Recent advances on ginseng research in China

Journal of Ethnopharmacology,

27

36 (1992) 27-38

Elsevier Scientific Publishers Ireland Ltd.

Review Article

Recent advances on ginseng research in China Chang-Xiao

Liu” and Pei-Gen

Xiaob

‘Tianjin Institute of Pharmaceutical Research, The State Pharmaceutical Administration of China, 308 An-Shun West Road, Tianjin 300193 and blnstitute of Medicinal Plant Development. Chinese Academy of Medical Sciences. Beging 100094 (People’s Republic of China)

Ginseng, Panax ginseng C.A. Meyer, is a well-known Chinese traditional medicine. There have been more than 300 original papers in Chinese and in English during the last 10 years in China. This review paper summarizes some achievements from some of these published papers. Tewnty-eight ginsenosides and some minor constituents were extracted and isolated from the root, root-stock, stems, leaves, flowers and flower-buds of ginseng. The chemical analysis demonstrated that the content of ginsenosides is related to the source, part and growth years of ginseng. The drug has a wide range of pharmacological and therapeutical actions, it acts on the central nervous system, cardiovascular system and endocrine secretion, promotes immune function and metabolism, possesses biomodulation action, anti-stress and anti-ageing activities, and so on. Many preparations of ginseng have been offtcially approved for clinical application in China. Clinical evaluation has shown that these preparations play a special role in medicinal use. Key words: ginseng; resource; chemistry; pharmacology;

application

Introduction Ginseng is one of the tonics in traditional Chinese medicine; the drug consists of the dried roots of Asiatic ginseng, Panax ginseng C.A. Meyer. According to the literature, ginseng has been known in Chinese ethnopharmacology for more than 3000 years. Its medicinal use has been adequately explored not only in China and Korea but also in Japan, the Soviet Union and the United States of America. A large number of the articles based on original research of ginseng has been published by Chinese scholars. They have made a greater contribution to the studies on the botany, chemistry, pharmacology and clinical application of ginseng, and are still studying its medicinal basis and application (Liu, 1975; Wang, 1980; Wang, 1985; Nanjing Traditional Medical College, 1985; Jiang and Xiao, 1985). During the last 10 years, there have been more than 300 original papers in Chinese and in English. Two books on ginseng Correspondence to: C.-X. Liu, Tianjin Institute of Pharmaceutical Research, The State Pharmaceutical Administration of China, 308 An-Shan West Road, Tianjin 300193, People’s Republic of China.

research in China have recently been published. Ginseng Research (Wang, 1985) and Ginseng Research and Cultivation (Xiao, et al., 1987). This paper will summarize some recent achievements from some of the published papers in the studies on ginseng research from 1979 to 1990 in China. Gene resources of the Chinese Panax genus Including American ginseng, there are seven species and three varieties of the genus Panax grown in China. Thus, China has the most abundant gene resources of Panax worldwide (Table 1). Ethnophamacologic Panax genus

investigation

of

Chinese

The results in terms of statistics are shown in Table 2. From this table it is seen that all Panax species possess tonic and roborant activities, especially Panax ginseng and Panax quinquefolium, and both of them also demonstrate tranquillizing and ‘body fluids’ producing activities, with Panax quinquefolium still showing the efficacy of nourishing the Yin and eliminating the fever due to

0378-8741/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

28

1

TABLE GENE

TABLE

RESOURCES

OF CHINESE

PANAX

GENUS

THE TOTAL

F.H. Chen

Locality

Yield (tons)

Jilin Liaoning

1203.8 199.7

I

‘San-chi’ Panax nofogineseng (Burk.) (Yunnan, Kwangsi)

II

‘Hsi-yang-shen’ P. quinquefolium L. (Cultivated in Northeast, North and East China) ‘Jen-shen’ P. ginseng CA. Meyer (Cultivated on large scale in Northeast China)

III

V VI

(Southwest China) ‘Chu-tzu-shen’ P. japonicus var. major (Burk.) C.Y. Wu et K.M. Feng (North, Northwest Southwest China)

VIb

VIC

K.M.

Feng (Southeast

IN 1985

157.4 1560.9

With the rapidly increasing demand for ginseng, special efforts on ginseng cultivation have been carried out in China, including the development of culture varieties by selection, field cultivation, reutilization of the wasted ginseng plantation, ginseng cultivation under forestry, as well as prevention and treatment of ginseng diseases and pests. As a result, both the quality and quantity of the ginseng produced have been significantly improved: the total national purchased amount of ginseng in 1957 was reportedly to be 71.7 tons, while the total national yield of ginseng in 1985 had reached 1560.9 tons (Table 3) (Yu, 1987). In the processing of ginseng, several techniques have been developed: fresh reservation, freezeprocessing and high-pressure packaging of red ginseng etc. Evaluated by the active principle con-

and

Yunnan)

Yin deficiency. Additionally, Panax notoginseng, Panax japonicus as well as Panax japonicus var. major exhibit the action activating the blood cir-

culation. This information would be of value for further research and development of those medicinal Panax species. TABLE

