Ginseng As A Biological Response Modifier

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Understanding the actions of ginseng has, until now, always been complicated by the mixed nature of the chemical compositions of the ginseng products used. Therefore it has not yet been possible to clearly define the biological response modifier. Ginseng preparations have been shewn to improve liver function as well as immune function and it is therefore probable that the protective action is related to an immunomodulatory effect. Pretreatment with ginseng extracts was found to prolong the survival times of test animals suffering experimental trypanosomiasis, to prevent the development of fevers induced by typhoid and paratyphoid vaccines in rabbits, and to retard the development of diseased (leukopenic) white blood cells in bacillary dysentery. Ginseng treatment stimulated the production of specific antibodies in guinea pigs immunised with influenza vaccine and in rats immunised with diphtheria toxoid and was more effective at lower doses. In mice, ginseng extracts offered protection against experimental viral infection (Semliki forest virus) and increased the antiviral resistance developed by an interferon inducer of fungal origin viz. 6-MFA. Ginseng extracts were shewn in vitro to be effective inducers of interferon production in human peripheral white blood cells and to increase the natural killer and antibody dependent cytotoxic activity; thus immunomodulatory activity has been confirmed (Sonnenborn, 1987).

Knowledge of the body's defence mechanisms is a prerequisite for understanding of ginseng's immunomodulatory properties. Phagocytes, white blood cells that engulf and destroy harmful particulate matter, micro-organisms such as bacteria, and waste matter, may be predominantly sessile macrophages (monocytes, histiocytes, reticulocytes, etc.) or mobile macrophages (polymorphonuclear neutrophils which form some 62 per cent of the white blood cells). They form a first line of defence giving nonspecific resistance or innate immunity. The second line of defence is usually called acquired or adaptive immunity and comprises two groups a) the development of circulating globulin molecules known as antibodies which attack invading agents and b) the formation of the lymphocytes (some 30 per cent of the white blood cells). Lymphocytes include the B-lymphocytes derived from the foetal liver and the T- lymphocytes arising from the stem cells of the thymus gland. The B-lymphocytes are involved in the antibody-mediated immune response system producing humoral antibodies while the T-cells control the cell-bound defence mechanism. T-cells include the important T4 cells with helper and inducer actions and T8 cells with suppressor and killer actions. Contact between an antigen and a helper T4 cell prompts the circulating B-cells to multiply and differentiate into plasma cells which develop and release antibodies and memory cells essential for sustained immunity.

The phagocytic activity of the guinea pig tissue macrophage system (frequently but incorrectly called the reticuloendothelial system) was increased after intragastric infusion of total ginsenosides from P. ginseng stems and leaves for 3 days at a daily dose of 400 mg/kg (Cui et al., 1982). Nie et al. (1989) also noted that ginsenosides effectively increased the number of macrophages as well as stimulating the activities of the enzymes acid phosphatase, cytochrome oxidase and succinate dehydrogenase. There was no apparent linear parallel dose/effect relationship, low doses producing a stimulating effect but large doses had little effect. Intraperitoneal injection of ginsenosides in mice also increased the serum levels of specific antibodies and of the common antibodies IgA, IgG and IgM (Cui et al., 1982). Jie et al. (1984) treated mice orally for 5-6 days with 10, 50 or 250 mg/kg of an aqueous total ginsenoside extract. In response to a primary or secondary challenge with sheep red cells there was enhanced production of antibodies in a dose dependent manner. At the highest dose level, the primary IgM antibody response was increased by 50 per cent and the secondary IgG and IgM antibody responses by 50 per cent and 199 per cent respectively. Natural killer cell activity was also increased markedly.The effect of ginsenosides on natural killer cell activity and its correlation with the pituitary-adrenal axis system were studied using a mouse surgical stress model (Lui and Yang, 1991). Ginsenoside was found to antagonise the reduction in killer cell activity and to reduce the plasma ACTH and cortisone increase induced by stress. Regulation of the natural killer cells was thus possibly via the pituitary-adrenal axis in surgical stress. Such immunostimulating effects observed in vivo mirrored the in vitro stimulation of interferon production.

The action of crude extract, total saponins and especially the principal saponin, majonoside R2, from Vietnamese ginseng was shewn by the results of bactericidal and carbon clearance tests to enhance phagocytic activity in mice both in vivo and in vitro (Huong et al., 1997b). Test animals were protected from the toxic action of Escherichia coli ATCC 25922 and there was a significant increase in the phagocytic index.

