Rg1 Administration Research Articles

Ginsenoside Rg1 ameliorates cerebral ischemia-reperfusion injury by regulating Pink1/ Parkin-mediated mitochondrial autophagy and inhibiting microglia NLRP3 activation

ObjectiveThis study aimed to further elucidate the mechanism of ginsenoside Rg1 in the treatment of cerebral ischemia-reperfusion. MethodsIn this study, we observed the apoptosis of RM cells (microglia) after oxygen-glucose deprivation/reoxygenation (OGD/R) modeling before and after Rg1 administration, changes in mitochondrial membrane potential, changes in the content of Reactive oxygen species (ROS) and inflammatory vesicles NLR Family Pyrin Domain Containing 3 (NLRP3), and the expression levels of autophagy-related proteins, inflammatory factors, and apoptosis proteins. We further examined the pathomorphological changes in brain tissue, neuronal damage, changes in mitochondrial morphology and mitochondrial structure, and the autophagy-related proteins, inflammatory factors, and apoptosis proteins expression levels in CI/RI rats before and after administration of Rg1 in vivo experiments. ResultsIn vitro experiments showed that Rg1 induced mitochondrial autophagy, decreased mitochondrial membrane potential, and reduced ROS content thereby inhibiting NLRP3 activation, decreasing secretion of inflammatory factors and RM cell apoptosis by regulating the PTEN induced putative kinase 1(Pink1) /Parkin signaling pathway. In vivo experiments showed that Rg1 induced mitochondrial autophagy, inhibited NLRP3 activation, improved inflammatory response, and reduced apoptosis by regulating the Pink1/Parkin signaling pathway, and Rg1 significantly reduced the area of cerebral infarcts, improved the pathological state of brain tissue, and attenuated the neuronal damage, thus improving cerebral ischemia/reperfusion injury in rats. ConclusionOur results suggest that ginsenoside Rg1 can ameliorate cerebral ischemia-reperfusion injury by modulating Pink1/ Parkin-mediated mitochondrial autophagy in microglia and inhibiting microglial NLRP3 activation.

Ginsenoside Rg1 alleviates chronic inflammation-induced neuronal ferroptosis and cognitive impairments via regulation of AIM2 - Nrf2 signaling pathway

Ethnopharmacological relevanceGinseng is a valuable herb in traditional Chinese medicine. Modern research has shown that it has various benefits, including tonifying vital energy, nourishing and strengthening the body, calming the mind, improving cognitive function, regulating fluids, and returning blood pressure, etc. Rg1 is a primary active component of ginseng. It protects hippocampal neurons, improves synaptic plasticity, enhances cognitive function, and boosts immunity. Furthermore, it exhibits anti-aging and anti-fatigue properties and holds great potential for preventing and managing neurodegenerative diseases (NDDs). Aim of the studyThe objective of this study was to examine the role of Rg1 in treating chronic inflammatory NDDs and its molecular mechanisms. Materials and methodsIn vivo, we investigated the protective effects of Rg1 against chronic neuroinflammation and cognitive deficits in mice induced by 200 μg/kg lipopolysaccharide (LPS) for 21 days using behavioral tests, pathological sections, Western blot, qPCR and immunostaining. In vitro experiments involved the stimulation of HT22 cells with 10 μg/ml of LPS, verification of the therapeutic effect of Rg1, and elucidation of its potential mechanism of action using H2DCFDA staining, BODIPY™ 581/591 C11, JC-1 staining, Western blot, and immunostaining. ResultsFirstly, it was found that Rg1 significantly improved chronic LPS-induced behavioral and cognitive dysfunction in mice. Further studies showed that Rg1 significantly attenuated LPS-induced neuronal damage by reducing levels of IL-6, IL-1β and ROS, and inhibiting AIM2 inflammasome. Furthermore, chronic LPS exposure induced the onset of neuronal ferroptosis by increasing the lipid peroxidation product MDA and regulating the ferroptosis-associated proteins Gpx4, xCT, FSP1, DMT1 and TfR, which were reversed by Rg1 treatment. Additionally, Rg1 was found to activate Nrf2 and its downstream antioxidant enzymes, such as HO1 and NQO1, both in vivo and in vitro. In vitro studies also showed that the Nrf2 inhibitor ML385 could inhibit the anti-inflammatory, antioxidant, and anti-ferroptosis effects of Rg1. ConclusionsThis study demonstrated that Rg1 administration ameliorated chronic LPS-induced cognitive deficits and neuronal ferroptosis in mice by inhibiting neuroinflammation and oxidative stress. The underlying mechanisms may be related to the inhibition of AIM2 inflammasome and activation of Nrf2 signaling. These findings provide valuable insights into the treatment of chronic neuroinflammation and associated NDDs.