GINSENG

Cultivation, processing and tissue culture of ginseng

‘Yu-yeh-shen’ P. japonicus var. bipinnatijidus (Seem.) C.Y. Wu et K.M. Feng (Northwest, Southwest China) ‘Ping-ping-san-chi’ P. stipuleanatus H.T. Tsai et

VII

OF CHINESE

Total

‘Chu-chieh-jen-shen’ P. japonicus C.A. Mey. (East, Middle-south, South and Southeast Yunnan) ‘Chai-yeh-chu-chieh-shen’ P. japonicus CA. Mey. var. angustifolius (Burk.) Cheng et Chu

Via

YIELD

Heilongiiang

‘Chia-jen-shen’ P. pseudo-ginseng Wall. (South Tibet) ‘Chaing-chuang-san-chi’ P. zingiberensis C.Y. Wu et K.M. Feng (South and Southeast Yunnan)

IV

3

2

ETHNOPHARMACOLOGIC

DATA

Ethnopharmacologic efficacy

I

Tonic and roborant Tranquillizing and ‘body-fluids’ producing

OF CHINESE II

2114”

III

PANAX

GENUS IV

V

( 212

11

VI

7110

Via

VIb

Vlc

VII

l/2

7112

518

212

effects Blood activating stagnant eliminating effects Hemostasis and anodyne Antirheumatic and for fracture and injury Antitussive and expectorant

14114

212

212

lo/lo

212

10112

618

212

14114

212

212

S/10

212

12112

818

212

3114

112

3110

l/2

6112

3/8

5110

112

3/12

114

1112

Tonifying the Yin and clearing the fever due to Yin deficiency “Times of efficacy

appeared/times

of investigation;

0, concentrated

ethnopharmacologic

usage.

[

29

ginseng root saponin, such as the action of CNS stimulation, anti-fatigue, increasing of the white blood cells and anti-hyperglycemia etc. Potentially it is feasible to apply these techniques to industrial production.

tents of ginseng, the quality of Chinese ginseng is absolutely by no means inferior to Korean ginseng. In respect to the tissue culture of ginseng, the induction and development of the callus tissue, the solid medium culture, the liquid medium culture and submerged culture of the ginseng callus have already been conducted with success (Zhu, et al., 1979; Li, et al., 1989). It was demonstrated that the ginseng callus masses do contain similar saponin ingredients to that found in the cultivated ginseng root. In addition, the ginseng callus masses showed similar pharmacological activities as that of

OH

Studies on chemical constituents Ginsenosides are the main active constituents of ginseng. Twenty-eight ginsenosides were found from the root, root-stock, stems, leaves, flowers and flower-buds of the ginseng plant (Zhang et al., 1979, 1980; Cai et al., 1982; Kuang et al., 1982;

‘d-u’

R, -0

Fig. 1. The chemical

structures

of.ginsenosides.

Ginsenoside

RI

R2

R3

R4

Ral Ra2

&glc-glc

H H H H H H H H H H H 0-@-glc-rham 0-/3-glc-glc o-p-glc 0-fl-glc-rham H o-p-glc-glc o-p-glc H 0-fl-glc-rham o-p-glc H

W W CHJ CH, CHs CH, W CH, CH, CH, W W

0-/3-glc-ara-xyl 0-fl-glc-ara-xyl o-p-glc-glc o-p-glc-glc 0-@-glc-ara(pyr) 0-&glc-aratpyr) 0-fl-glc-xyltpyr) 0-fl-glc-ara(fur) 0-fl-glc-aratfur) o-13-glc o-&glc o-p-glc OH o-8-glc OH

Rbl Rb 1-COCH,COOH Rb2 RbZ-COCH,COOH Rb3 Rc Rc-COCH&OOH Rd Rd-COCH$OOH Re Rf Rgt Rg2 Rg3 R-20-glc-Rf Rhl 20(S)Rg3 2WWRg2 2OtR)Rhl Rh2 Fl F2 F3 Rsl Rs2

p-glc-glc p-glc-glc &glc-glc-COCH,COOH 8-glc-glc fl-glc-glc-COCH$OOH p-glc-glc p-glc-glc p-glc-glc p-glc-glc p-glc-glc H H H H p-glc-glc H H 8-glc-glc H H P-glc H P-glc H &glc-&-AC fl-glc-&-AC

OH H OH H H

CH3 CH, W

OH CH3 CH3 9

OH OH CJ-‘, ‘W CH, W CH, W

CH, o-p-glc OH OH CH3 CH3

OH o-p-glc o-p-glc 0-B-glc-ara(pyr) 0-@-glc-ara(pyr) 0-@-glc-ara(fur)

30 TABLE 4 THE PHYSIC~HEMICAL Saponins

PARAMETERS

OF GiNSENOSlDES

Molecular formula

m.p. (“C)