The effects of long term oral administration of ginseng (P. ginseng) extract to mice was investigated by Kim et al. (1997). They were particularly interested in the serum protein profile and the occurrence of immunoglobulin (Ig) isotypes. Healthy female mice received either 30 mg/kg/day or 150 mg/kg/day of ginseng extract orally. Serum protein electrophoretograms shewed that the levels of y-globulin decreased dose-dependently to 82 per cent and 56 per cent of control values at 30 and 150 mg/kg/day respectively. The levels of total protein, albumin, a2- and ¿¡-globulin fractions and the ratio of albumin to globulin did not vary significantly but the a1-globulin level increased by 24 per cent with both dose regimens. Of the Ig isotypes (including IgA, IgG1, IgG2a, IgG2b, IgG3 and IgM), serum IgG1 was dose-dependently reduced to 68 per cent of the control values with the dose regimen of 150 mg/kg/day. There was no marked change of other Ig isotypes. The IgG1 isotype is seldom cytotoxic and can therefore function as a blocking antibody; its selective reduction by ginseng extract without changes in the cytotoxic antibodies such as Ig2a may aid the prevention and inhibition of cancers.

Immunomodulatory actions have been investigated in double blind trials employing aqueous ginseng extract, the carefully standardised preparation G115 (Pharmaton SA), and placebo. In an eight week trial 60 healthy volunteers aged between 18 and 50 years were divided into three groups (Scaglione et al., 1990). One group was given capsules containing 100 mg of an aqueous extract of ginseng root, a second group received similar capsules containing 100 mg of the standardised ginseng extract G115 and the final group received similar capsules containing lactose and caramel. The capsules were ingested orally, one capsule every 12 hours. Volunteers were tested at the commencement of the trial, after 4 weeks treatment and finally after 8 weeks treatment. Tests or measurements applied in triplicate to venous blood samples were 1) chemotaxis of circulating polymorphonuclear leukocytes (a measure of the specific attraction of leucocytes etc. by substances dissolved in the medium less the spontaneous migration), 2)

phagocytosis (the destroying activity of phagocytes which being electronegative attract the electropositive substances such as dead tissues, foreign particulate matter, etc. as well as rough surfaced particulate matter; the result, the phagocytic index, is expressed as the ratio of phagocyted microorganisms to the total number of polymorphonuclear leukocytes), 3) the phagocytosis index, the ratio of phagocyting polymorphonuclear leukocytes to the total number of polymorphonuclear leukocytes, 4) intracellular killing expressed as a percentage of killed microorganisms, 5) the total lymphocytes, 6) the T-helper (T4) subset, 7) suppressor cells (T8) subset, 8) the T4/T8 ratio, 9) blastogenesis of circulating lymphocytes assessed after mitogen stimulation (concanavalin A, pokeweed and lipopolysaccharide) and 3H-thymidine labelling, and 10) the natural killer cell activity assessed by 51Cr release in tumoural K562 target cells. The results obtained indicated that the ginseng extracts did stimulate an immune response in man. There was a significant increase in chemotaxis for both extracts after 4 weeks (p<0.05) and a more significant increase after 8 weeks (p <0.001) although no such increase was observed in the placebo group. Both the phagocytic index and the phagocytic fraction shewed similar trends, rising significantly after 4 weeks (p<0.001) for the G115 extract and maintaining high levels until the 8th week; results for the unstandardised extract were less significant, attaining a reasonable level (p<0.05) only after 8 weeks. Intracellular killing with both ginseng preparations also rose markedly (p<0.01 after 4 weeks, p<0.001 after 8 weeks); the placebo treatment also increased intracellular killing by the end of the trial (p<0.05).

Scaglioni and his colleagues correlated the total T-lymphocytes with the helper T4 and suppressor T8 cells. They noted that the total number of lymphocytes was elevated for the ginseng-treated volunteers from the fourth week onwards and significantly by the 8th week (p<0.001). For the T4 helper cells it was clear that the G115 extract produced a significant increase after 4 weeks (p<0.05) and this was maintained for the rest of the trial (p<0.001). The aqueous extract group yielded a lesser increase, only significant after 8 weeks (p<0.05) and the placebo group showed no change. The T8 cell count revealed no significant increase over the trial period for all three groups. The T4/T8 ratio showed little change although the G115 group produced a significant result after 4 weeks and this was maintained up to the 8th week (p<0.05). These results indicate that the standardised G115 preparation induced an onset of immune response earlier than the aqueous extract did.