Ginsenoside Rg1 Alleviates Sepsis-Induced Acute Lung Injury by Reducing FBXO3 Stability in an m6A-Dependent Manner to Activate PGC-1α/Nrf2 Signaling Pathway.

Sepsis-induced acute lung injury (ALI) is one of the serious life-threatening complications of sepsis and is pathologically associated with mitochondrial dysfunction. Ginsenoside Rg1 has good therapeutic effects on ALI. Herein, the pharmacological effects of Rg1 in sepsis-induced ALI were investigated. Sepsis-induced ALI models were established by CLP operation and LPS treatment. HE staining was adopted to analyze lung pathological changes. The expression and secretion of cytokines were measured by RT-qPCR and ELISA. Cell viability and apoptosis were assessed by MTT assay, flow cytometry and TUNEL staining. ROS level and mitochondrial membrane potential (MMP) were analyzed using DHE probe and JC-1 staining, respectively. FBXO3 m6A level was assessed using MeRIP assay. The interactions between FBXO3, YTHDF1, and PGC-1α were analyzed by Co-IP or RIP. Rg1 administration ameliorated LPS-induced epithelial cell inflammation, apoptosis, and mitochondrial dysfunction in a dose-dependent manner. Mechanically, Rg1 reduced PGC-1α ubiquitination modification level by inhibiting FBXO3 expression m6A-YTHDF1 dependently. As expected, Rg1's mitigative effect on LPS-induced inflammation, apoptosis and mitochondrial dysfunction in lung epithelial cells was abolished by FBXO3 overexpression. Moreover, FBXO3 upregulation eliminated the restoring effect of Rg1 on CLP-induced lung injury in rats. Rg1 activated PGC-1α/Nrf2 signaling pathway by reducing FBXO3 stability in an m6A-YTHDF1-dependent manner to improve mitochondrial function in lung epithelial cells during sepsis-induced ALI progression.

Ginsenoside Rg1 alleviates vascular remodeling in hypoxia-induced pulmonary hypertension mice through the calpain-1/STAT3 signaling pathway

BackgroundHypoxic pulmonary hypertension (HPH) is the main pathological change in vascular remodeling, a complex cardiopulmonary disease caused by hypoxia. Some research results have shown that ginsenoside Rg1 (Rg1) can improve vascular remodeling, but the effect and mechanism of Rg1 on hypoxia-induced pulmonary hypertension are not clear. The purpose of this study was to discuss the potential mechanism of action of Rg1 on HPH. MethodsC57BL/6 mice, calpain-1 knockout mice and Pulmonary artery smooth muscle cells (PASMCs) were exposed to a low oxygen environment with or without different treatments. The effect of Rg1 and calpain-1 silencing on inflammation, fibrosis, proliferation and the protein expression levels of calpain-1, STAT3 and p-STAT3 were determined at the animal and cellular levels. ResultsAt the mouse and cellular levels, hypoxia promotes inflammation, fibrosis, and cell proliferation, and the expression of calpain-1 and p-STAT3 is also increased. Ginsenoside Rg1 administration and calpain-1 knockdown, MDL-28170, and HY-13818 treatment showed protective effects on hypoxia-induced inflammation, fibrosis, and cell proliferation, which may be associated with the downregulation of calpain-1 and p-STAT3 expression in mice and cells. In addition, overexpression of calpain 1 increased p-STAT3 expression, accelerating the onset of inflammation, fibrosis and cell proliferation in hypoxic PASMCs. ConclusionGinsenoside Rg1 may ameliorate hypoxia-induced pulmonary vascular remodeling by suppressing the calpain-1/STAT3 signaling pathway.

Ginsenoside Rg1 Attenuates Chronic Sleep Deprivation-Induced Hippocampal Mitochondrial Dysfunction and Improves Memory by the AMPK-SIRT3 Pathway.

