The Protective Effect and Mechanism of Action of Gynostemma Pentaphyllum Saponins on Neurological Diseases

Gynostemma pentaphyllum Makino is a perennial vine herbaceous plant, also known as pentaphyllum or seven-leaved ginseng, belonging to the model species of the genus Gynostemma pentaphyllum of the Cucurbitaceae family. The main medicinal ingredient of Gynostemma pentaphyllum is the dammarane-type gypenosides (GP). Cellular and animal experiments have shown that gypenosides have antioxidant, anti-inflammatory, immune-enhancing, hypolipidemic, and hypoglycemic effects. In neurological diseases, gypenosides exhibit good protective effects against Alzheimer's disease, Parkinson's disease, depression, and hypoxic brain injury.

Protective Effects of Gypenosides on Neurological Diseases

1. Prevention and Treatment of Alzheimer's Disease by Gypenosides

Alzheimer's disease (AD) is the most common form of senile dementia. The pathological characteristics of AD include senile plaques, neurofibrillary tangles, and progressive neuronal loss. The typical pathogenesis of AD involves the deposition of amyloid-beta (Aβ) in the brain, which induces neurotoxicity through mechanisms including oxidative stress, apoptosis, and autophagy. Studies have found that the active monomer compound gypenosides can alleviate spatial learning and memory impairments in AD transgenic mice. Administering a certain dose of gypenosides through intragastric infusion to AD transgenic mice can prolong their target quadrant time and increase the number of platform crossings. Furthermore, in the hippocampus and cortex tissues of mice, gypenosides can promote the autophagic clearance of Aβ deposits in the brain by activating the transcription factor EB (TFEB). Additionally, research has shown that gypenosides have a protective effect against Aβ25-35-induced PC12 cell death.

2.Prevention and Treatment of Parkinson's Disease by Gypenosides

Parkinson's disease (PD) is a degenerative disorder of the central nervous system that occurs in the elderly, characterized clinically by tremors, muscular rigidity, and bradykinesia, accompanied by the degeneration and death of dopaminergic neurons in the substantia nigra and a decrease in dopamine neurotransmitter content in the striatum. Studies have found that gypenosides have a protective effect against oxidative damage to dopaminergic neurons induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Pretreatment, simultaneous treatment, or post-treatment with gypenosides can dose-dependently reduce MPTP-induced oxidative damage, decreased dopamine uptake, loss of tyrosine hydroxylase (TH)-positive neurons, and degeneration of TH-positive neurons. Additionally, the results indicate that the preventive effect of gypenosides may have more potential than its therapeutic effect.

3.Prevention and Treatment of Depression by Gypenosides

Depression is a severe mental illness with a high lifetime prevalence and suicide rate, significantly impacting the quality of life of patients and their families. In experimental research, the chronic unpredictable mild stress (CUMS) model is a well-validated animal model of depression. Studies based on the mouse CUMS model have found that gypenosides can antagonize depression by activating the brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinase (ERK)/protein kinase B (Akt) signaling pathway in the hippocampus. Gypenosides can increase the expression of BDNF and neuronal proliferation in the hippocampus. Additionally, research has shown that gypenosides can also inhibit the elevation of proinflammatory cytokine levels in the hippocampus of CUMS mice, contributing to its antidepressant effects.

4.Improvement of Hypoxic Brain Injury by Gypenosides

Animal experimental studies have shown that gypenosides can prevent brain injury induced by simulated high-altitude hypoxia in mice. Pretreatment with gypenosides not only reduces neuronal damage in the hippocampus caused by hypoxia but also improves spatial memory impairment resulting from hypoxia. Further drug purification and identification have confirmed that dammarane-type triterpenoid saponins play a crucial role in the protective effects of gypenosides against hypoxic brain injury.

In pathological hypoxic brain injury animal experiments, it was found that pretreatment with a certain dose of gypenosides for 10 days significantly reduced the infarct volume in the brain tissue of rats with middle cerebral artery occlusion (MCAO) and improved motor function. Pretreatment with gypenosides promoted cell proliferation in the subventricular zone (SVZ) of the lateral ventricle in MCAO rats, increasing the number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells in both SVZs of MCAO rats.

5.Improvement of Anxiety Disorders by Gypenosides

Studies have shown that gypenosides also have an ameliorating effect on stress-induced anxiety disorders. The elevated plus maze test and marble burying test were used to investigate the improvement of chronic stress-induced anxiety disorders in mice by gypenosides. It was found that gypenosides treatment increased the number of entries into and the time spent in the open arms of the maze, as well as reduced the number of marbles buried. Furthermore, gypenosides restored the decreased levels of dopamine and serotonin in the brain caused by anxiety and reduced the induced elevation of serum corticosterone levels.