Ro Ral

239-41 202-06

Ra2 Rbl Rb2 Rb3

197-8 ZOO-3 193-5

Rc Rd RZO-gl-Rf Re

199-201 206-9 182-4 201-3 197-8 194-6 187-9

Rf Rgl Rg2 20(R)Rhl

214-6

2OWRg2

Shao et at., 1982; Wang et al., 1983; Wang, 1985; Xu et al., 1986; Xu et al., 1986a, 1996b). In addition to ginsenosides, polysaccharides, flavonoids, daucosterin, mucilaginous substances, amino acids, bitter substances, vitamins, choline, pectin, fatty oil and ethereal oil were found in the different parts of ginseng plant (Liu, 197.5; Zhang et al., 1979, 1980; Chen et al., 1983; Wang, 1985; Wang et al., 1986; Chen 1987). ~hemica~ structure and physiochemical parameters of ginsenosides Ginsenosides are tri-terpenoid glycosides of the dammaran series. According to their chemical structure characteristics, they can be divided into three types: oleanolic acid, panaxadiol and panaxatriol types. Ginsenoside Ro is due to oleanolic acid saponin, the other ginsenosides are due to panaxadiol and panaxatriol saponins. The chemical structures of these ginsenosides have been detected by IR, MS, HNMR, ‘%J-NMR and chemical reactions. The chemical structures of 28

Rotation (Co, MeOH)

IR (KBr) (cm-‘)

+15.93(0.91) +14.0(1.00) -2.4(1.10) +12.42(0.91) +3.05(0.98) +19.39(0.98)

3400, 1740, 1728 3360 3400, 1620 3400, 1620 3420, 1620

+ I .93( 1.03) +19.39(1.03) +2l.O(l.OI) - I .OO(1.OO)

3420, 3400, 3420, 3380,

1620 1620 1620 1620

+6.99( I .OO) +32.0 -13.0(1.03) +20.4(0.23) -5.8(0.28)

3380, 3400, 3400, 3370,

1620 1620 1620 1630

3370, 1629

ginsenosides are shown in Fig. 1, the main physiochemical parameters of some ginsenosides are listed in Table 4 (Wang, 1985). The content of ginsenos~des in different parts of ginseng Ginsenosides exist not only in root but also in the other parts such as stems, root-stock, leaves, flowers and flower-buds of the ginseng plant. Zbang et al. compared the content of ginsenosides in different parts of ginseng. The results showed that the total saponins in flower-buds, leaves and root-stock are more than that in the root; panaxadiol and panaxatriol saponins are largest in flower-buds (see Table 5, Zhang et al., 1980). It is suggested that use of the full ginseng plant is worth examining. The relationship between ginsenoside content and years of growth of ginseng The relationship between the growth period and quality of ginseng has been noticed by ginseng

TABLE 5 THE CONTENT Part

Root Root-stock Flower-buds Leaves

OF SAPGNINS IN DIFFERENT

PARTS OF THE GINSENG PLANT

Oleanolic type

Panaxadiol type

Panaxatriol type

Total amount

(“/I

(o/u)

(“A)

VW

1.11 1.14 0.95 1.62

2.19 4.53 5.27 3.00

0.89 1.94 4.69 3.02

4.19 7.61 10.91 7.64

31 TABLE

cal components of polyccharides in cultured cells of Panax ginseng were also almost the same as those in the root of cultivated Panax ginseng. Some differences were found in the ratio among the monosaccharides when the two products were compared (Zhu et al., 1989).

6

THE COMPARISON 2-9-YEAR GROWING

OF SAPONIN GINSENG

Years

Total saponins (%)

2 3 4 5 6 9

I .9-l 2.20 4.75 4.60 3.84 3.81

CONTENT

OF

Ro SW 0.88 I .03 2.27 2.08 1.94 2.32

0.54 0.62 1.10 1.19 0.81 0.46

0.13 0.17 0.40 0.21 0.29 0.40

The minor compounds from ginseng

Early studies revealed that ginseng possesses the biomodulatory effects on the higher centers of the central nervous system, faciliting both physical and mental activities. It has a noteworthy effect on the endocrine system in regulating the blood sugar level as demonstrated in alloxan diabetics. Recent experimental and clinical studies concluded that it has a wide range of effects, such as remarkable anti-shock effect in circulatory failure, modulatory effects on the immune functions, modulation of cellular metabolic processes, modulation of neuroendocrine system activities, improvement of learning and memory processes, and so forth (see Table 8) (Zhou, 1986).

of tissue culture of ginseng

7

COMPARISON

OF GINSENOSIDES

OF TISSUE

CULTURE

WITH CULTIVATED

GINSENG

Sidegenin content (o/o)

Liquid culture Solid culture Cultivated ginseng

of

Studies on pharmacological activities

In order to exploit the source and guarantee the quality of ginseng, China Pharmaceutical University carried out the studies on tissue culture of Panax ginseng. The chemical components of ginsenosides in cultured cells of Panax ginseng were almost the same as those in the root of cultivated Punax ginseng, the difference was found in the ratio among the three kinds of saponins (see Table 7) (Wang et al., 1980). Ginseng poiysaccharides are the active principles which affect immune functions. The chemiTABLE

parts

In 1987, Chen et al. isolated four new minor saponins from the leaves of Panax ginseng on the basis of IR, MS, HNMR, 13C-NMR and chemical evidence. They are 20(R)-protopanaxatriol, duncosterin, ginsenoside Rh3 and 20(R)-ginsenosideRh2 (Chen et al., 1987). The flavonoid constituents isolated from the stems and leaves of Panax ginseng were identified as kaempferol, trifolin and panaxasenoide, respectively, on the basis of chemical and spectroscopic analysis (Wang et al., 1986). Besides ginsenosides and flavanoids, volatile oils were found in ginseng. They are cw-guaiene, crfarnesene, at-santalene, ar-patchoulene, @-farnesene, @-elemene, ~-~rjunene, transcrcaryophyIlene, humulene and eremophilene (Chen et al., 1983).