Ginsenoside Rg1 (Rg1) is the main bioactive ginseng component. This study investigates the effects of Rg1 on cognitive deficits triggered by chronic sleep deprivation stress (CSDS) and explores its underlying mechanisms. Rg1 effectively improved spatial working and recognition memory, as evidenced by various behavioral tests. RNA-sequence analysis revealed differential gene expression in the metabolic pathway. Treatment with Rg1 abrogated reductions in SOD and CAT activity, lowered MDA content, and increased Nrf2 and HO-1 protein levels. Rg1 administration alleviated hippocampal mitochondrial dysfunction by restoring normal ultrastructure and enhancing ATP activities and Mfn2 expression while regulating Drp-1 expression. Rg1 mitigated neuronal apoptosis by reducing the Bax/Bcl-2 ratio and the levels of cleaved caspase-3. Additionally, Rg1 upregulated AMPK and SIRT3 protein expressions. These findings suggest that Rg1 has potential as a robust intervention for cognitive dysfunction associated with sleep deprivation, acting through the modulation of mitochondrial function, oxidative stress, apoptosis, and the AMPK-SIRT3 axis.

Ginsenoside Rg1 Attenuates Eccentric Exercise-Induced Muscle Damage via the Modulation of Lipid Peroxidation and Inflammation

Eccentric exercise (EE) may lead to skeletal muscle injury, including oxidative stress and inflammation induction. Ginsenoside Rg1, a glycosylated triterpene present in the traditional Chinese medicine ginseng, was previously shown to prevent the development of multiple diseases through the attenuation of oxidative stress and inflammation. Therefore, this article hopes to investigate whether Rg1 exhibits anti-oxidant and anti-inflammatory effects in eccentric exercise-induced muscle damage (EEIMD). Additionally, Adult male Wistar rats were intraperitoneally injected with Rg1 (20 or 40 mg/kg) every day before EE for 5 consecutive days. The impact of Rg1 administration on levels of serum creatine kinase was evaluated, followed by observation of histological muscle damage through H&E staining. To assess protein nitrotyrosylation, lipid peroxidation and leukocyte infiltration in rat skeletal muscles, the levels of nitrotyrosine, MDA and MPO protein were analysed through western blotting analysis. The inflammatory response was evaluated by detecting iNOS, COX-2, IL-1β, IL-6, MCP-1 and TNF-α mRNA and protein levels in rat skeletal muscles. The regulation of Rg1 on the NF-κB pathway was examined through the analysis of phosphorylated NF-κB p65 and IκBα protein levels. Result display, EE resulted in elevated serum creatine kinase levels, widespread leukocyte infiltration, and notable muscle cell vacuolization and fragmentation in muscles. Furthermore, EE increased nitrotyrosine, MDA, MPO, iNOS, COX-2, IL-1β, IL-6, MCP-1, and TNF-α levels in rats. However, these changes were reversed by Rg1 treatment. Furthermore, EE-induced upregulation in phosphorylated NF-κB p65 and IκBα levels was counteracted by Rg1. Overall, ginsenoside Rg1 plays an anti-oxidant and anti-inflammatory role in EEIMD through suppressing this NF-κB signaling pathway.

Ginsenoside Rg1 attenuates cerebral ischemia-reperfusion injury through inhibiting the inflammatory activation of microglia.

It is recognized that the cerebral ischemia/reperfusion (I/R) injury triggers inflammatory activation of microglia and supports microglia-driven neuronal damage. Our previous studies have shown that ginsenoside Rg1 had a significant protective effect on focal cerebral I/R injury in middle cerebral artery occlusion (MCAO) rats. However, the mechanism still needs further clarification. Here, we firstly reported that ginsenoside Rg1 effectively suppressed the inflammatory activation of brain microglia cells under I/R conditions depending on the inhibition of Toll-likereceptor4 (TLR4) proteins. In vivo experiments showed that the ginsenoside Rg1 administration could significantly improve the cognitive function of MCAO rats, and in vitro experimental data showed that ginsenoside Rg1 significantly alleviated neuronal damage via inhibiting the inflammatory response in microglia cells co-cultured under oxygen and glucose deprivation/reoxygenation (OGD/R) condition in gradient dependent. The mechanism study showed that the effect of ginsenoside Rg1 depends on the suppression of TLR4/MyD88/NF-κB and TLR4/TRIF/IRF-3 pathways in microglia cells. In a word, our research shows that ginsenoside Rg1 has great application potential in attenuating the cerebral I/R injury by targeting TLR4 protein in the microglia cells.

Evaluating the effect of ginsenoside Rg1 on CPF-induced brain injury in mice via PI3k/AKT pathway.

