- 1 Clinical note — Adaptogens
- 2 ADAPTOGEN
- 3 CARDIOVASCULAR EFFECTS
- 4 GASTROINTESTINAL
- 5 ANTI-INFLAMMATORY
- 6 IMMUNOMODULA TION
- 7 ANTICANCER
- 8 NEUROLOGICAL
- 9 ANTIDIABETIC
- 10 STEROID RECEPTOR ACTIVITY
Clinical note — Adaptogens
Adaptogens are innocuous agents, non-specifically increasing resistance against physical, chemical or biological factors (stressors), having a normalising effect independent of the nature of the pathological state (original definition of adaptogen by Brekhman & Dardymov 1969).
Adaptogens are natural bioregulators, which increase the ability of the organism to adapt to environmental factors and to avoid damage from such factor (revised definition by Panossian et al 1999).
(Refer to the Siberian ginseng post for more information about adaptogens and allostasis.)
The pharmacological effects of ginseng are many and varied, contributing to its reputation as a potent adaptogen. The adrenal gland and the pituitary gland are both known to have an effect on the body’s ability to respond to stress and alter work capacity, and ginseng is thought to profoundly influence the hypothalamic-pituitary-adrenal axis. The active metabolites of protopanaxadiol and protopanaxatriol saponins reduce acetylcholine-induced catecholamine secretion in animal models and this may help to explain the purported antistress effects of ginseng.
Ginseng has been shown in numerous animal experiments to increase resistance to a wide variety of chemical, physical and biological stressors. Ginseng extract or its isolated constituents have been shown to prevent immunosuppression induced by cold water swim stress, to counter stress-induced changes from heat stress, food deprivation, electroshock and radiation exposure. As there are more than 1 500 studies on ginseng and its constituents, it is outside the scope of this monograph to include all studies, so we have attempted to include those studies most relevant to the oral use of ginseng.
Animal models suggest that ginseng is most useful for chronic rather than acute stress, significantly reducing elevated scores on ulcer index, adrenal gland weight, plasma glucose, triglycerides, creatine kinase activity, and serum corticosterone during chronic stress.
According to in vitro and animal studies ginseng may benefit the cardiovascular system ‘through diverse mechanisms, including antioxidant, modifying vasomotor function, reducing platelet adhesion, influencing ion channels, altering autonomic neurotransmitters release, improving lipid profiles’, and glycaemic control.
Red ginseng has been used as an antihypertensive agent in Korea, but its clinical effect is unclear despite several in vivo and in vitro experimental studies. Recent preliminary data suggests that the antihypertensive effects may be partly attributed to an angiotensin-converting enzyme (ACE) inhibitory effect demonstrated by P. ginseng extract in vitro. These effects were additive to the traditional ACE inhibitor enalapril.
A study of isolated muscle preparations of animal heart and aorta with an alcohol-based extract of ginseng suggest that the hypotensive effect of ginseng is associated with a direct inhibition of myocardial contractility due to a reduction of calcium ion influx into cardiac cells, as well as the inhibition of catecholamine-induced contractility of vascular smooth muscles.
In a prospective, randomised, double-blind placebo-controlled study of 30 healthy adults, 200 mg ginseng extract given for 28 days was found to increase the QTc interval and decrease diastolic blood pressure 2 hours after ingestion on the first day of therapy. These changes, however, were not thought to be clinically significant.
Although reports from recent in vitro and in vivo assays claim that P. ginseng is not one of the herbs that contributes to the antiplatelet effects of a Korean combination formula known as Dae-Jo-Hwan, a number of studies have found that several ginsenosides inhibit platelet aggregation. Panaxynol has been shown to inhibit platelet aggregation induced by adenosine disphosphate (ADP), collagen and arachidonic acid. Panaxydol and ginsenosides Ro, Rg, and Rg2 inhibit rabbit platelets while panaxydol prevented platelet aggregation and thromboxane formation.
Ginsenoside Rb1 has been shown to lower triglyceride and cholesterol levels via cAMP-production in the rat liver. Panax ginseng extract (6 g/day) for 8 weeks resulted in a reduction in serum total cholesterol, triglyceride, LDL and plasma malondialdehyde levels and an increase in HDL in eight males. Ginseng has also been reported to decrease hepatic cholesterol and triglyceride levels in rats, indicating a potential use of ginseng in the treatment of fatty liver.
Other cardiovascular effects
Ginsenoside Rb2 has been shown to enhance the fibrinolytic activity of bovine aortic endothelial cells. In animal studies ginseng inhibits cardiomyocyte apoptosis induced by ischaemia and reperfusion and the crude saponins have been shown to reduce body weight, food intake, and fat content in rats fed a high-fat diet.