farmers. It is generally believed that the quality of ginseng growing 5-6 years accords with the demand for medicinal use. Zhang et al. used thin layer chromatography and calorimetric methods for quantitative comparison of saponin contents in ginseng growing for different numbers of years (Zhang et al., 1980). Table 6 shows the differences of total saponins, ginsenoside Rb, Rg and Ro contents. It is clear that the contents of total saponins, ginsenoside Ro, Rb and Rg are highest at 4 or 5 years of growth, lowest at 2 years and reduce after the sixth year. This result suggests that the collecting period detected by ginseng farmers is scientific. The active principles

the d$ferent

Oleanolic acid

Panaxadiol

Panaxatriol

Total amount

0.0699 0.0600 0.205

0.0614 0.138 0.276

0.0359 0.114 0.169

0.167 0.277 0.650

32

TABLE

8

THE CLINICAL AND PHARMACOLOGICAL ACTIVITIES OF GINSENG Anti-stress activity Anti-circulatory shock effects and modulation

of cardiovascu-

lar activities Improvement or facilitation of learning and memory Modulation of neuro-endocrine system activities, hypothalamic-adrenal-gonadal system Modulation of cellular metabolic fat and protein metabolism Promotion of hematopoesis Modulation of immune functions Protection

against

radiation

processes

processes

on carbohydrate,

and liver toxicities

Anti-stress activities and effects on central neurotransmitters. Some original research papers reported that anti-stress activities and effects on central neurotransmitters in hypobaric hypoxia, heatstressed and cold-stressed mice and pithed rats. Anti-hypoxia stress. In order to research the effect of ginseng on antihypoxia and analyse the mechanism of the action, an acute hypoxia due to negative air pressure was performed. The results showed that ginsenosides from the root, stems and leaves could significantly increase the survival in mice in acute hypoxia and could significantly delay the time of survival of cortex electroencephalogram in unanesthetized rats in acute hypoxia. The anti-hypoxia effect is probably related to the effect improving or raising cerebral resistance to hypoxia and reducing cerebral consumption of oxygen in acute hypoxia (Qu et al., 1988). When mice were exposed to hypobaric environment for 5 min, mitochondria of heart and brain cells of mice were seriously damaged and brain neurotransmitters, norepinephrine (NE), dopamine (DA), serotonin (5-HT) and acetylcholine (Ach), were significantly decreased, which were preserved and diminished by ginseng root saponin (GRS) (i.p. 10 mgkg). GRS increased the level of serum corticosterone and prolonged survival time of mice in hypobaric environment, but it had no effect on adrenalectory mice. These evidences indicated that the protective action of GRS on hypobaric hypoxic mice may be related to the action of GRS on pituitary-adrenal gland axis (Lu et al., 1988). GRS markedly prolonged the survival time in normobaric hypoxia stress mice, and revived locomotor activity in mice subjected 15 min hypoxia stress within 60 min (Chen et al., 1988).

Anti-cold and anti-heat stress. When mice were put in -2°C environment for 60 min, the rectal temperature fell significantly while i.g. 50 or 100 mg/kg of GRS caused a slow fall in rectal temperature of mice in the same condition. The contents of brain NE, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) were decreased in mice in -4°C environment for 60 mm, and increased in mice after i.g. GRS 100 mg/kg. But DA showed no change both in cold stress and GRS groups. When rats were put in -2°C for 60 min, the rectal temperature also fell markedly, the plasma corticosterone increased while with i.g. 70 mg/kg of GRS, the rectal temperature showed no change, the brain Ach and plasma corticocterone increased apparently, but there was no change in brain GABA, Glu and Asp (Chen et al., 1988). Mice were exposed to 45°C environment for 15 min. The core body temperature and serum corticosterone increased, brain 5-HT and NE decreased, but brain DA was unchanged. GRS (100 and 200 mg/kg, i.p.) attenuated the increase in body temperature and corticosterone, and the decrease in brain 5-HT and NE, but did not alter brain DA in the stressed mice. GRS decreased body temperature in the unstressed mice as well i.p. injection 25 mg/kg of reserpin abolished the effects of GRS on lowering body temperature in the unstressed and stressed mice. However, PCPA (300 mg/kg, i.p.) only reversed the effect of GRS in the stressed mice, but not in the unstressed mice. These results suggested that the anti-heat stress effects of GRS may be mediated by brain monoamines and HPA system (Yuan et al., 1988). GRS alleviated rectal temperature precipitation fell in mice subjected to hypoxia and did not change the brain Ach concentration (Chen et al., 1988). Effect on neurotransmitters in pithed animals. Zhang et al. found that GRS (30 mg/kg, i.v.) did not affect the pressor response of exogenous NE in pithed rats. However, GRS significantly attenuated the pressor action of NE released by electric stimulation on spinal T7-13. Since yohimbine is a selective prejunctional aZreceptor blocker, it inhibited the presynaptic negative feedback on NE release, yohimbine (0.05 mg/kg, i.v.) augmented the pressor response of spinal electric stimulation, and GRS blunted significantly the augmentation. It is proposed that GRS serves as a presynaptic a2-receptor against, and its hypotensive effect is attributed to the reduction of transmitter release of sympathetic nerves. Its hypotensive effect is ex-