Organophosphorus pesticides (OPs) have long been used extensively on agricultural land and can lead to significant improvements in crop yields. Due to occupational exposure, humans are exposed to pesticides through dermal contact, inhalation, and ingestion. The effects of OPs on the organism are currently studied for their effects on livers, kidneys, hearts, blood indicators, neurotoxicity,and teratogenic, carcinogenic, and mutagenic effects, while studies in the direction of brain tissue damage have not been reported in detail. Previous reports have confirmed that ginsenoside Rg1 is a prominent and representative tetracyclic triterpenoid derivative rich in ginseng and has good neuroprotective activity. Considering that, the aim of this study was to establish a mouse model of brain tissue injury by using the OP-type pesticide chlorpyrifos (CPF) and to explore the therapeutic effects and possible molecular mechanisms of Rg1. Mice in the experimental group were pre-protected with Rg1 by gavage for 1 week, and brain tissue damage was induced using CPF (5 mg/kg for 1 week) to assess the effect of Rg1 (80 and160 mg/kg for 3 weeks) in alleviating brain damage. Morris water maze and histopathological analysis were performed to assess cognitive function and pathological changes in the mouse brain, respectively. Protein expression levels of Bax, Bcl-2, Caspase-3, Cl-Cas-3, Caspase-9, Cl-Cas-9, phosphoinositide 3-kinase (PI3K), phosphorylated-PI3K, protein kinase B (AKT), and phosphorylated-AKT were quantified by protein blotting analysis. Rg1 obviously restored CPF-induced oxidative stress damage in mouse brain tissue, increased the levels of antioxidant parameters (total superoxide dismutase, total antioxidative capacity, and glutathione) in the brain, and significantly reduced the overexpression of apoptosis-related proteins induced by CPF. At the same time, Rg1 also markedly attenuated the histopathological changes in the brain induced by CPF exposure. Mechanistically, Rg1 could effectively activate the phosphorylation of PI3K/AKT. Furthermore, molecular docking studies revealed a stronger binding capacity between Rg1 and PI3K. Rg1 attenuated neurobehavioural alterations and reduced lipid peroxidation in the mouse brain to a great extent. Apart from that, Rg1 administration improved brain histopathology in CPF-induced rats. All results suggest that ginsenoside Rg1 has potential antioxidant effects on CPF-induced oxidative brain injury, and it is evident that Rg1 could be used as a promising therapeutic strategy for the study of brain injury from OPpoisoning.

Ginsenoside Rg1 regulates thiram-induced chondrocytes' apoptosis and angiogenesis in broiler chickens.

Tibial dyschondroplasia (TD) is a developmental cartilaginous disease due to thiram toxicity. The abnormity of chondrocytes and insufficient angiogenesis within the growth plate are the major factors leading to the occurrence of TD in most cases. In the current study, we evaluated the beneficial effects of ginsenoside (Rg1) against thiram-induced TD for knowing the possible underlying mechanisms in broiler chickens through in vivo and in vitro assessment. Arbor acres broilers (1-day-old, n = 120) were randomly divided for the in vivo evaluation. The control broilers were fed under normal conditions during the whole experiment cycle (18days). The TD broilers were fed with 50mg/kg thiram, while the treatment group was given 40mg/kg of Rg1. According to our findings, thiram caused a decrease in production performance and tibia parameters (p < 0.05), which were significantly reversed by Rg1 administration. In addition, the results from the histological evaluation showed that the proliferative zone had a smaller number of blood vessels, surrounded by inviable chondrocytes, proving apoptosis during the occurrence of TD, while Rg1 treatment significantly increased blood vessels and decreased apoptotic cells. Furthermore, it was found that Rg1 effectively ameliorated the angiogenesis by regulation of HIF-1α/VEGFA/VEGFR2 signaling pathway and the chondrocytes' apoptosis via the mitochondrial pathway. Hence, these findings suggest that Rg1 might be a perfect choice in the prevention and treatment of TD via regulating chondrocytes apoptosis and angiogenesis. Also, it might be a potential therapeutic drug for humans to overcome different bone disorders, involving chondrocytes.

Ginsenoside Rg1 modulates intestinal microbiota and supports re-generation of immune cells in dexamethasone-treated mice.

