Ginseng has been widely used as a folk medicine in East Asian countries for thousands of years, mainly as a general tonic and adaptogen to maintain the body’s resistance to adverse factors and homeostasis, including improving physical and sexual function, general vitality, and antiaging.
Ginseng and ginsenosides seem to be beneficial for immunity, cancer, diabetes, CNS functions, and other conditions. Although a single ginsenoside is demonstrated to be beneficial regarding some effects or conditions, it remains to be determined whether a single component or mixtures of components derived from ginseng can maximize benefit across several diseases and conditions. Therefore, more research works concerning the structure–activity relationship between ginseng constituents, acting individually or synergistically in a mixture, are required for predicting and ensuring physiological and pharmacological efficacy. In addition, as many steps must be taken to standardize the usage of ginseng root through isolating specific ginsenosides, the formulated standardization of ginseng extract and ginsenoside isolation is clearly required to have constant results and desirable efficacy in animal and human experiments.
Finally, large-scale, controlled clinical studies are needed to validate the results in terms of their applicability to humans to extend those reported experiments that have been performed using animal models.
Ginsenoside Rh2 was identified as an active ingredient of ginseng that can act at the hippocampal NMDA receptors, but its neuroprotective activity came from an in vivo experiment showing that at 100 mg/kg p.o., ginsenoside Rh2 protects brain from ischemia-reperfusion injury. These results indicate that ginsenoside Rg3 protects neurons in vitro from NMDA-induced neurotoxicity and in vivo ginsenoside Rh2 protects from ischemiareperfusion brain injury. The neuroprotective activity of these ginsenosides can be attributed to the specific inhibition of NMDA-induced receptor activation.
Alzheimer’s disease, characterized microscopically by the deposition of amyloid plaques and formation of neurofibrillary tangles in the brain, has become the most common cause of senile dementia. Loss of cholinergic neurons along with muscarinic ACH receptors in the cerebral cortex and hippocampus is closely associated with Alzheimer’s disease. It was reported that Rg3 effectively decreased inflammatory cytokine expression in Abeta42-treated murine BV-2 microglial cells, inhibited the binding of NF-κB p65 to its DNA consensus sequences, and significantly decreased expression of TNF-α in activated microglia. Results suggest that inhibition of the inflammatory repertoire of microglia, neuroprotection, and increased macrophage scavenger receptor type A expression induced by Rg3 may at least partly explain its therapeutic effects in chronic neurodegenerative diseases. In addition, the effect of ginsenoside Rg3 on the metabolism of Abeta40 and Abeta42 was investigated in SK-N-SH cells transfected with Swedish mutant β-amyloid precursor protein. The results of enzyme-linked immunosorbent assay (ELISA) and Western blot analysis showed that Rg3 significantly lowered levels of Abeta40 and Abeta42, leading to the suggestion that Rg3 would be useful for treating patients suffering from Alzheimer’s disease.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is introduced as a neurotrophic factor to promote cell survival. Ginsenoside Rh2 stimulated PACAP gene expression and cell proliferation in type 1 rat brain astrocytes (RBA1) cells and ameliorated the RBA1 growth inhibition of Abeta. These results suggested that Rh2 can induce an increase in PACAP to activate PAC1 and thereby lead to attenuating Abeta-induced toxicity. Thus, it is suggested that ginseng is useful in the prevention of age-related neurodegenerative diseases such as dementia.
To summarize this section, ginsenosides Rg1, Rb1, Rg3, and Rh2 were shown to be effective in potentiating learning and memory acquisition, enhancing releases of ACH and glutamate, inhibiting apoptosis, and protecting neurons from neurotoxic insults. Ginsenosides Rg3 and Rh2 were particularly effective in protecting CNS, preventing neurodegenerative diseases, and might also be useful in the treatment of Alzheimer’s disease.
Apoptosis is a process by which a cell actively commits suicide under tightly controlled circumstances, and it plays a fundamental role in the development of multicellular organisms, maintenance of homeostasis, and numerous pathophysiological processes.
