Rare Ginsenosides Pave the Way for Future Medicine

Researchers examined the structural and functional properties, traditional and modern applications, modes of action, toxicity, and current production strategies of rare ginsenosides (RGs) in a recent review published in the Journal of Advanced Research. RGs are the secondary metabolic derivatives of major ginsenosides, which are beneficial chemicals derived from Panax ginseng.

This analysis summarizes over 350 articles on these substances and finds that 144 RGs have been found with clinical uses such as immunoregulatory, anti-aging, anti-cancer, cerebrovascular, and cardiovascular. This study delves deeper into the breakthroughs in large-scale RG manufacturing and may serve as the foundation for future research into the applications of these extraordinary chemicals.

Novel knowledge for an ancient medicine

The root of plants in the genus Panax is known as gingseng. It has been utilized for thousands of years in traditional Chinese and Korean medicine and cuisine to cure chronic diseases ranging from erectile dysfunction to memory loss. However, due to inconsistencies in recent clinical studies, the use of ginseng and its extracts remains controversial, and the plant has yet to be approved as a prescription medicine by the United States (US) Food and medicine Administration (FDA).

Ginsenosides are a type of dammarane-type triterpenoids that can be derived from any of the three ginseng species – Panax ginseng, P. notoginseng, or P. quinquefolius – and account for the majority of therapeutically and pharmacologically helpful metabolites of these herbs. Ginsenosides are classified based on their relative abundance into the substantially more abundant primary (macro) saponins and the rare ginsenosides (RGs), which are naturally found in concentrations less than 0.1% by volume. Steaming, microbial transformation, and acid/alkali treatment are all used in the industrial production of RGs from primary saponins.

Until recently, most study on the therapeutically relevant effects of ginseng and its compounds concentrated on primary saponins, owing to RGs’ apparent limited in vivo bioavailability. Recent study, however, has called this concept into question, revealing that the disparities between the putative pharmacological effects of RGs and their poor in vivo performance are attributable to gut microbiome-mediated digestion. This triggered a torrent of research on RG’s potential medical benefits, most notably in the treatment of malignancies, cerebrovascular illnesses, and cardiovascular ailments.

While research on RGs is expanding rapidly, a review evaluating the overall impact of these chemicals is still absent. The current review tries to fill this void by synthesizing information on RG research stored in the Web of Science core collection between 2001 and 2021.

Classification of ginsenosides and their production

Recent bioprospecting advancements have identified over 500 saponins from the Panax genus, the majority of which are main saponins. While naturally occurring RGs are scarce, developments in natural product chemistry have led to the discovery of 144 RGs produced from parent saponins through transformations such as steaming, bio-, and chemical transformations. Encouragingly, these techniques use ginseng stems and leaves as raw materials, which is cost-effective given that ginseng roots have historically been the most expensive herb component.

Rk1, Rg5, Rg6, F4, 20(R/S)-Rs3, Rh4, Rs5, 20(R/S)-Rg3, Rk3, and Rs4 were identified using high temperature steaming. However, because the yield and quality of the generated RGs are temperature and time dependent, acid/alkali chemical transformation is the most dependable method for batch RG manufacture.

“Strong acid hydrolysis shows a higher conversion efficiency, leading to not only deglycocylation of ginsenosides, but also the side chain derivatization such as dehydration, cyclization, and double bond displacement, especially configuration inversion at C-20 of aglycones. In contrast, alkali hydrolysis has the advantages of high conversion, mild reaction conditions which cause no epimerization and no cyclization of the side chain.”

Given its environmental benefits, biotransformation by microorganisms has lately been investigated as the next stage in RG synthesis. So far, microbes or their enzymes have been used to successfully create K, Rh2, Mc, F2, F1, and aglycones.

Pharmacological benefits

Historically, red ginseng P. ginseng has been used for about 2000 years, according to the classic Bencao Mengquan, a traditional Chinese medicine (TCM) monograph. The herb was prized for its apparent pharmacological properties, including immunity boosting, memory improvement, and fatigue reduction, after it was shown to be rich in RGs (by steaming). Recent research has showed that red ginseng compounds offer significant anti-cancer, cognitive enhancement, and cardiovascular disease-fighting properties.