Ginsenoside Rg1 is one of the major ginsenosides found in roots of Panax ginseng and Panax notoginseng. Ginsenoside Rg1 is known to possess various biological activities including immunity enhancement activity. However, it is not clear whether the regulation of immune function by Rg1 is related to the intestinal microbiota. In the present study, the immuno-modulatory and gut microbiota-reshaping effects of ginsenoside Rg1 were evaluated. Ginsenoside Rg1 acts as an immune-enhancing agent to increase spleen index and the number of T, B and dendritic cells in dexamethasone (Dex)-treated mice. Ginsenoside Rg1 also increased the production of sIgA and regulated the expression of interleukin 2 (IL-2), IL-4, IL-10 and IFN-γ. Meanwhile, Rg1 administration regulated the structure of intestinal microbiota. The relative abundance of mouse intestinal microbial groups, such as Alistipes, Ruminococcaceae, Lachnospiraceae, and Roseburia were increased by Rg1 administration, whereas a decrease in the potential pathogens like Helicobacteraceae, Dubosiella, Mycoplasma, Alloprevotella, Allobaculum was observed. Moreover, Rg1 metabolites of Lachnospiraceae bacterium enhanced the proliferation of CD4+ T cells and T regulatory (Treg) cells. Ginsenoside Rg1 improved the inflammatory condition of the colonic tissue and repaired the destructed mucosal barrier. This study suggested that Rg1 strengthens immunity with regulating the homeostasis of intestinal microbiota in mice.

Ameliorative effect of ginsenoside Rg1 on dextran sulfate sodium-induced colitis: involvement of intestinal barrier remodeling in mice.

Ginsenoside Rg1, a major bioactive ingredient of Panax notoginseng, has been shown to reduce gut inflammation and ameliorate experimental colitis in mice. However, it is not yet known whether it affects the intestinal barrier injury of colitis. This study explored the effect of ginsenoside Rg1 on intestinal barrier injury in dextran sulfate sodium (DSS)-induced colitis mice through an ultrastructure observation of the colonic mucosa and analysis of the expression of colonic cytoplasmatic zonula occludens-1 (ZO-1) protein. Treatment with ginsenoside Rg1, especially high-dose use, significantly ameliorated colonic histopathologic features and the severity of the colitis and reduced colonic tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) levels and increase IL-4 levels in a mouse model of DSS-induced colitis. Its observed efficacy was comparable to that of 5-Aminosalicylic acid (5-ASA), a first-line therapeutic agent for ulcerative colitis. Notably, ginsenoside Rg1 administration was shown to up-regulate the expression of colonic ZO-1 protein, and it repaired the intestinal barrier structure in DSS-induced colitis mice. Taken together, our findings demonstrated that ginsenoside Rg1 treatment can significantly ameliorate the severity of DSS-induced colitis in mice, which involves intestinal barrier structure remodeling through lowering the levels of the colonic pro-inflammatory cytokines TNF-α and IFN-γ and increasing the anti-inflammatory cytokine IL-4. These results suggest the potential therapeutic use of ginsenoside Rg1 as a promising approach for the treatment of inflammatory bowel disease (IBD).

Ginsenoside Rg1 attenuates LPS-induced cognitive impairments and neuroinflammation by inhibiting NOX2 and Ca2+–CN–NFAT1 signaling in mice

The levels of lipopolysaccharide (LPS) are increased in the brain and blood of Alzheimer’s disease (AD) patients and contribute to neuroinflammation and neurodegeneration in AD. Ginsenoside Rg1 (Rg1) is reported to possess neuroprotective effects on neurodegenerative diseases by improving oxidative stress and inflammation. However, the protective effect and mechanism of Rg1 in neuroinflammation and neuronal damage in LPS-induced mice remain unclear. In this study, the results demonstrated that exposure to LPS for 14 days significantly induced cognitive impairment, neuronal injury and NLRP1 inflammasome activation, significantly increased ROS generation and NADPH oxidase 2 (NOX2) expression and elevated the levels of p-PLC, calcineurin (CN) and nuclear factor of activated T cells 1 (NFAT1) in the hippocampus. Treatment with Rg1, tempol (a superoxide dismutase mimic) and apocynin (an inhibitor of NOX) significantly improved cognitive impairment and neuronal damage, inhibited the activation of NLRP1 inflammasome, reduced ROS generation and NOX2 expression and decreased the levels of p-PLC, CN and NFAT1 in the hippocampus. Additionally, the calcium imaging results suggested that Rg1 administration significantly inhibits [Ca2+]i overload and maintains calcium homeostasis in LPS-induced HT22 cells. These results suggest that Rg1 treatment can improve LPS-induced activation of the NLRP1 inflammasome and neuronal damage through inhibiting NOX2, [Ca2+]i overload and CN-NFAT1 activation.

