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The effect of ginseng extract on locomotor sensitization and conditioned place preference induced by methamphetamine and cocaine in mice.

Repeated i.p. injections of 2 mg/kg methamphetamine (MA) or 20 mg/kg cocaine at 48-h intervals induced reverse tolerance to their ambulation-enhancing effects (behavioral sensitization). Furthermore, the reappearance of the sensitized state was observed at the time of readministration of MA or cocaine even after a 30-day discontinuation of drug administration. A concomitant injection of ginseng extract (GE), 200 mg/kg, i.p., suppressed the development of reverse tolerance and the reappearance of sensitization to MA and cocaine. Conditioned place preference to MA (1, 2, and 4 mg/kg, i.p.) and cocaine (1, 4, 10, and 20 mg/kg, i.p.), was completely blocked by GE, 200 mg/kg, i.p. combined treatment with MA of cocaine. Meanwhile, spontaneous motor activity and place preference were not affected by GE alone. These results provide evidence that GE may be useful clinically for the prevention of adverse actions of MA and cocaine.

Animals↗

Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice.

1. Ginseng total saponin (GTS), 200 mg/kg i.p. 3 hr prior to morphine, inhibited the development of reverse tolerance to the ambulatory-accelerating effect of morphine. 2. GTS, 200 mg/kg, also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of morphine, 10 mg/kg a day for 7 days. 3. These results suggest that GTS may be useful for the prevention and therapy of the adverse action of morphine.

Animals↗

Blockade by ginseng total saponin of methamphetamine-induced hyperactivity and conditioned place preference in mice.

Ginseng total saponin (GTS) inhibited methamphetamine-induced hyperactivity and conditioned place preference (CPP). Dopamine (DA) receptor supersensitivity was developed in methamphetamine-induced CPP mice and it was inhibited by GTS. GTS also inhibited apomorphine-induced climbing behavior, showing the antidopaminergic activity of GTS. These results suggest that GTS inhibition of the methamphetamine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by methamphetamine.

Animals↗

A double-blind, placebo-controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers.

Various tests of psychomotor performance were carried out in a group of 16 healthy male volunteers given a standardized preparation of Korean ginseng (G 115; 100 mg twice a day for 12 weeks) and in a similar group given identical placebo capsules under double-blind conditions. A favourable effect of G 115 relative to baseline performance was observed in attention (cancellation test), processing (mental arithmetic, logical deduction), integrated sensory-motor function (choice reaction time) and auditory reaction time. However, end performance of the G 115 group was superior statistically to the placebo group only in mental arithmetic. No difference between G 115 and placebo was found in tests of pure motor function (tapping test), recognition (digit symbol substitution) and visual reaction time. No adverse effects were reported. It is concluded that G 115 may be superior to placebo in improving certain psychomotor functions in healthy subjects.

Adult↗

Cytoprotective activity of pectic polysaccharides from the root of panax ginseng.

An acidic polysaccharide fraction, GRA-4, of the root extract of Panax ginseng, when administered from 50 to 200 mg/kg orally, inhibited gastric lesions induced by HCl-ethanol or absolute ethanol, in a dose-dependent manner. The cytoprotective activity of GRA-4 decreased after its treatment with periodate but not after protein digestion, indicating that the carbohydrate moiety of this acidic polysaccharide contributes to this activity.

Administration, Oral↗

Effect of non-saponin fraction from Panax ginseng on cGMP and thromboxane A2 in human platelet aggregation.

The non-saponin fraction (NSF; lipophilic fraction) from the roots of Panax ginseng inhibited the aggregation of human platelets induced by thrombin (0.1 units/ml) in a dose-dependent manner. NSF induced the elevation of cGMP concentration in human platelets in a similar manner to molsidomine, a known vasodilator. NSF also inhibited Ca(2+)-influx into platelets. While verapamil, a Ca(2+)-antagonist, increased the cAMP level in platelets stimulated by thrombin, NSF had little effect on cAMP formation. Instead, NSF potently inhibited the thromboxane A2 (TXA2) production. The results suggest that NSF may regulate the levels of cGMP and TXA2 to inhibit platelet aggregation induced by thrombin.

Alkynes↗

Effects of Siberian ginseng (Eleutherococcus senticosus maxim.) on elderly quality of life: a randomized clinical trial.