33

plained as a result of less selective action on postsynaptic crl- and possibly aZreceptors in vascular muscles (Zhang et al., 1987). Effects on the circadian rhythm in neurotransmitter release. The circadian levels of NE, DA, 5-HT and 5-HIAA in brain as well as serum corticosterone investigated the influence of GRS on circadian rhythms in mice. The result showed that the levels of brain biogenic amines and serum corticosterone vary diurnally. The 5-HT and 5-HIAA levels of whole brain were elevated during the light phase and decreased to a low level after the onset of darkness. The DA and NE contents were highest during the dark phase. Serum corticosterone showed a concordant circadian rhythm with hypothalamus, 5-HT, GRS i.p. injection altered the levels and circadian pattern brain biogenic amines and serum corticosterone over control values. Serum corticosterone was directly correlated with hypothalamus 5-HT level but inversely correlated with that of NE; however, it was significantly correlated with brain DA level. It seems that GRS selectively modulates the circadian variations of brain 5-HT, 5-HIAA, NE and DA, but as a function of the time of the light-dark cycle (Li et al., 1987, 1988). Cardiovascular pharmacology earlier The studies (1920- 1950) have demonstrated that ginseng possesses a wide range of cardiovascular pharmacological activities including effects on heart, heart rate, blood pressure and vasculature. Recent studies on the cardiovascular system focus on the following aspects. Effect on cardiac performance and hemodynamics. In anesthetized dogs, ginsenosides intravenous injection 25 mglkg caused a significant decrease of AP and dpldtmax of LVP, and slowing of HR, but no alternation in contractility and pump function of the heart as shown by Vce-cpip, SI and CI. As a result of heart rate slowing and LVP reduction, LVWI and tension-time index were reduced, which suggest that the myocardial oxygen consumption is decreased. After intravenous injection of ginsenosides, in contrast with the decrease of femoral vertebral vascular resistance, heightened renal vascular resistance resulted from reduction of renal blood flow. The renal blood flow was also reduced remarkably by intravenous injection of ginsenosides or intravertebral artery, without affecting AP and CO simultaneously. The renal vascular constricting action was not nullified by either a-receptor blockade or 5-HT-receptor blockade (Chen et al., 1982).

Protective action against myocardial infarction. Ginsenosides possess protective action against myocardial infarction. Li et al. reported results indicating that LDH release from myocyte during anoxia and reoxygenation was significantly depressed by 83 mg/ml of ginsenosides. The CPK release from isolated rat heart during reperfusion was significantly reduced by the dose and its component Rb and Ro with 8.3 mg/ml in the infusion solution (Li et al., 1987). Fang et al. considered that the beneficial effect on PGI$TXA2 seems to contribute to the myocardial protective action. In myocardial infarction and reperfusion of dogs, ginsenosides 30 mglkg decreased CPX and TXB2, increased 6-ketoPGF 1, hence increased metabolites of PG12/TXA2 ratio after both coronary occlusion and reperfusion. The result indicated the ginsenosides possess protective effects on myocardial ischemia and reperfusion injury of dogs (Fang et al., 1986). According to the results in the different experiments, it is generally agreed that the protective effect of ginsenosides on myocardial ischemia is related to the following actions: (1) slowing heart rate, reducing oxygen consumption and decreasing peripheral blood vascular resistance; (2) improving myocardial metabolism, correcting sugar and fat metabolic processes; (3) promoting PGr:! release and inhibiting TXA, production; (4) reducing release and inhibiting calcium influx. Besides ginsenosides, ginseng flavonoid influences cardiac performance and hemodynamics. When flavonoid was given as intravenous injection (20 mg/kg) in anesthetized dogs, the myocardial oxygen consumption declined, the dp/dtmax was elevated remarkably, the parameters of CO, PF as well as CI, SI and dp/dt/CPIP did not markedly alter. The decrease of blood pressure was not related to CO, CI and SF, and was induced by dilating peripheral blood vessels (Pan et al., 1986). Effects on noradrenaline and histamine response. In the isolated artery of the rabbit ear, ginsenosides 100 and 300 pg/ml shifted the dose response curve of NA induced artery contraction to the right in a dose related manner. The dose response curve of histamine contraction shifted to the right with 300 &ml and also depressed the maximal contraction, 100 &ml enhanced the electric stimulation induced the H-NA release at both 1 Hz and 3 Hz, similar enhancement occurred in idozoxan 3 x lo-’ mol induced H-NA release. No significant effect on the response to Na in a calcium ion free perfusion solution was shown with 300 pgml. It was concluded that ginsenosides