Rg1 exerts protective effect in CPZ-induced demyelination mouse model via inhibiting CXCL10-mediated glial response.

Myelin damage and abnormal remyelination processes lead to central nervous system dysfunction. Glial activation-induced microenvironment changes are characteristic features of the diseases with myelin abnormalities. We previously showed that ginsenoside Rg1, a main component of ginseng, ameliorated MPTP-mediated myelin damage in mice, but the underlying mechanisms are unclear. In this study we investigated the effects of Rg1 and mechanisms in cuprizone (CPZ)-induced demyelination mouse model. Mice were treated with CPZ solution (300 mg· kg-1· d-1, ig) for 5 weeks; from week 2, the mice received Rg1 (5, 10, and 20 mg· kg-1· d-1, ig) for 4 weeks. We showed that Rg1 administration dose-dependently alleviated bradykinesia and improved CPZ-disrupted motor coordination ability in CPZ-treated mice. Furthermore, Rg1 administration significantly decreased demyelination and axonal injury in pathological assays. We further revealed that the neuroprotective effects of Rg1 were associated with inhibiting CXCL10-mediated modulation of glial response, which was mediated by NF-κB nuclear translocation and CXCL10 promoter activation. In microglial cell line BV-2, we demonstrated that the effects of Rg1 on pro-inflammatory and migratory phenotypes of microglia were related to CXCL10, while Rg1-induced phagocytosis of microglia was not directly related to CXCL10. In CPZ-induced demyelination mouse model, injection of AAV-CXCL10 shRNA into mouse lateral ventricles 3 weeks prior CPZ treatment occluded the beneficial effects of Rg1 administration in behavioral and pathological assays. In conclusion, CXCL10 mediates the protective role of Rg1 in CPZ-induced demyelination mouse model. This study provides new insight into potential disease-modifying therapies for myelin abnormalities.

The protective effect of ginsenoside Rg1 on depression may benefit from the gap junction function in hippocampal astrocytes

Studies have shown that the ginsenoside Rg1 can improve depressive symptoms in vitro and in vivo. However, the efficacy of Rg1on the hippocampal astrocyte gap junctions in depression are unclear. We mainly aimed to explore the relationship between Rg1, hippocampal astrocyte gap junctions and depression. Using primary cultured astrocytes, corticosterone (CORT) was used to induce stress. CORT (100 μM) significantly reduced the survival rate in astrocytes, and this effect was prevented by additional Rg1 administration. Interestingly, the gap junction blocker carbenoxolone (CBX) was able to revert this Rg1 effect. In in vivo models, one group was exposed to chronic unpredictable stress (CUS) for 47 days, while another group was bilaterally injected with CBX (100 μM) into the hippocampal CA1 region. Rats treated with Rg1 (20 mg/kg) showed an improvement in the sucrose preference and the forced swimming test in both models, indicating an antidepressive activity of Rg1. The levels of astrocyte gap junction connexin 43 (Cx43) were detected by immunofluorescence (IF) and western blotting. The levels of glial fibrillary acidic protein (GFAP) were detected by IF. The gap junctions in the hippocampal CA1 area were evaluated using dye transfer and electron microscopy. The reduction in Cx43 expression, the decrease in the Cx43 to GFAP ratio, the shorter dye diffusion distance, and the abnormal ultrastructure of gap junctions in rats exposed to CUS were markedly alleviated by concomitant Rg1 treatment. Taken together, the ginsenoside Rg1 could improve depression-like behavior in rats induced by astrocyte gap junction dysfunction in the hippocampus.

Ginsenoside Rg1 ameliorates chronic social defeat stress-induced depressive-like behaviors and hippocampal neuroinflammation