However, defective control of apoptosis might play a role in the etiology of cancer, autoimmune diseases, and neurodegenerative disorders. It was first reported that ginsenoside Rg1 inhibited apoptosis induced by withdrawing serum from the culture system of primary cortical neurons. An antiapoptotic effect of Rg1 was shown in aged rats in vivo. Further studies demonstrated that mechanisms of Rg1 on apoptosis involved decreasing NO content and NOS activity, reducing intracellular calcium concentration and enhancing superoxide dismutase activity. Li et al. (1997) found that both NOS expression and the activity of NOS were elevated significantly in aged rats, which leads to increased NO concentration in rat cortex. NO played a role in the acceleration of senescence, and the inhibitory effect of Rg1 on NOS activity may be related to its antiaging function.
Other studies on the antiapoptotic effect of Rg1 on neurons suggest that the effect of Rg1 may contribute to enhancing the ratio of Bcl-2 to Bax protein and inhibiting activation of caspase-3. Among 11 ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg2, Rg3, Rh1, and Rh2), Rg3 was the most effective ginsenoside in terms of inhibitory activity of N-methyl-D-aspartic acid (NMDA) on hippocampal neurons. Selective blockers of the active glycine site on NMDA receptors are considered to be promising therapeutics that may decrease the devastating effects of excitotoxicity. It was demonstrated that ginsenoside Rg3 significantly protects neurons from NMDA-induced neurotoxicity by blocking the glycine-binding site. Homocysteine could exert its excitotoxicity through NMDA receptor activation. It was shown that ginsenoside Rg3 significantly and dose-dependently inhibits homocysteine-induced hippocampal cell death. Ginsenoside Rg3 not only significantly lowered homocysteine-induced DNA damage, but also in vitro attenuated caspase-3 activity in a dose-dependent manner. Furthermore, it was also demonstrated that Rg3 dose-dependently inhibits homocysteine-induced increase of intracellular Ca2+ levels.
In addition, ginsenoside Rg3 dose-dependently inhibited homocysteine- induced currents in Xenopus oocytes expressing NMDA receptors. These results collectively suggest that ginsenoside Rg3 protects from homocysteine-induced neurotoxicity in rat hippocampus; this effect is likely to be due to inhibition of homocysteine-mediated activation of NMDA receptors.
Various memory-impairment models have been used to evaluate the effects of ginseng and its active ingredients on learning and memory. In passive avoidance test, ginsenoside Rg1 improved learning and memory acquisition, consolidation, and retrieval, indicating that Rg1 can improve all stages of memory.
To study the effect of ginsenoside Rg1 on learning and memory loss induced by β-amyloid, passive avoidance and performance in the Morris water maze were assayed after the final treatment. Ginsenoside Rg1 significantly decreased latency and swimming distance, improved corresponding changes in search strategies in the Morris water maze, and increased stepthrough latency. In another study, Rg1 significantly improved memory deficits in aged rats, ovariectomized rats, and cerebral ischemia-reperfusion rats. Results showed that ginseng extract and ginsenosides Rg1 and Rb1 facilitated acquisition and retrieval of memory. Moreover, these ginsenosides also antagonized memory loss and cognitive deficit under various pathological conditions, such as cerebral ischemia and dementia.
Among the mechanisms underlying the positive impact on brain aging related to impairment of cognitive function and memory, ginsenosides might potentiate the cholinergic system in CNS. ACH is a very important neurotransmitter in the brain, and its scarcity often leads to learning and memory impairment. Ginsenosides Rg1 and Rb1 were found to enhance the functions of the cholinergic system by increasing the density of central M-cholinergic receptors and increasing the level of ACH in the CNS. Glutamate, another neurotransmitter, is also important for learning, memory, and cognitive function. Ginsenosides Rb1 and Rg1 facilitate the release of glutamate evoked by 4-aminopyridine, a potassium channel blocker that depolarizes nerve terminals in vitro, in a manner corresponding to in vivo depolarization. Ginsenosides Rb1 and Rg1 mediated facilitations of glutamate release are associated with an enhancement of vesicular exocytosis, an increase in Ca2+ influx through presynaptic N- and P/ Q-type voltage-dependent Ca2+ channels and protein kinase A, which subsequently enhances Ca2+ entry to cause an increase in evoked glutamate release from rat cortical synaptosomes.