Testing with mitogens (substances stimulating cell division) viz. concanavalin A, pokeweed mitogen and lipopolysaccharide, enabled assessment of the mitogen-induced blastogenesis or generation of circulating lymphocytes by measurement of radioactivity counts per minute of incorporated 3H-thymidine. Although the placebo group remained unaffected and the response to the first two mitogens only caused a significant increase (p<0.05) after 8 weeks treatment for both the ginseng aqueous extract and the G115 extract, lipopolysaccharide caused a very significant increase (p<0.001) only for G115 extract.

Scaglioni's group also investigated the activity of natural killer cells using K562 target cells as foreign tumour cells and measurement of the 51Cr isotope released on their destruction. The results showed that only extract G115 produced a statistically significant enhancement of activity after 4 weeks (p <0.05) and more so after 8 weeks (p<0.001).

The results of these in vivo experiments confirm the cited earlier in vitro work of Singh et al. and Jie et al. in 1984 indicating that ginseng extracts can stimulate immune reactions and that the standardised G115 extract can positively influence a higher number of subsets in the immune system. Another interesting observation was reported by Mizuno et al. (1994); they observed that a hot water extract prepared from wild ginseng and given orally to mice shewed mitogenic activity to lymphocytes but extract of cultured ginseng did not. Polysaccharides may be involved and lymphocyte stimulation by lipopolysaccharide requires further investigation.

A further study by Scaglioni et al. (1994) concerned 40 volunteers who were smokers (20 cigarettes per day) and suffered from chronic bronchitis. The participants were divided into two groups; the test group received 100 mg ginseng extract G115 at 12 hour intervals and the placebo group were given similar capsules containing 100 mg lactose and caramel. Parameters were determined on macrophages from bronchoalveolar lavage at the start and at the 4th and 8th weeks. Alveolar macrophages were separated from the lavage fluid and immediately assayed. Phagocytosis frequency (phagocyting alveolar macrophages), phagocytosis index (percentage of C. albicans phagocyted after 20 min incubation at 37° C) and intracellular killing power towards the yeast-like organism Candida albicans (percentage of yeast cells killed and stained with methylene blue (0.01 per cent in distilled water)) were estimated. Results revealed that the extract G115 could improve the immune response of alveolar macrophages in human subjects and significantly so by the 8th week of treatment (p<0.001 vs the respective controls). The ability of extract G115 to restore and increase the activity of alveolar macrophages renders such treatment useful in treating chronic bronchitis and related respiratory disorders. Such observations were supplemented by the work of Rimar et al. (1996) who had perfused rabbit lungs with artificially digested extract G115. Using extract G115 in undigested, gastric digested and intestinal digested forms, they were able to demonstrate that the pulmonary vasoconstriction induced by compound U46619 and the free radical injury caused by electrolysis could be countered by all three preparations. Acetylcholine induced vasodilation following injury could also be maintained using all three preparations. Therefore artificially digested and normal oral G115 extracts have potential as pulmonary vasodilators protecting against free radical injury.

Another research group (Song et al., 1997) investigated the value of ginseng treatment for patients with cystic fibrosis. The main pathogen affecting such patients is Pseudomonas aeruginosa which causes chronic lung infection, pneumonia with resultant progressive pulmonary insufficiency. Rats were injected subcutaneously with an aqueous ginseng extract (25 mg/kg) for 10 days and control animals received cortisone (25 mg/kg) and saline (0.9 per cent, 1 ml/kg). Two weeks after the challenge with P. aeruginosa, the ginseng-treated animals demonstrated a significant improvement in bacterial clearance from the lungs, less severe lung pathology, a lower incidence of lung abscesses and fewer mast cell numbers in the lung foci. In addition, lower total immunoglobulin G (IgG) levels and higher IgG2a levels were detected in serum against P. aeruginosa sonicate and there was a shift from an acute to a chronic type of lung inflammation as compared with the cortisone-treated and saline-treated control groups. Ginseng treatment of this pneumonia in rats promotes a cellular response that suggests potential value in the treatment of chronic P. aeruginosa lung infection in human cystic fibrosis patients.