Oral administration of Korean red ginseng (250 and 500 mg/kg) on liver regeneration has been investigated in 1 5 dogs with partial hepatectomy. All haematological values except leukocyte counts were within normal ranges for 3 days postoperatively. The levels of AST and ALT in the ginseng groups were significantly decreased compared with those in the control group (P < 0.05). The numbers of degenerative cells and area of connective tissue were significantly decreased in the livers of the dogs treated with ginseng (P < 0.01).
Ginseng has been shown in several studies to protect against ulceration. Among the hexane, chloroform, butanol and water fractions, the butanol fraction of a ginseng extract has been shown to be the most potent inhibitor of HCI-induced gastric lesions and ulcers induced by aspirin, acetic acid and Shay (ulcer induced by pylorus ligation). The butanol fraction showed significant increase in mucin secretion, and inhibited malondialdehydeand H+/K+ ATPase activity in the stomach. These results indicate that the effectiveness of ginseng on gastric damage might be related to inhibition of acid secretion, increased mucin secretion and antioxidant properties.
Effects on peristalsis
Ginseng root extract, and its components, ginsenoside Rbl (4) and ginsenoside Rd(7), have been shown to significantly ameliorate chemically induced acceleration of small intestinal transit in vivo. The test results suggest that the protective mechanism involves both an inhibitory effect on the cholinergic nervous system and a direct suppressive effect on intestinal muscles.
Both a crude and a standardised extract (G115) of ginseng varying in saponin concentrations have been found to protect against muscle fibre injury and inflammation after eccentric muscle contractions in rats on a treadmill. The oral ginseng extracts significantly reduced plasma creatine kinase levels by about 25% and lipid peroxidation by 1 5%. Certain markers of inflammation were also significantly reduced. In a later study, pretreatment with ginseng extract (3, 10, 100 or 500 mg/kg) administered orally for 3 months to male Wistar rats resulted in a 74% decrease in lipid peroxidation caused by eccentric exercise.
The many and varied effects of ginseng may be partly associated with the inhibition of transcription factor NF-kappa B, which is pivotal in the regulation of inflammatory genes. Inhibition of NF-kappa B may reduce inflammation and protect cells against damage.
Topical application of several ginsenosides (Rb1, Rc, Re, Rg1, Rg3) significantly attenuated chemically induced ear oedema in mice. The ginsenosides also suppressed expression of COX-2 and activation of NF-kappa B in the skin. Of the ginsenosides tested, Rg3 was found to be most effective.
The immunomodulatory effect of ginseng is based on the production of cytokines, activation of macrophages, stimulation of bone marrow cells and stimulation of iNOS, which produces high levels of NO in response to activating signals from Th1-associated cytokines and plays an important role in cytotoxicity and cytostasis (growth inhibition) against many pathogenic microorganisms. In addition to its direct effector function, NO serves as a potent immunoregulatory factor.
Ginseng enhances IL-12 production and may therefore inducea stronger Th1 response, resulting in improved protection against infection from a variety of pathogens, including Pseudomonas aeruginosa lung infection in animal models, although other studies suggest that it may also assist in the correction of Th1 -dominant pathological disorders.
Ginseng polysaccharides have been shown to increase the cytotoxic activity of macrophages against melanoma cells, increase phagocytosis and to induce the levels of cytokines, including TNF-alpha, IL-1 -beta, IL-6 and IFN-gamma in vitro. Ginseng has been shown to bean immunomodulatorand to enhance anti-tumour activity of macrophages in vitro. Ginseng has also been shown significantly to enhance NK function in an antibody-dependent cellular cytotoxicity of peripheral blood mononuclear cells in vitro.
Incubation of macrophages with increasing amounts of an aqueous extract of ginseng showed a dose-dependent stimulation of iNOS. Polysaccharides isolated from ginseng showed strong stimulation of iNOS, whereas a triterpene-enriched fraction from an aqueous extract did not show any stimulation. As NO plays an important role in immune function, ginseng could modulate several aspects of host defence mechanisms due to stimulation of the iNOS.
Ginseng promotes the production of granulocytes in the bone marrow (granulocytopoiesis). The ginseng saponins have been shown to directly and/or indirectly promote the stromal cells and lymphocytes to produce human granulocyte-macrophage colony-stimulating factor (GM-CSF) and other cytokines and induce bone marrow haemopoietic cells to express GM-CSF receptors, leading to a proliferation of human colony-forming units for granulocytes and macrophages in vitro.
Ginseng polysaccharides have been shown to have potent antisepticaemic activity by stimulating macrophages and helping modulate the reaction against sepsis induced by Staphylococcus aureus. Ginseng polysaccharides have been shown to reduce the intracellular concentration of S. aureus in macrophages in infected animals by 50% compared with controls. Combination of the ginseng polysaccharides with vancomycin resulted in 100% survival of the animals whereas only 67% or 50% of the animals survived, respectively, when treated with the ginseng polysaccharides or vancomycin alone.