Further study of this group showed that ginsenosides Rb1 and Rg1 enhanced glutamate exocytosis from rat cortical nerve terminals by affecting vesicle mobilization through the activation of protein kinase C.
Obesity is a major obstacle to human health because it predisposes individuals to various diseases, such as type 2 diabetes, cardiovascular diseases, and cancer.
Two major proteins regulate adipocyte differentiation: AMPK and the peroxisome proliferator-activated receptor (PPAR). Both AMPK and PPAR-γ are major regulatory proteins involved in both obesity and diabetes. PPAR-γ is activated under conditions of adipocyte differentiation. AMPK plays a role in intracellular energy homeostasis. The AMPK signaling pathway is induced by genistein, epigallocatechin gallate, and capsaicin and by decreasing 3T3-L1 adipocyte differentiation. Ginsenoside Rh2 effectively inhibited adipocyte differentiation via PPAR-γ inhibition and activated AMPK in 3T3 L1 adipocytes (Hwang et al. 2007).
Another study showed that ginsenoside Rb1 and Rg1 suppress triglycerides accumulation in 3T3-L1 adipocytes by activating PKA with increased intracellular cAMP. However, the insulin-stimulated glucose uptake was enhanced by Rb1 and Rg1 via activation of P13-kinase, and these ginsenosides promoted glucosestimulated insulin secretion and cell viability in Min6 cells through PKA, which was associated with insulin response substrate 2 expression to insulin and insulin-like growth factor 1 signaling. Some ginsenosides in ginseng improve insulin resistance by decreasing intracellular triglycerides accumulation. Ginsenoside Rb1 reduces rat liver triglycerides and Rh2 decreases triglyceride accumulation through AMPK activation in 3T3-L1 adipocytes. Ginsenoside Rg3 was effective in inhibiting 3T3-L1 adipocyte differentiation through PPAR-γ induction by rosiglitazone and also was effective in activating AMPK.
The antiobesity effects of ginseng and ginsenosides Rg3, Rh2, and Rb1 may involve the AMPK and PPAR-γ signaling pathways. Further studies on the connection between the AMPK and PPAR-γ signaling pathways may be desirable to understand the antiobesity qualities of ginseng and its use in antidiabetic treatment.
There are numerous reports of ginseng root improving diabetic conditions in both human and animal studies. In animal studies, orally administrated ginseng root was able to counteract the effect of high fructose-induced insulin resistance in rats after 4 weeks, decreasing glucose concentration and inhibiting insulin resistance.
Ethanol extract of wild ginseng root prevented weight gain and elevated fasting blood glucose, triglycerides, and high free fatty acid levels in a high fat-induced hyperglycemia mouse model. Ginsenoside Re decreased blood glucose, cholesterol, and triglyceride levels as well as decreased oxidative stress in the eye and kidney of diabetic rats. It is suggested that ginseng is useful for the prevention of diabetes in healthy people and for improved glycemic control in type 2 diabetes patients.
Clinical studies have reported that American ginseng lowers blood glucose in diabetic patients. In these studies, both type 2 diabetic patients and nondiabetic subjects were shown to benefit from intake of American ginseng in terms of stabilizing postprandial glycemia. More studies are required to confirm that ginseng administration decreases the dietary glycemic index, an indicator of carbohydrate’s ability to raise blood glucose level.
P. ginseng has been shown to increase glucose transport-2 protein in the liver of normal and hyperglycemic mice. Recently, Shang et al. (2008) showed that ginsenoside Rb1 stimulated basal and insulin-mediated glucose uptake in a time- and dose-dependent manner in 3T3-L1 adipocytes and C2C12 myotubes. In adipocytes, Rb1 promoted GLUT1 and GLUT4 translocation to the cell membrane and further increased the phosphorylation of insulin receptor substrate-1, protein kinase B, and stimulated phosphatidylinositol 3(P13)-kinase activity in the absence of the activation of the insulin receptor. Ginsenoside Rg3 enhanced glucose-stimulated insulin secretion and AMPactivated protein kinase (AMPK) in HIT-T15 cells, and further lowered the plasma glucose level by stimulating insulin secretion in ICR mice associated with ATP-sensitive K+ channels. AMPK is considered a master switch, regulating glucose and lipid metabolism, and an enzyme that works as a fuel gauge that is activated in conditions of high-energy phosphate depletion.