Mechanisms of Gypenosides in Improving Neurological Diseases

1. Anti-Inflammatory Effects

Neuroinflammation is a major contributor to various neurological disorders, including ischemic stroke, Parkinson's disease (PD), and Alzheimer's disease (AD). Studies have confirmed that gypenosides can improve neurological diseases by inhibiting neuroinflammation. Injecting lipopolysaccharide (LPS) into the lateral ventricle of rats induces inflammatory responses and memory impairment. Treatment with gypenosides significantly reduces the levels of inflammatory factors interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the brain and inhibits the activity of the nuclear factor kappa-B (NF-κB) signaling pathway. Furthermore, gypenosides decrease the LPS-induced activation of inducible nitric oxide synthase (iNOS). Research has also shown that high levels of Aβ in the brain can activate microglia to secrete proinflammatory factors such as TNF-α, IL-1β, and IL-6, leading to neuronal damage or even death. Microglia activation can be classified into two types: classical activation (M1) or alternative activation (M2). Therefore, inhibiting Aβ-induced microglia activation is considered an effective therapeutic strategy for AD. Additionally, studies have found that targeted knockdown of the inhibitory protein SOCS1 in the IL-6/IL-6R/Stat3 pathway significantly eliminates the effects of gypenosides on the M1 and M2 states of microglia.

2. Antioxidant Stress

Reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide, and hydroxyl radicals, mediate oxidative stress, which is a significant contributor to neuronal damage. ROS can cause oxidative damage to lipids, proteins, and DNA, manifested by significant increases in lipid peroxidation, protein carbonylation, and 8-hydroxyguanine levels. Gypenosides treatment, on the other hand, can significantly enhance the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase, while also increasing the content of glutathione (GSH). Due to its good lipid solubility, gypenosides can directly diffuse into the cell nucleus, triggering the gene expression of GSH, GPx, SOD, or catalase, thereby significantly increasing the levels of these antioxidant proteins. Alternatively, gypenosides can also directly interact with these enzymes, augmenting their catalytic activities.

3. Promotion of Neurogenesis

Neurogenesis plays a pivotal role in the neuroprotective effects of gypenosides on the nervous system. Gypenosides can promote the proliferation of neural stem cells (NSCs) within the subventricular zone (SVZ) of the lateral ventricle in middle cerebral artery occlusion (MCAO) rats and facilitate the differentiation of NSCs into neuroblasts. Pretreatment with gypenosides significantly increases the number of BrdU-positive cells in the bilateral SVZ of MCAO rats. Double-labeling immunohistochemistry confirms that the proliferating cells in the SVZ are GFAP (glial fibrillary acidic protein)/nestin-positive type B cells and doublecortin/nestin-positive type A cells. Thus, gypenosides can alleviate stroke-induced neuronal damage by enhancing neurogenesis in the SVZ.

Gynostemma pentaphyllum, as a traditional Chinese medicinal herb, is widely distributed and produced in large quantities in China, exhibiting considerable potential for development and becoming a research hotspot in recent years. The physiological activity of gypenosides, which are similar to the well-known ginsenosides, with fewer adverse effects, makes them promising for broad clinical applications. However, current research on the pharmacological effects and molecular mechanisms of gypenosides is mostly focused on cellular and animal models, with limited preclinical pharmacodynamic evaluations. Moreover, the complexity of gypenosides' composition, including over 20 dammarane-type triterpenoid saponin monomers alone, poses additional challenges. Therefore, further investigations into the active ingredients and mechanisms of action of gypenosides will contribute significantly to unlocking their clinical potential and advancing their value.

References

[1] Shen Zilin, Wang Zhenbo, Hou Huifang, Zhang Li, Huang Jianjun. Recent Advances in the Research on the Chemical Constituents, Pharmacological Effects, and Applications of Gynostemma pentaphyllum [J]. Ginseng Research, 2020, 32(05): 59-64. DOI: 10.19403/j.cnki.1671-1521.2020.05.015.

[2] Geng Yanan, Zhao Ming, Fan Ming, Zhu Lingling. Research Progress on the Protective Effects and Mechanisms of Gypenosides in Neurological Diseases [J]. Chinese Pharmacological Bulletin, 2021, 37(06): 765-768.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.