Ginsenoside Rg1: A Multifunctional Saponin with Neuroprotective, Antitumor, and Antidepressant Activities

Ginsenoside Rg1, as a member of the PPT type ginsenosides, is responsible for main pharmacological actions. It has multi-target effects, fewer side effects, and neuroprotective effects. The research on Rg1 has been conducted and yielded in recent years, e.g., pharmacological activities, pharmaceutics, pharmacokinetics, and bioavailability. Ginsenoside Rg1 exhibits a wide range of positive pharmacological activities. It can confer neuroprotective effects in the nervous system, as reported by. In the cardiovascular domain, it treats myocardial ischemia. Moreover, it plays a role in repairing hematopoietic immune disorders within the immune systems. So far, several clinical trials have been registered on clinicaltrials.gov, e.g., Sjögren's syndrome, vascular dementia, hyperlipidemia, rheumatic diseases, hypertension, and ischemic stroke. In addition, Rg1 is a key active ingredient of Kai-Xin-San, which is a famous antidepressant formula. Ginsenoside Rg1 could alleviate depression-like behaviors through diverse antidepressant mechanisms, e.g., anti-inflammation, anti-oxidative stress, and an increase of serotonin and norepinephrine.

Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy

Adoptive cell therapy (ACT) is a fourth option for treating tumors, following surgery, chemotherapy, and radiotherapy. It has been classified into 2 categories: nonspecific and specific ACT. The former includes lymphokine-activated killer cell therapy, cytokine-induced killer cell therapy and dendritic cell therapy, all of which can improve the response and cytotoxicity of immune cells without targeting specific antigens. Notably, ginsenoside Rg1 is one of the main active components, and its pharmacological activities and underlying mechanisms have been thoroughly explored. 1. Anti-tumor activity: When co-cultured with the chronic myeloid leukemia cell line K562, ginsenoside Rg1 was able to induce tumor cell cycle arrest in the S phase and inhibit cell proliferation. 2. Antioxidative activity: Rg1 increased the survival rate of SH-SY5Y cells injured by hydrogen peroxide by reducing the amount of released lactate dehydrogenase (LDH) and increasing superoxide dismutase activity. 3. Immunoregulatory activity: A number of studies have shown that Rg1 improves immunity by modulating multiple immune cells. Considering the potential effect on immunoregulatory activity, we planned to explore the regulating effect of ginsenoside Rg1 on ACTs. We introduced Rg1 during the in vitro activation and expansion phase of T cells isolated from human PBMCs.[1]

The application of ACT products, especially those used in CAR-T cell therapy, has become one of the most promising clinical therapy methods for tumors. Multiple approved products and clinical trials have revealed that CAR-T is highly efficient against B-cell malignant hematological tumors, in which the CR reaches almost 90%. Based on the fact that ginsenoside was able to activate T cells and promote cytokine secretion, in this study, we explored the function of ginsenoside Rg1 during the in vitro expansion phase of T cells isolated from human PBMCs. We first found that Rg1 addition enhanced T cell activation and proliferation induced by anti-CD3/CD28 beads. Two activation markers expressed on the cell surface, CD69 and CD25, were significantly upregulated. The notable changes observed in the activation and maturation phenotypes of T cells prompted us to explore whether Rg1 treatment affects the T cell effector function. PRF1, GZMA, and GZMK, 3 key effector molecules, were shown to be upregulated, and Rg1-pretreated T cells showed a stronger tumor lytic function at different effector: target cell ratios. In summary, our study revealed that ginsenoside Rg1 could enhance the activation and proliferation of T cells. Mitochondrial biosynthesis and effector functions were significantly improved. Moreover, the effect was consistent in CAR-T cells. These results suggest that ginsenoside Rg1 has the potential to become a synergist for ACT products and promote their application.