Collectively, the findings provide insight into the hypoglycemic and antidiabetic properties of ginseng and ginsenosides and their potential to provide beneficial treatment for diabetes.
Ginseng might mediate its antidiabetic action through a variety of mechanisms, including actions on the insulin-secreting pancreatic β-cells and the target tissues that take up glucose. Korean white ginseng (KWG) and KRG, one of the heat-processed Korean ginsengs, have a long history as herbal remedies with antidiabetic effects. KWG has been reported to stimulate glucose-induced insulin release from pancreatic islets as a potentiator. The mode of the insulinotropic action of KRG was to act as an initiator for insulin release, not in a glucose-dependent manner. In general, the heat-processed KRG has been reported to have more potent pharmacological activities than nonprocessed KWG.
KRG significantly evoked a stimulation of insulin release in normal pancreatic rat islets and may act by inhibiting the KATP channel, thereby depolarizing the β-cells and stimulating Ca2+ influx. These findings suggest that P. ginseng has beneficial effects in the treatment of diabetes at least in part via the stimulation of insulin release. Antihyperglycemic and antiobese effects of P. ginseng berry extract have been observed; its major constituent is ginsenoside Re. Ginsenoside Rg3 enhanced glucose-stimulated insulin secretion and was further metabolized to ginsenoside Rh2 by human intestinal bacteria, which seems to be more effective. Intravenous injection of ginsenoside Rh2 into rats decreased plasma glucose and increased plasma insulin by activation of muscarinic M3 receptors in pancreatic β-cells via acetylcholine (ACH) release from cholinergic terminals. PPD ginsenoside potentiated an insulin secretion stimulated by a low concentration of glucose, and C-K, a final metabolite of PPD ginsenoside, showed the most potent insulin secretion in pancreatic β-cells through action on the KATP-channeldependent pathway.
These observations were confirmed in an oral glucose tolerance test in ICR mice. In db/db mice, multiple administration of C-K showed hypoglycemic effects and improved glucose tolerance with β-cell preservation. Both Rh2 and C-K appear to have some therapeutic value for the treatment of diabetes and might be useful candidates for the development of new antidiabetic drugs.
One of the major obstacles to the effective treatment of human malignancy is the acquisition of broad anticancer drug resistance by tumor cells. This phenomenon is called multidrug resistance. MDR is a major problem in cancer chemotherapy, and it is correlated with the overexpression of P-glycoprotein (Pgp) in the plasma membrane of resistant cells.
Ginsenoside Rg1, Re, Rc, and Rd were found to have a moderate inhibitory effect on the drug efflux pump in MDR mouse lymphoma and to increase intracellular drug accumulation. Ginsenoside Rg3, among several ginseng components, was shown to have the most potent inhibitory activity on MDR human fibroblast carcinoma KBV20C. Rg3 treatment of drug-resistant KBV20C cells specifically inhibited Pgp-mediated drug accumulation and further increased life span in mice implanted with adriamycin-resistant murine leukemia P388 cells in vivo. Subsequent studies demonstrated that Rg3 was cytotoxic against a multidrug-resistant human fibrocarcinoma KBV20C cells but not against normal WI cells in vitro, and Rg3 also promoted the accumulation of rhodamine 123 in adriamycin-resistant murine leukemia P388 cells in vivo by mediating decreased membrane fluidity, thereby blocking drug efflux. Another study showed that ginsenoside metabolites Rh2, PPD, and PPT significantly enhanced the cytotoxicity of mitoxantrone (MX) to human breast carcinoma and may be potential inhibitors of breast cancer resistance protein (BCRP) in MCF-7/MX cells, which overexpress BCRP.