Chronic social defeat stress (CSDS) is an ethologically relevant psychosocial stress animal model and has been widely used in depression studies. Ginsenoside Rg1 (Rg1) is the major active ingredients of ginseng with low toxicity and neuroprotective effects. The present study aims to investigate the antidepressant effects of Rg1 in CSDS mice and explore its molecular mechanism. We found that Rg1 (20 or 40 mg/kg, i.g.) administration significantly alleviated depressive-like behaviors caused by 4-week CSDS exposure, as measured by social interaction test and sucrose preference test, tail suspension test and forced swim test. Additionally, Rg1 treatment inhibited CSDS-induced production of IL-6, TNF-α and IL-1β, decreased the expression of iNOS, COX2, and caspase-9 and -3, and inhibited microglial activation (Iba1) in the hippocampus. Rg1 was found to significantly downregulate p-JNK1/2 and p-P38 MAPK levels, upregulate p-ERK1/2 levels and inhibit the expression of phosphorylated NF-κB in the hippocampus. Meanwhile, Rg1 regulated SIRT1 and decreased the levels of acetylated p65 (ac-p65) in the hippocampus. Moreover, the reduction in adult hippocampal neurogenesis in CSDS mice was reversed by Rg1 treatment. In conclusion, our findings suggest that Rg1 prevents depressive-like behavior in CSDS-exposed mice, partially through the downregulation of hippocampal neuroinflammation and the upregulation of adult hippocampal neurogenesis and that these changes presumably occur through increased anti-inflammatory effects and the inhibition of proinflammatory cytokine and neurotoxic mediator expression and microglial activation, which is partly mediated by the regulation of the MAPK and SIRT1 signaling pathways and results in the inhibition of NF-κB transcriptional activity.

Rg1 improves LPS-induced Parkinsonian symptoms in mice via inhibition of NF-κB signaling and modulation of M1/M2 polarization.

Ginsenoside Rg1 is one of the most active ingredients in ginseng, which has been reported to protect dopaminergic neurons and improve behavioral defects in MPTP model, 6-OHDA model and rotenone model. However, it is unclear whether Rg1 exerted neuroprotection in LPS-induced sub-acute PD model. In this study, we investigated the neuroprotective effect of Rg1 in the sub-acute PD mouse model and explored the related mechanisms. Rg1 (10, 20, 40 mg·kg−1·d−1) was orally administered to mice for 18 days. A sub-acute PD model was established in the mice through LPS microinjection into the substantia nigra (SN) from D8 to D13. We found that Rg1 administration dose-dependently inhibited LPS-induced damage of dopaminergic neurons and activation of glial cells in the substantia nigra pars compacta (SNpc). The neuroprotective effects of Rg1 were associated with the reduction of pro-inflammatory cytokines and the improvement of anti-inflammatory cytokines and neurotrophin in the midbrain. Rg1 shifted the polarization of microglia towards the M2 phenotype from M1, evidenced by decreased M1 markers (inducible NO synthase, CD16, etc.) and increased M2 markers (arginase 1 (Arg1), CD206, etc) in the midbrain. Furthermore, Rg1 administration markedly inhibited nuclear translocation of NF-κB in midbrain microglia. In conclusion, Rg1 protects PD mice induced by continuous LPS injection by inhibiting the nuclear entry of NF-κB and regulating the polarization balance of microglia, shedding new light on a disease-modifying therapy of PD.

Metabolomic Profiling of the Synergistic Effects of Ginsenoside Rg1 in Combination with Neural Stem Cell Transplantation in Ischemic Stroke Rats.

As the greatest medical and socioeconomic problem in developing countries, stroke is the second or third leading cause of death in China and worldwide. In adult organisms suffering from stroke, transplanted stem cells have the ability to repair damaged tissues by regenerating autologous cells, while ginsenoside Rg1 could promote proliferation and differentiation of stem cells. Although obvious antistroke effects of ginsenoside Rg1 and transplanted stem cells have been verified in publications, the mechanism exploration remains challenging. Our study was carried out to investigate the synergistic effects of ginsenoside Rg1 and neural stem cell (NSC) transplantation on MCAO rats with a 1H NMR-based nontargeted metabolomics method to identify potential biomarkers and protein targets and discover the potential mechanism. NSCs transplantation after MCAO combined with ginsenoside Rg1 administration could significantly improve the cerebral infarct and neurological deficits. The treatment significantly intervened the levels of ten metabolites, and perturbed energy metabolism, amino acids metabolism, and lipids metabolism. And 11 enzymes were identified and verified as the targets of NSCs transplantation and ginsenoside Rg1 administration on MCAO rats. Our findings helped to improve the antistroke mechanism of NSCs transplantation and ginsenoside Rg1 and supply a theory basis for the combined research of stem cells and Chinese medicine in the future.

Ginsenosides Rb1 and Rg1 Protect Primary Cultured Astrocytes against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury via Improving Mitochondrial Function.