A clinical trial of 228 patients with hepatocellular carcinoma (HCC) found that the uncommon ginsenoside Rg3 increased overall survival from 10.1 months to 13.2 months, most likely by inhibiting vascular endothelial growth factor (VEGF). Clinical research on red ginseng’s cardiovascular benefits indicated that herb extracts improved coronary flow reserve (CFR) and raised circulating angiogenic cells, effectively combating acute myocardial infarction (AMI). Daily red ginseng extract consumption significantly improved Alzheimer’s disease assessment scale (ADAS) scores and reduced clinical dementia in Alzheimer’s disease patients, according to studies.

“Rare ginsenosides also showed clinical potential for other diseases such as liver dysfunction, physical performance deficiency. In addition, the clinical pharmacokinetics study provided the evidence for drug administration, for instance, the plasma concentration of ginsenoside Rh2 reached steady state after oral administration of Rh2 twice daily for 5 days, which supported the twice-a-day dosing regimen.”

Mechanisms of action

Numerous potential RG targets have been found through research. Independent elucidation of bile acid receptors, steroid hormone receptors, and platelet adenosine diphosphate (ADP) receptors lends evidence to ginseng’s traditionally asserted “adaptogen-like effect.” This result proposes that ginseng and its extracts can help maintain homeostasis by controlling somatic abnormalities caused by both internal and external disruptors.

“The genus name of Panax derived from “panacea” (heal-all diseases) may represent the ancient cognition of those herbs. The bidirectional regulation of immune system was considered undoubtedly as the peculiar way of ginseng and ginseng-related products participated in complex pharmacological network.”

Surprisingly, RGs have been shown to have anti-aging characteristics in mouse models through processes of acetylcholinesterase (AChE) and malondialdehyde (MDA) suppression, as well as superoxide dismutase (SOD) and catalase (CAT) upregulation. Similarly, F1 and Rg3 were discovered to postpone senescence (cell aging) by inhibiting NF-B activation, avoiding oxidative aging and increasing mitochondrial function.

Why take the trouble to produce RGs? Why not just use natural ginseng?

“The steamed P. ginseng, P. notoginseng, and P. quinquefolius showed superior efficacy in the treatment of cancer, CVDs, and cognitive disorders than raw ones, which were attributed to the production of rare ginsenosides.”

Numerous studies have confirmed that RGs are responsible for the majority of natural ginseng’s health and therapeutic advantages. Unfortunately, ginseng roots are expensive and only contain about 0.1% RGs, necessitating bulk manufacturing of the chemicals. The utilization of ginseng leaves and stems is an added benefit of industrial-scale RG manufacturing; these components are traditionally considered trash and are typically destroyed, making their usage in RG production cost-effective and environmentally beneficial.

What about toxicity? Are RGs safe?

While human clinical trials are limited, animal studies have indicated that ginseng extracts are generally safe at therapeutically given doses. Even when these concentrations are surpassed or during long-term usage, the majority of negative effects are transient and can be rectified by reducing the dosage. Human clinical trials are needed to corroborate these findings, although millennia of traditional Chinese and Korean medicine hint that the herb’s benefits much outweigh any potential side effects of misuse.

Challenges for the future

Future studies should focus on RGs’ specific protein targets, which are required for their medically approved usage in anti-cancer and cardiovascular therapy. Similarly, before suggested clinical dosages of RGs can be determined, the role and amount of gut microbial modifications of ginseng extracts must be established. Finally, microbial transformations of primary ginsenosides have previously been limited to the laboratory, with chemical transformations dominating at the industrial scale. Scaling up these microbial and enzymatic processes would enable safer and more ecologically conscientious RG batch manufacturing, putting RGs at the forefront of future therapeutic interventions.

For more information: Fan, W., Fan, L., Wang, Z., Mei, Y., Liu, L., Li, L., Yang, L., & Wang, Z. (2024). Rare ginsenosides: A unique perspective of ginseng research. Journal of Advanced Research, DOI – https://doi.org/10.1016/j.jare.2024.01.003