34

show a prejunctional excitatory effect on Na release and postjunctional inhibitory effect on histamine and NA response which involves interference with calcium influx process (Zhang et al., 1988). Inhibitory effects on platelet aggregation. In the past 20 years, interest in antiplatelet, antithrombotic drugs has burgeoned. The clinical trials have been conducted to evaluate the efficacy of platelet aggregation inhibitors in the prevention of myocardial infarction, stroke, postoperative deep thrombosis, vascular graft occlusion, peripheral arterial disease, etc. Ginsenosides inhibited the rabbit platelet ag-

thrombin, it markedly decreased the production and release of TXBz from the platelets and increased the amount of CAMP in the platelets. The mechanism could be related to the inhibition of TXB2 production and the consequent increase of CAMP in the platelets (Yang et al., 1988). (3) The inhibition of prostacyclin (PGI,) production. The study on effects of ginseng saponins on Carachidonic acid metabolism in rabbit platelets indicated that the ginsenosides blocked the biosynthesis of platelet PG12 production (see Table 9, Shen et al., 1987). The mechanism of action was shown to be inhibition of both cyclooxygenase and thromboxane synthetase activities.

gregation induced by adenosine diphosphate (ADP), arachidonic acid (AA), collegen and thrombin in vitro and in vivo. This effect was demonstrated in different tests (Shen et al., 1987; MO et al., 1988; Yang et al., 1988). The mechanism of action of ginsenosides has been investigated, and while not completely understood, a number of observations have been made. The inhibitory action may be demonstrated to be the following three pathways: (1) The rise of platelet cyclic adenosine monophosphatase (CAMP) level may be of the mechanism of the inhibitory one effect on platelet aggregation. The CAMP level in platelets pretreated with ginsenosides was elevated markedly. The further study found that ginsenosides stimulated adenylate cyclase in platelet membrane and inhibited the activity of phosphodiesterase (PDE) of platelet. These findings may interpret the elevation of the CAMP level in platelets (MO et al., 1988). (2) The decrease of production and release of TXB2. ADP, AA and collagen induced the production of a considerable amount of TXB2 and reduced the CAMP level in platelets. Ginsenosides inhibited the platelet aggregation induced by ADP, AA, collagen and

Modulation of metabolic processes Ginsenosides induce a significant increase of serum corticosterone and decrease of liver glycogen, they exhibited highly stimulating effects on the synthesis of kidney DNA and RNA in mice. It suggests that ginsenosides have an analogic effect (Li et al., 1988). An investigation found that ginsenosides influence the circadian variation on plasma corticosterone and liver glycogen in rats. The circadian rhythm may be an important factor in pharmacological response to ginseng saponins (Li et al., 1987). Ginseng saponins can stimulate the synthesis of RNA, DNA and protein if the administration is prolonged, it is also a possible physiological basis for the anti-fatigue property (Zhang et al., 1986).

TABLE

Modulation of immune functions Polysaccharides of ginseng root were found to be able to markedly stimulate phagocytosis of the reticuloendothelial system and the production of antibody. They caused an increase of serum complement content in guinea pigs, and raised serum IgG level in mice and increased B-lymphatic to Tlymphtic cell ratio (Wang et al., 1980).

9

THE EFFECTS OF GINSENOSIDES “C-ARACHIDONIC ACID Ginsenosides mg/ml

ON THE PRODUCTION

TXB, production

ratio

6.83 2.18 1.05 0.64 24.8

PGlz production

ratio

(‘%a)

(‘K) 0.25 0.5 1.0 2.0 Control (Tris 0.05 M/I)

OF TXB, AND

f 2.99 zt 0.35 f 0.18 l 0.19 f 3.49

1.00 1.01 1.26 1.20 2.81

f 0.25 f 0.13 f 0.39 l 0.45 f 1.10

PGI,

AND THE UTILIZATION

AA utilization W) 91.58 89.00 63.80 44.30 97.10

l

f f zt f

ratio

1.64 3.08 6.21 6.12 4.54

OF

35

The two polysaccharides from tissue culture of ginseng and from cultivated ginseng root have the same effect on immune functions. The two polysaccharides with 20 and 40 mg/kg intravenous injection caused marked increase of spleen weight and enhanced the clearance rate of charcoal particles in mice. The two polysaccharides also significantly promoted the production of serum specific antibody hemolysins in mice and the IgG level. They also enhanced DTH of footpad induced by SRBL in mice, but they had no effect on GVHR in mice (Li et al., 1982). The numbers of plaque forming cells (PFC) and specific rosette forming cells (SRFC) in tumor bearing mice immunized with SRBC were markedly increased after oral administration of ginseng polysaccharides 400-800 mg/kg for 10 days. both serum Polysaccharides also increased hemolysin and SRBC hemolysis mediated by quantitative spleen cells in vitro. In normal mice, however, there were no significant changes in these immunological parameters. These results indicated that the inhibition effect to tumor may be related to immunological reaction in host (Qian et al., 1987).

(6) (10)

R.&W, R.H,

d-R

25-hyroxy-20(S)-Rh,

25-hyroxy-2O(S)-PPT

Fig. 2. Biotransformation

(Bj (12)

R-gEy R-H,

2Z;~YrOXY-ZO(R)25-hY:oXY-LO(R)-FPT

of ginsenoside 20(S)-Rg,.