The protective influence and the complementary therapeutic potential of ginseng for cancer treatment have been shown by extensive laboratory, preclinical, and epidemiological studies. Two Korean cohort studies have suggested that ginseng consumers are associated with a 60–70% reduction in the risk of gastric cancer. However, ginseng consumers in the Shanghai women’s cohort study showed no beneficial effects on gastric cancer risk. Further careful evaluation in Asian cohort studies may help clarify ginseng’s effect on gastric carcinogenesis and other cancers. Additional clinical studies are needed to evaluate the potential beneficial effects of ginseng on chemoprevention and complementary therapy of cancers.
Several studies have been conducted to evaluate the inhibitory effect of ginseng on carcinogenesis induced by various chemical carcinogens. Earlier studies showed that long-term oral administration of KRG extract inhibited the incidence and the proliferation of tumors induced by 7,12-DMBA, urethane, and aflatoxin B1. The chemopreventive potential of ginseng was evaluated using DMBA-induced skin tumorigenesis.
There was a marked reduction not only in tumor incidence but also in cumulative tumor frequency at the initiation phase of tumorigenesis. Ginsenosides Rg3 and Rg5 showed statistically significant reduction of lung cancer, and Rh2 tended to decrease the incidence.Panwar et al. (2005) showed that P. ginseng extract inhibited lung adenoma induced by benzo[a]pyrene and decreased the frequencies of chromosomal aberrations and micronuclei. Another study showed that Rh2 had an antiproliferative effect on human lung adenocarcinoma A549 cells with G1 arrest by downregulation of cyclin proteins and kinases and further apoptosis mediated by caspase-8. Dietary administration of KRG suppressed colon carcinogenesis induced by 1, 2-dimethylhydrazine with inhibition of cell proliferation, acting on aberrant crypt foci in the colon mucosa. In addition, an anticarcinogenic effect of KRG on the development of liver cancer induced by diethylnitrosamine in rats was identified in preventive and curative events.
Ginsenoside Rh2 was shown to inhibit cell growth at low concentrations, to induce apoptosis at high concentrations, and, interestingly, to act either additively or synergistically with chemotherapeutic drugs on cancer cells, especially breast cancer cells to paclitaxel. Panaxadiol (PD) enhanced the anticancer effects of 5-fluorouracil (5-FU) in human colorectal cancer cells by inducing apoptosis. The enhancement of S-phase arrest and the increased susceptibility to apoptosis are synergistic effects of PD on 5-FU.
Ginsenoside Rg3 inhibited tumor invasion and metastasis of F16 melanoma cells without impairing cell growth and proliferation of tumor cells. Rg3 inhibited the metastasis of ovarian cancer; the inhibitory effect is partially due to inhibition of tumor-induced angiogenesis and the decreased invasive ability and MMP-9 expression of SKOV-3 cells. Ginsenoside Rg3 significantly inhibited growth and angiogenesis of ovarian cancer when used alone or combined with cyclophosphamide (CTX).
Another study found that low-dose CTX combined with Rg3 produced significant antiangiogenic effects, without overt toxicity, because Rg3 is capable of specific blockade of activated endothelial cell survival mechanisms. These studies indicated that a ginsenoside Rg3 and CTX combination reinforced the antitumor effect on each other and improved the living quality and survival time of mice with tumors. As an antiangiogenic method, this regimen has the advantage of a lowered susceptibility to drug-resistance mechanisms and improved animal survival.
Another ginsenoside, Rb1, suppressed the formation of endothelial tube-like structures through modulation of pigment epithelium-derived factors through estrogen β receptors. These findings demonstrated several novel mechanisms of these ginsenosides that may have value in anticancer and antiangiogenesis therapy. Ginsenoside 20(S)-PPD inhibited the proliferation and invasion of human fibrosarcoma HT1080 cells due to downregulation of the expression MMP-2. A ginseng saponin metabolite (C-K) suppressed phorbol ester-induced MMP-9 expression through inhibition of AP-1 and MAP kinase signaling pathways in human astroglioma cells. Ginsenoside Rp1, a semisynthesized ginseng saponin, strongly inhibited metastatic lung transfer of B16-melanoma cells by downregulation of β1-intergrin activation and further directly blocked the viability of cancer cells.