This study aimed to evaluate whether ginsenosides Rb1 (20-S-protopanaxadiol aglycon) and Rg1 (20-S-protopanaxatriol aglycon) have mitochondrial protective effects against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in primary mouse astrocytes and to explore the mechanisms involved. The OGD/R model was used to mimic the pathological process of cerebral ischemia-reperfusion in vitro. Astrocytes were treated with normal conditions, OGD/R, OGD/R plus Rb1, or OGD/R plus Rg1. Cell viability was measured to evaluate the cytotoxicity of Rb1 and Rg1. Intracellular reactive oxygen species (ROS) and catalase (CAT) were detected to evaluate oxidative stress. The mitochondrial DNA (mtDNA) copy number and mitochondrial membrane potential (MMP) were measured to evaluate mitochondrial function. The activities of the mitochondrial respiratory chain (MRC) complexes I–V and the level of cellular adenosine triphosphate (ATP) were measured to evaluate oxidative phosphorylation (OXPHOS) levels. Cell viability was significantly decreased in the OGD/R group compared to the control group. Rb1 or Rg1 administration significantly increased cell viability. Moreover, OGD/R caused a significant increase in ROS formation and, subsequently, it decreased the activity of CAT and the mtDNA copy number. At the same time, treatment with OGD/R depolarized the MMP in the astrocytes. Rb1 or Rg1 administration reduced ROS production, increased CAT activity, elevated the mtDNA content, and attenuated the MMP depolarization. In addition, Rb1 or Rg1 administration increased the activities of complexes I, II, III, and V and elevated the level of ATP, compared to those in the OGD/R groups. Rb1 and Rg1 have different chemical structures, but exert similar protective effects against astrocyte damage induced by OGD/R. The mechanism may be related to improved efficiency of mitochondrial oxidative phosphorylation and the reduction in ROS production in cultured astrocytes.

Antiobesity Effects of Ginsenoside Rg1 on 3T3-L1 Preadipocytes and High Fat Diet-Induced Obese Mice Mediated by AMPK.

Ginsenosides Rg1 is one of the major pharmacologically active saponins in ginseng, which as an antioxidant reduces oxidative damage in the liver and can also be used to prevent cardiovascular diseases and diabetes. However, there is no research targeting the effect of lipid metabolism in high-fat diet (HFD)-induced mice. In this study, we evaluated the anti-obesity effects of Rg1 in 3T3-L1 adipocyte cells and HFD-induced obese C57BL/6J mice. Administration of Rg1 to HFD-induced obese mice significantly decreased body weight, total cholesterol, and total triglyceride levels. In addition to effects in 3T3-L1 cells, Rg1 reduced the accumulation of lipid droplets in a dose-dependent manner. Furthermore, Rg1 exhibits an anti-adipogenic effect via regulation of the expression of the transcriptional factors and lipid metabolism-related genes in vivo and in vitro. We observed that Rg1 administration significantly increased the phosphorylation level of AMP-activated protein kinase (AMPK) in both epididymal white adipose tissue and 3T3-L1 cells. These results indicated that Rg1 works both in an anti-adipogenic and anti-obesity manner through inducing AMPK activation, inhibiting lipogenesis, and decreasing intracellular lipid content, adipocyte size, and adipose weight.

Ginsenoside Rg1 Exhibits Anti-asthmatic Activity in an Aspergillus Protease-Induced Asthma Model in Mice

Asthma is one of the most common chronic airway diseases and is characterized by symptoms, such as, wheezing and coughing. Its prevalence in Korea is gradually increasing among children and adults, especially among those older than 60 years. In this study, we investigated the effects of ginsenoside Rg1 (Rg1), one of the major constituents of Panax ginseng Meyer on ovalbumin (OVA) plus Aspergillus protease ( A. protease) allergen-induced asthmatic mice. Mice were orally administered Rg1 for 10 days from 8 days after OVA + A. protease sensitization and intranasally administered booster doses of OVA + A. protease for 4 days from 14 days after sensitization. The effects of Rg1 administration on airway hyperresponsiveness (AHR), immune cell distributions in bronchoalveolar lavage fluid (BALF), and serum level of immunoglobulin E (IgE) were investigated at 18 days after sensitization. Histopathological changes in hematoxylin and eosin (H&amp;E)-stained lung sections were also examined. Treatment of OVA + A. protease-sensitized/challenged asthmatic mice with Rg1 significantly decreased total eosinophil counts in BALF as compared with those of phosphate-buffered saline (PBS)-treated sensitized/challenged controls, and significantly decreased methacholine-induced AHR. Furthermore, IgE serum levels were significantly lower in Rg1 administered OVA + A. protease-sensitized asthmatic mice than in PBS-treated sensitized/challenged controls. The study shows Rg1 protects against A. protease allergen-induced asthma in mice.