Nootropic pharmacology

Ginsenoside Rgl and Rbl are nootropic principles of ginseng (Zhang, 1989; Liu, 1988). The two substances improve memory and learning in normal animals and in animals whose cognitive functions are impaired. The mechanism is multiplicity in biological effects: (1) Rgl and Rbl influence brain cholinergic mechanism, increase the synthesis and release of AcH; (2) decrease 5-HT level in brain; (3) promote nucleotide and protein metabolism in brain; (4) decrease and clear oxygen free radical. Therefore, there is some reason to conclude that ginseng can be a nootropic drug in nootropic and anti-ageing therapy. Studies on metabolism and pharmacokinetics

Up to now, metabolism and pharmacokinetics of ginsenosides and other constituents of ginseng were found in a few reports in China. Chen et al. studied the biotransformation of ginsenoside 20(S)-Rg2 which is one of main constituents in the root and leaves of ginseng (Chen et al., 1987) and Huo et al. studied the pharmacokinetics of ginsenoside Rgl (Huo et al., 1986). Biotransformation

In stomach, unstable 20(S)-Rg2 was transformed into stable 20(S)-Rg2(3) and a hydronium

reaction occurred in A24 to change into 25hydroxy-20(S)-Rg2 and 25-hydroxy-20(R)RG2 (2 and 4). In the intestine, 20(S)-Rg2 and its metabolites, (2), (3) and (4), continue biotransformation. 20(S)-Rg2 was hydrolyzed to change into 20(S)-Rhl(5) and 20(S)-portopanaxatriol (20(s)PPT, (9)), 20(R)-Rg2 into 20(R)-Rhl(7) and 20(R)portopanaxatriol (20(R)-PPT, (11)); 25-hydroxy20(S)-Rg2 was hydrolyzed to change into 25hydroxy-20(R)-RH l(6) and 25-hydroxy-20(S)PPT( lo), and 25-hydroxy-20(R)-Rg2 into 25hydroxy-20(R)-Rh l(8) and 25-hydroxy-20(R)PPT(12). The result (Fig. 2) indicates that the biotransformation of ginsenosides is very complex. It seems that understanding about the biotransformation pathways of all constituents of ginseng will be quite difficult. Pharmacokinetics

After intravenous injection of 3H-ginsenoside Rgl in mice, a tri-phasic decline in blood radioactivity was observed. The pharmacokinetic parameters are listed in Table 10. The blood radioactivity following oral administration of 3HRgl peaked at 2.1 h. The peak level was 489053 dpm, the area under the concentration-time curve

36 TABLE 10 PHARMACOKINETIC PARAMETERS OF 3H-GINSENOSIDE RG, AFTER INTRAVENOUS ADMINISTRATION IN MICE Parameter

Unit

Value

K12 K13 KlO K21 K31

h-’ h-’ h-’ h-’ h-’ h h h l/kg l/kg l/kg.h dprn/ml per h

5.2 13.0 0.18 4.0 0.31 0.069 0.87 25.0 44.0 6.1 122.0 311.0

Tin TV2 Tu2

Vd vc CL AUC

was 151. The absolute bioavailability (F) calculated from whole blood radioactivity following oral and intravenous administration was 49%. Studies on the tissue distribution of 3H-Rgl indicated that the radioactivity was decreased with the following order: kidney, adrenal gland, liver, lungs, spleen, pancreas, heart, testes and brain. The protein binding was 24% in plasma, 48% in liver, 22% in testes and 8% in brain, Preparations and application

According to theory and prescription principle of Chinese traditional medicine, ginseng is applied to many prescription formulations and Chinese patent medicines. A great number of prescription formulations and preparations containing ginseng have been used clinically for a long time. A number of preparations have been officially ap-

TABLE 11 SOME GINSENG PREPARATIONS

AND PATENT MEDICINES CONTAINING

GINSENG

Drug Name

Actions and Indications

Ginseng royal jelly

This preparation is a tonic which has the effects on invigorating the physical energy, benefiting the vital energy, relieving uneasiness of body and mind and nourishing the liver and spleen. It is used for the treatment of poor appetite, neurasihenia, debility, hair rarelication, hepatitis, rhemarthritis, gastric ulcer etc.

Ginseng pilose antler life preserving pills

This robora is a remedy to strengthen the body and internal organs. It is used for weariness of limbs and back marasmus, loss of appetite, amnesia, insomnia, vertigo, night sweat, anemia, premature senility, impotency in the male and flooding and leucorrhea in the female.

Ginseng antler pills

Improving health and mental functions, invigorating the bodily constitution. The indications are debility and anemia, lassitude of limbs, pale complexion, anemia, nocturnal emission, cardiasthenia dyspepsia, vertigo, night sweat, vague pains in the loin and legs, general weakness.

Blood circulation activating pills

This remedy relaxes sinews, stimulates blood circulation and expels rheumatism. The indications are overall numbness, rheumatic paralysis, muscular pain, facial convulsion, hemiplegia, cramps, backache, stiff neck and dysphesia.

