finally, electron microscopy analysis was used to observe the synapse and ultrastructural pathology. Results Here, we found that the capacity for agomelatine to ameliorate depression and anxiety in a lipopolysaccharide (LPS)-induced rat model of depression was associated with an alleviation of neuroinflammation, abnormal autophagy and neuronal apoptosis as well as the promotion of neurogenesis in the hippocampal dentate gyrus (DG) region of these rats. We also found that the 5-HT2C receptor is coupled with G alphai (2) (Gαi-2) protein within hippocampal neurons and, agomelatine, acting as a 5-HT2C receptor antagonist, can up-regulate activity of the Gαi-2-cAMP-PKA pathway. Such events then suppress activation of the apoptosis signal-regulating kinase 1 (ASK1) pathway, a member of the mitogen-activated protein kinase (MAPK) family involved in pathological processes of many diseases. Conclusion Taken together, these results suggest that agomelatine plays a neuroprotective role in regulating neuroinflammation, autophagy disorder and apoptosis in this LPS-induced rat model of depression, effects which are associated with the display of antidepressant behaviors. These findings provide evidence for some of the potential mechanisms for the antidepressant effects of agomelatine. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02479-x. Highlights Agomelatine ameliorated anxiety and depression-like behaviors in rats. Agomelatine regulated LPS-induced neuroinflammation and neuronal apoptosis. Agomelatine decreased the enhanced autophagy and synaptic damage in LPS-treated rats. Agomelatine alleviated neural injury via suppression of Gαi-2-PKA-ASK1 pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02479-x.

Project description:BackgroundDiabetic nephropathy (DN) is one of the most common microvascular complications in diabetes mellitus. Ginsenoside Rg1 (Rg1) is an important active ingredient extracted from Panax ginseng. This study aimed to investigate the role and molecular mechanism of Rg1 in DN model.MethodsThe mesangial cell line HBZY-1 was induced by high glucose (HG; 30 mM D-glucose). HG-induced HBZY-1 cells were treated with Rg1 (2.5, 5, 10 µmol/L). Cell viability was measured by the MTT assay. Apoptosis was detected by flow cytometry. Related proteins were measured by western blot. Reactive oxygen species (ROS) production was measured by dichlorodihydrofluorescein diacetate (DCFH-DA). Inflammatory factors and molecules associated with oxidative stress were detected by enzyme-linked immunoassay (ELISA). DN rats model were treated with 50mg/kg/d Rg1 for 8 weeks, the histopathological changes and the expression of relevant markers were analyzed.ResultsWe found that Rg1 treatment markedly elevated the survival rates of HG-induced HBZY-1 cells and reduced apoptosis induced by HG. Rg1 treatment attenuated the HG-induced inflammatory response by decreasing the high levels of TNF-α, IL-1β, and IL-6. Furthermore, Rg1 treatment alleviated HG-induced oxidative stress by decreasing ROS generation, malondialdehyde (MDA), and lactate dehydrogenase (LDH) accumulation and increasing the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). After Rg1 (50 mg/kg/d) treatment, the severe glomerular thylakoid hyperplasia, glomerular atrophy, tubule dermal cell exfoliation, basement membrane exposure, interstitial edema and inflammatory cell cytoplasmic infiltration were alleviated in DN rats. DN rat model treated with Rg1 (50 mg/kg/d) showed good anti-inflammatory and antioxidant activities. Rg1 treatment also increased the levels of the phosphorylation of PI3K (p-PI3K) and AKT (p-AKT) and promoted the transfer of FOXO3 from the nucleus to the cytoplasm in vitro and in vivo.ConclusionsRg1 exhibited protective effects on DN-induced inflammatory responses and oxidative stress via regulating the PI3K/AKT/FOXO3 pathway in in vitro and in vivo. The results suggest that Rg1 may be a potential therapeutic agent for DN treatment.

Dataset Information

Ginsenoside-Rg1 Rescues Stress-Induced Depression-Like Behaviors via Suppression of Oxidative Stress and Neural Inflammation in Rats.

Publications

Ginsenoside-Rg1 Rescues Stress-Induced Depression-Like Behaviors via Suppression of Oxidative Stress and Neural Inflammation in Rats.

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