Oral intake of standardised P. ginseng extract demonstrates a dose dependant (1, 3 or 10 mg/kg) chemoprotective and antimutagenic effect in animal studies and ginsenoside Rg3 has recently been produced as an antiangiogenic anticarcinogenic drug in China.
Oral administration of red ginseng extracts (1% in diet for 40 weeks) significantly (P < 0.05) suppressed spontaneous liver tumour formation in male mice. Oral white ginseng was also shown to suppress tumour promotion in vitro and in vivo.
Dietary administration of red ginseng in combination with 1,2-dimethylhydrazine suppresses colon carcinogenesis in rats (rats were fed 1% ginseng for 5 weeks). It is thought that the inhibition may be partly associated with inhibition of cell proliferation in the colonic mucosa.
Oral administration of 50 mg/kg/day for 4 weeks of a ginseng intestinal metabolite has been shown to partially protect against doxorubicin-induced testicular toxicity in mice. The metabolite significantly (P < 0.01) prevented decreases in body weight, spermatogenic activities, serum levels of lactate dehydrogenase and creatine phosphokinase induced by doxorubicin. It also significantly attenuated germ cell injuries.
The methanol extract of red ginseng has been shown to attenuate the lipid peroxidation in rat brain and scavenge superoxides in differentiated human promyelocytic leukaemia (HL-60) cells. Topical application of the same extract, as well as purified ginsenoside Rg3, has been demonstrated to suppress skin tumour promotion in mice. Rg3 also suppresses COX, NF-kappa B and extracellular-regulated protein kinase, which are all involved in tumour promotion.
Pretreatment with oral red ginseng extract significantly reduced the development of cancer from diethylnitrosamine-induced liver cancer nodules in rats (the developmental rate of liver cancer in the experimental group was 14.3% compared with 100% in the control group). When ginseng was given concomitantly with diethylnitrosamine, the hepatoma nodules were smaller than those of the control group, the structure of hepatic tissue was well preserved and the structure of hepatocytes was normal. Ginseng also prolonged the average life span. These findings suggest benefits of ginseng in the prevention and treatment of liver cancer.
Ginsenosides and specifically panaxadiol have been shown to have radioprotective effects in mice irradiated with high-dose and low-dose gamma radiation. Jejunal crypts were protected by pretreatment with extract of whole ginseng (50 mg/kg body weight intraperitoneally at 12 and 36 hours before irradiation, P < 0.005). Extract of whole ginseng (P < 0.005), total saponin (P< 0.01) or panaxadiol (P< 0.05) administration before irradiation (50 mg/kg body weight IP at 12 and 36 hours before irradiation) resulted in an increase in the formation of the endogenous spleen colony. The frequency of radiation-induced apoptosis in the intestinal crypt cells was also reduced by pretreatment with extract of whole ginseng, total saponin and panaxadiol.
These radioprotective effects are partly associated with the immunomodulatory effect of ginseng. Ginsan, a purified polysaccharide isolated from ginseng, has been shown to have a mitogenic activity, induce lymphokine-activated killer cells and increase levels of several cytokines. Ginsan reduced mutagenicity in a dose-dependent manner when applied to rats 30 min before or 1 5 min after 1.5 Gy of gamma-irradiation. The radioprotective effect of ginsan has been partly attributed to a reduction in radiation-induced genotoxicity. Ginsan has also been found to increase the number of bone marrow cells, spleen cells, granulocyte-macrophage colony-forming cells and circulating neutrophils, lymphocytes and platelets significantly in irradiated mice.
One of the causes of radiation damage is lipid peroxidation, which alters lysosomal membrane permeability leading to the release of hydrolytic enzymes. Ginseng has been shown to markedly inhibit lipid peroxidation and protect against radiation damage in testes of mice.
Antitumour, antiproliferative, antimetastatic and apoptosis-inducing
Stimulation of the phagocytic activity of macrophages may play a role in the anticarcinogenic and antimetastasic activities demonstrated for ginseng in vivo and research has continually found tumour inhibitory effects, especially in the promotion and progression phases.
Ginsenosides Rg3, Rg5, Rk1, Rs5 and Rs4 have been shown to be cytotoxic to Hep 1 hepatoma cancer cells in vitro. Their 50% growth inhibition concentration (GI50) values were 41, 11, 13, 37, and 13 micromol/L respectively. Cisplatin had a GI50 of 84 micromol/L in the same assay conditions.
Constituents in ginseng have also been shown to inhibit proliferation of cancer cells. Panaxytriol isolated from red ginseng was shown to have significant dose-dependent cytotoxicity activity and inhibit DNA synthesis in various tumour cells tested. Ginsenoside Rg3 has displayed inhibitory activity against human prostate cancer cells in vitro.