Ginsenoside Rg1 in neurological diseases: From bench to bedside

Neurological disorder is a general term for nervous system diseases and psychiatric diseases. It is a series of diseases that occur in the central nervous system (CNS) or peripheral nervous system and are mainly manifested by sensory, cognitive, emotional, behavioral and psychological disorders. Ginseng is derived from the root and rhizome of Panax ginseng C.A. Mey, a plant of Araliaceae. It has been used as a medicine in China for thousands of years. Modern pharmacological studies have shown that the main active substances of ginseng are ginsenosides, such as ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1) and ginsenoside Rg3 (Rg3), etc. These steroidal saponins have a variety of pharmacological effects. In order to further the development of Rg1, this review focuses on the recent experimental studies of Rg1 in depression, AD, and learning and memory dysfunction, and summarizes the mechanism of Rg1 in the treatment of dementia and depression. At the same time, the clinical potential of ginsenoside Rg1 and challenges are extensively discussed. Although depression and AD belong to two different types of neurological disorders, the presence of comorbidity suggests that the two diseases are related, and the occurrence of depression and AD has the same mechanisms and targets.[2]

According to the meta-analysis of the antidepressant effect of ginsenosides on animal model of depression, ginsenoside Rg1 is one of the most investigated ginsenosides. Although the antidepressant mechanism of Rg1 has not been clearly elucidated, the improvement effect of Rg1 on depression has been verified in several well-recognized pathogenesis of depression. ginsenoside Rg1 may exert its antidepressant effect by inhibiting the hyperfunction of HPA axis, regulating synaptic plasticity, inhibiting neuroinflammation and oxidative stress at the same time. Mou et al. used chronic unpredictable mild stress (CUMS) rats to evaluate the antidepressant effect of ginsenoside Rg1. The results showed that the CUMS rats showed obvious depression-like behavior, and the level of serum corticosterone (CORT) increased and the expression of glucocorticoid receptor decreased in the hippocampus. Many kinds of ginsenosides have definite neuroprotective effects and have been used in the research of anti-AD, among which Rg1 is one of the most investigated ginsenosides. ginsenoside Rg1 can reduce the activity of inflammatory factors induced by inflammasome activation and inhibit oxidative stress and apoptosis through anti-inflammatory and antioxidant effects.

Ginsenoside Rg1 exerts antidepressant effect

Major depressive disorder (MDD), a prevalent mental illness characterized by persistent low mood and anhedonia, is currently considered to be the main cause of suicide. It is well known that tryptophan (Trp) can be metabolized into 5-hydroxytryptamine (5-HT). The study of natural products as potential treatments and strategies for MDD has gained enormous interest in recent years. Ginsenoside Rg1, one of the major active components of ginseng, has been extensively investigated for its potential in treating brain disorders, especially depression. Studies have shown that ginsenoside Rg1 rescues depressive-like behaviors mainly due to its anti-inflammatory, antioxidant and neuroprotective activities. In our study, we used the chronic mild stress (CMS) mice model and the Kyn injection-induced depression model to investigate the mechanism of ginsenoside Rg1's antidepressant effect.  Furthermore, since our research focuses on the effect of it on Kyn metabolism, the Kyn-induced depression model is suitable for further investigation.[3]

The neuroprotective effect of ginsenoside Rg1 is indeed one of the current research hotspots. However, its limited ability to cross the blood-brain barrier results in low distribution within the brain. Thus, the mechanism through which affects the central nervous system needs further examination. Ginsenoside Rg1 upregulated the expression of KAT2 and KMO, thereby increasing the metabolism of Kyn in the liver. Further exploring its mechanism, we discovered that it increased the expression of KAT2 and KMO by promoting the interaction between the transcription factor HNF4α and PGC1α. Hepatic HNF4α knockdown abolished the antidepressant effects induced by ginsenoside Rg1.

References

[1]Liu Y, An L, Yang C, Wang X, Huang R, Zhang X. Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions. Blood Sci. 2023 Jun 30;5(3):170-179. doi: 10.1097/BS9.0000000000000165. PMID: 37546705; PMCID: PMC10400057.

[2]Yang, Shao-Jie et al. “Ginsenoside Rg1 in neurological diseases: From bench to bedside.” Acta pharmacologica Sinica vol. 44,5 (2023): 913-930. doi:10.1038/s41401-022-01022-1

[3]Jia K, Pan S, Wu W, Sun Y, Zhang Q. Ginsenoside Rg1 exerts antidepressant effect by regulating hepatic kynurenine metabolism through promoting the interaction between HNF4α and PGC1α. J Ginseng Res. 2025 Mar;49(2):179-188. doi: 10.1016/j.jgr.2024.12.002. Epub 2024 Dec 4. PMID: 40061483; PMCID: PMC11889386.