Heart strengthening remedy pills

Cardial stimulant and nerve soothing. It is used for lassitude, dizziness, ringing in ears, state of uneasiness, palpitation and shortness of breath, insomnia and poor memory.

Ginseng stomachic pills

This drug is used to strengthen the functioning of the spleen and stomach and regulate the flow of vital energy, for the treatment of weakness of the spleen and stomach with symptoms such as emaciation, feeble limbs, loss of appetite, alternate diarrhea and constipation.

Ginseng restorative pills

This drug is used for apoplectic coma and hemiplegia by dispelling windphlegm and promoting blood circulation.

Mind~asing tonic pills

This drug is used to calm the nerves by nourishing the blood of the heart, for the treatment of neurasthenia with restlessness, insomnia forgetfulness etc.

37

proved and produced for therapeutic use in China. Table 11 lists some preparations and their actions and indications (Xie et al., 1982; Han et al., 1985; Liu, 1989). In addition to the above well-known ginseng preparations, tablets, oral liquid etc., are used for therapeutic use. Administration of ginseng tablets increases the resistance to the adverse effect of antineoplastic medicines and protects the blood formation system. In 229 cases, the duration of the course of treatment was 30 days with ginseng tablets, the efficiency raising the WBC was 64.6% (Xue, 1986). A decoction of ginseng can improve brain function and immune function in 127 cases of old age patients with cancer (MO, 1987). Prostisol, an active fraction of ginseng root, is antitumor agent, possesses therapeutic effect on some tumors in clinical trials (Liu, 1976). Although some chemical constituents of ginseng with different pharmacological activities were isolated from different parts of Panax ginseng, these constituents were not widely applied clinically. In general, the wide range of therapeutic actions of ginseng are mainly produced by multiple constituents and no single chemical constituent. Therefore, for the reasonable utilization of these chemical compositions, we make great efforts to investigate their therapeutic value.

Cai, P.L., Xu, G.D. and Gu, R.Q. (1982) Isolation and identification of ginsenosides in the leaves of Jilin ginseng. Pharmaceutical

Bulletin

I I, 500.

Chen, X., Zhu, Q.Y., Li, L.Y. and Tang, X.L. (1982) Effect of ginsenosides on cardiac performance and hemodynamics of dogs. Acra Pharmacologica Sinica 3, 235-239. Chen, X. (1983) Protective and FFA metabolic effect of ginsenosides on myocardial ischemia. Journal of Medical Cell and Cardiology 25, 12 I- 123. Chen, Y.J., Liu, Y.L., Lin, G.F. and Luo, X.T. (1986) Effects of ginseng root saponins on central transmitters and plasma corticosterone in warm stress rats. Acra Pharmacologica Sinica 7, 6-8.

Chen, Y.J., Huang, Z.. Li, N.P., Cheng. G.R., Cao. S.L. and Zhang, Q.R. (1983) Studies on chemical constituents of ginseng. Journal of Shengyang College of Pharmacy 3 (3), 39-44.

Chen, Y.J., Su, S.X., Ma, Q.F., Pei, Y.P., Xie, H. and Yao. X.S. (1987) Studies on new minor saponins isolated from leaves of Panax

ginseng

CA.

Meyer.

Acra

Pharmaceutics

Sinica 22, 685-689.

Chen, Y.J. (1987) Studies on the metabolites of 20(s)ginsenoside Rg2. Journal ofshengyang College of Pharmacy 4 (3), 202-203.

Cheng, X.J., Liu, Y.L., Lin, G.F. and Luo, X.T. (1986) Comparison of action of Panax ginsenosides and Panax quinquonosides on anti-warm stress in mice. Journal o/ Shengyang

Acta Pharmacologica

College of Pharmacy

3 (3).

170-I 72.

Sinica 8, 486-489.

Cheng, X.J., Shi, X.R. and Lin, B. (1988) Effects of ginseng root saponins on brain Ach and serum corticosterone in normobaric hypoxia stress mice. 5th Southeast Asian and Western

Pacific

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Meeting

of

Pharmacologists.

Chinese Pharmacological Association, Beijing, pp. ~31.05. Fang, Y.X., Shen, N. and Chen, X. (1986) Beneficial changes in prostacyclin and thromboxane A2 by ginsenosides in myocardial infarction and reperfusion of dogs. Acra Pharmacologica

Sinica 7, 226-230.

Han, C.Q.. Fan, Z.Q. and Li, G.S. (1985) Tianjin Chinese Pafent Medicines. Tianjin. Huo, Y.S., Zhang, S.C., Zhuo, D., Yao, D.L., You, G.Y., Zhang, H.W., Ma, Q.Z., Gong, B. and Yi, M.G. (1986) Pharmacokinetics and tissue distribution of ‘H-ginsenoside RGI. Acta Pharmacologica Sinica 7, 519-521. J.W. and Xiao, Q.S. (1985) Handbook of Active constiPlants. People’s Health Publishers, Beijing. pp. 503-516. Kuang, H.X. and Xu, G.D. (1982) Separation and identitica-

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Li, J.C., Li, Y.P. and Xue, L.S. (1988) Influence of ginseng saponins on the circadian rhythm in brain monoamine 5th Southeast

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