Ginsenosides, especially 20(R)-ginsenoside Rg3, has been shown to specifically inhibit cancer cell invasion and metastasis and ginsenoside Rh2 has been shown to inhibit human ovarian cancer growth in mice. It is likely that the anti-tumour promoting activity of Rg3 is mediated through down-regulation of NF-kappa B and other transcription factors.
Oral administration of 20(S)-protopanaxatriol (M4), the main bacterial metabolite of protopanaxatriol-type ginsenosides, has been shown to inhibit melanoma growth in mice and pretreatment was shown to reduce metastases to the lungs. This effect is thought to be due to stimulation of NK-mediated tumour lysis.
The antimetastatic effects of ginseng are related to inhibition of the adhesion and invasion of tumour cells and also to antiangiogenesis activity. Ginsenosides Rg3 and Rb2 have been shown to significantly inhibit adhesion of melanoma cells to fibronectin and laminin, as well as preventing invasion into the basement membrane in vitro. Other experiments have demonstrated that the saponins exert significant antiapoptotic activity, decreasing the number of blood vessels oriented toward the tumour mass.
Ginseng saponins have also been found to promote apoptosis (programmed cell death) in cancer cells in vitro.
Intraperitoneal administration of ginsenoside Rf has been shown to potentiate opioid-induced analgesia in mice. Furthermore, ginsenosides prevented tolerance to the opiate that was not associated with opioid or GABA receptors.
Ginseng saponins have demonstrated dose-dependent neuroprotective activity in vitro and in vivo. Ginsenosides Rb1 and Rg1 have a partial neurotrophicand neuroprotective role in dopaminergic cell cultures and Rg3 has been shown to inhibit chemically induced injuries in hippocampal neurons. Pretreatment with ginsenosides (50 or 100 mg/kg IP for 7 days) has been shown to be neuroprotective in vivo. An in vitro survival assay demonstrated that ginsenosides Rb1 and Rg1 protect spinal cord neurons against damage. The ginsenosides protect spinal neurons from excitotoxicity induced by glutamate and kainic acid, as well as oxidative stress induced by H202. The optimal doses are 20-40 micromol/L for ginsenosides Rb1 and Rg1. The lipophilie fraction of ginseng has been shown to induce differentiation of neurons and promote neuronal survival in the rat cortex. The effect is thought to be mediated via protein-kinase-C-dependent pathways.
It has been suggested that the neuroprotective effects of ginseng against hypoperfusion/reperfusion induced brain injury demonstrated in animal models, suggests a potential for use in CVD.
Following oral consumption, the active metabolites of protopanaxadiol saponins may reactivate neuronal function in Alzheimer’s disease according to in vivo evidence. Ginseng also enhances the survival of newly generated neurons in the hippocampus which may contribute to the purported benefits of ginseng for improving learning tasks.
Pretreatment (30 minutes) with 100 mg/kg ginseng significantly protected rats against pentylenetetrazole-induced seizures.
Human and animal studies have found American ginseng to lower blood glucose level. Results for Korean ginseng are less consistent. Both ginseng root and berry (150 mg/kg) have been shown to significantly decrease fasting blood glucose levels in hyperglycaemic rats. Intraperitoneal administration of glycans (polysaccharides known as panaxan) and other unidentified compounds have demonstrated hypoglycaemic activity in both normal and alloxan-induced hyperglycaemic mice.
Oral administration of Panax ginseng root (125.0 mg/kg) three times daily for three days reduced hyperglycaemia and improved insulin sensitivity in rats fed a high-fructose chow suggesting a possible role in delaying or preventing insulin resistance. However, these doses are very high and human trials need to be conducted to confirm these results.
Aqueous extract of ginseng was shown to exert no significant effect on weight in normal rats, while it prevented weight loss in rats with streptozotocin-induced diabetes. Cell proliferation in the dentate gyrus of diabetic rats was increased by ginseng treatment, but it had no effect on cell proliferation in normal rats. These results suggest that ginseng may help reduce the long-term central nervous system complications of diabetes mellitus.
According to experimental studies ginseng may also inhibit the formation of glycated hemoglobin due to its anti-oxidative activity.
STEROID RECEPTOR ACTIVITY
Ginseng has been shown to increase the mounting behaviour of male rats and increase sperm counts in rabbit testes. The effect is not by a direct sex-hormone-like function, but probably via a gonadotropin-like action. Ginsenoside Rb1 has been shown to increase LH secretion by acting directly on the anterior pituitary gland in male rats. Ginsenoside Rh1 failed to activate the glucocorticoid and androgen receptors, but did demonstrate an interaction with oestrogen receptors in vitro. The effect was much weaker than 17-beta-oestradiol. Ginseng is therefore considered to contain phyto-oestrogens. However, there are conflicting reports about oestrogen binding activity which may in part be explained by the presence or absence of zearalenone, an oestrogenic mycotoxin contaminant.