Increased immune response should augment the efficacy of vaccination against the common cold and/or influenza syndrome. Therefore Scaglioni et al. (1996) devised a double-blind, placebo-controlled, randomized, multicentre study; 227 suitable volunteers were grouped into 114 participants receiving Ginsana G115 standardised extract (100 mg orally every 12 hours) and 113 taking similar placebo capsules (also every 12 hours). Vaccination with anti-influenza polyvalent vaccine 0.5 ml was effected 4 weeks after commencement of the trial and the capsules were taken for 12 weeks from the start of the investigation. Data regarding safety parameters (24 laboratory tests e.g. sedimentation rate, haemoglobin, albumin, glucose, creatinine, etc.) were collected at the start and finish of the trial. There was no statistically significant variation between the initial and final results for the Ginsana G115 or placebo groups. At the three medical centres natural killer cell activity and antibody titre was assessed at 0, 4, 8 and 12 weeks; concomitant diseases were checked at 2, 4, 8 and 12 weeks and adverse events at 2, 4, 6, 8, 10 and 12 weeks. Only 9 patients (8 taking ginseng G115 and 1 placebo) reported minor side reactions e.g. nausea, insomnia and epigastralgia. The results of the trial clearly demonstrated that the standardised ginseng extract G115 improved the immune response in vivo in human subjects thus protecting against common cold and influenza. Natural killer activity and antibody titre were significantly higher (p<0.001) after 8 and 12 weeks. Therefore significantly fewer volunteers in the G115 treatment group succumbed to these complaints.

Using Echinacea purpurea rhizomes and Panax ginseng roots See et al. (1997) reported that extracts of both plants enhanced the cellular immune function of peripheral blood mononuclear cells from normal individuals and from patients with depressed cellular immunity due to chronic fatigue syndrome or acquired immunodeficiency. Natural killer cell function was enhanced against K562 cells and antibody-dependent cellular cytotoxicity was improved versus human herpes virus 6 infected H9 cells.

Other workers investigated the immunological effects of the ginseng hetero-polysaccharides, compounds with molecular weights in the range 20,000 to 180,000 and comprising structural units such as arabinose, fucose, galactose, glucose, rhamnose, xylose and galacturonic acid and obtained from various Panax species and from the waste after such species are propagated by tissue culture. For example, sanchinan A, isolated from P. notoginseng roots, had a molecular weight of 1,500,000 and proved to be an arabinogalactan with remarkable tissue macrophage system stimulating effects (Ohtani et al., 1987).

Working with mice, Wang et al. (1981) recorded the effects of gastric infusion of a ginseng polysaccharide preparation at doses of 50-400 mg/kg body weight per day for 3-7 days. The effects were 1) stimulation of the phagocytic function of the tissue macrophage or reticuloendothelial system, 2) an increase in the serum specific antibodies and IgG antibodies, and 3) an increase in the relative percentages of B-lymphocyte cells. They also noted that a gastric infusion of 50mg of the ginseng polysaccharide preparation/kg/day in guinea pigs increased the serum complement level. Their conclusions indicated that ginseng polysaccharides apparently enhanced immune function.

Ginseng polysaccharide administered orally, intraperitoneally or subcutaneously to mice at doses of 100/200 mg/kg for 5-8 days countered the immunodeficiency induced by cyclophosphamide and also normalised suppressed macrophage phagocytosis and haemolysin formation and the delayed hypersensitivity reaction (Wang et al., 1985; Yuan et al., 1986). Similar conclusions were drawn by Kim et al. (1991) who observed that a ginseng polysaccharide fraction inhibited the decreases in the ratio of spleen weight to body weight, the white blood cell count and plaque-forming cell count induced by cyclophosphamide and also increased these factors in normal mice. In normal animals the ginseng saponin fraction increased the haemoglobin level and plaque-forming cell count in the spleen. The polyacetylene panaxytriol (20 mg/kg) prevented decreases in the white blood cell count caused by cyclophosphamide although neither the saponin fraction nor panaxytriol had any effect on the plaque-forming cell count and the antibody titres in cyclophosphamide treated mice. Such observations indicate that it is the polysaccharide fraction that probably reduces the immunotoxicity of cyclophosphamide and may have potential as a stimulator of immune functions in man.

Some polysaccharides comprising arabinose, galactose, glucose, mannose, xylose and uronic acid demonstrated varying degrees of anticomplementary action mediated by classical and alternative pathways whilst still retaining immunostimulating effects such as enhanced immune-complex binding to macrophages (Sun et al., 1994; Gao et al., 1996). Kim et al. (1998b) also reported strong anticomplementary activity initiated by the total saponins and the major saponins and discussed structure-activity relationships.

Studying immune deficiency in guinea pigs with a decomplementary and hypophagocytic state induced by cobra anticomplementary factor, Zhuang et al. (1996) administered ginseng polysaccharides (20 mg/kg intraperitoneally twice daily for 6 days) and discovered that the normal serum complement level was not influenced although there was recovery from the low complement level and reduced phagocytic rate caused by the cobra anticomplementary factor. Examination of isolated neutrophils by electron microscopy revealed that the polysaccharides reduced the number of neutrophilic granules which had increased following cobra anticomplementary factor treatment.

Patents for potential immunostimulatory pharmaceutical products based on ginseng polysaccharides and polypeptides are listed in Chapter 9.

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