An unspecific feeling of fatigue and asthenia often pushes elderly patients to require any form of help even from non medically trained people. Traditional Chinese medicine suggest that Siberian ginseng could act as safe "adaptogenic" substance. Our aim was thus to test the effect of a middle term Eleutherococcus senticosus Maxim. (Araliaceae) administration on elderly, health related quality of life (HRQOL). 20 elderly hypertensive and digitalized volunteers (age >/= 65 years) were randomized in a double -blind manner to E. senticosus dry extract 300 mg/day (n = 10) or placebo (n = 10) for 8 weeks. The short form-36 health survey version 2 (SF-36v2), a validated general health status questionnaire, was used to access HRQOL at baseline and at 4 and 8 weeks. There were no significant differences in baseline demographics and SF-36v2 scores between the groups. At each visit, controls of digitalemia and blood pressure level were carried out. After 4 weeks of therapy, higher scores in social functioning (p = 0.02) scales were observed in patients randomized to E. senticosus; these differences did not persist to the 8-week time point. No adverse event has been observed in both groups of patients. No significant difference in both blood pressure control and digitalemia was observed in both treatment groups. Subjects give E. senticosus (70%) were more likely to state that they received active therapy than subjects given placebo (20%; p < 0.05). In conclusion, E. senticosus safely improves some aspects of mental health and social functioning after 4 weeks of therapy, although these differences attenuate with continued use.

Aged↗

Panax ginseng C.A. Mayer G115 modulates pro-inflammatory cytokine production in mice throughout the increase of macrophage toll-like receptor 4 expression during physical stress.

The effect of Panax ginseng C.A. Meyer G115 on inflammatory cytokine production and toll-like receptor 4 (TLR4) RNA expression was examined in mice during 4 weeks of swimming stress. Mice were assigned to four groups: (1) control (no exercise); (2) control-G115 (25 mg/kg/day p.o.); (3) stress (kept swimming for 60 min daily); and (4) stress-G115 (25 mg/kg/day p.o. and kept swimming for 60 min daily). Peritoneal macrophages were collected at rest each week. RNA was extracted and processed for real-time PCR. An aliquot of macrophages was lipopolysaccharide (LPS)-stimulated for TNF-alpha and IL-1beta production. Different expression patterns between untreated and treated groups, and between TLR2 and TLR4 were found. High levels of TLR4 expression in the control-G115 group were detectable significantly at the first, and at the second week (P<.01 and P<.001, respectively). In the stress group, TLR4 showed a peak at the first week (P<.001 vs. controls) and then decreased gradually. In the stress-G115 group, the levels of TLR4 expression increased gradually at the second week (P<.001 vs. controls) with a peak at the third week (P<.001). Levels of TLR4 expression at the fourth week had returned to the basal level. Levels of TLR2 expression were not affected by treatment in all groups. A significant increase of LPS-stimulated IL-1beta and TNF-alpha concentrations was present in trained animals with similar patterns of TLR4 expression. These results support the hypothesis that enhancement of the production of pro-inflammatory cytokine can be linked to an increased expression of TLR4 on macrophages. Moreover, G115 increases the expression of TLR4 and the release of cytokines with a different pattern compared to the stressed alone group.

Analysis of Variance↗

Inhibitory effects of Pfaffia paniculata (Brazilian ginseng) on preneoplastic and neoplastic lesions in a mouse hepatocarcinogenesis model.

Studies have been demonstrating Pfaffia paniculata root (Brazilian ginseng) anticarcinogenic activities. We evaluated its chemopreventive effects on preneoplastic hepatic lesions. BALB/c aged-15 days received 10mug/g of diethylnitrosamine carcinogen, i.p. They were fed with the powdered root added to the diet: 0.5, 2 or 10% during 27 weeks. After being sacrificed, the macroscopic lesions in the livers were examined. Preneoplastic or neoplastic lesions were measured, quantified and classified morphologically. The treatment reduced the incidence, mean area and number of lesions, indicating an inhibitory effect of these roots on hepatocarcinogenesis promotion or progression steps.

Adenoma↗

Natural products from ginseng inhibit [3H]batrachotoxinin A 20-alpha-benzoate binding to Na+ channels in mammalian brain.

A [(3)H]batrachotoxinin A-20alpha-benzoate ([(3)H]BTX-B) binding assay was used to investigate the interaction of two ginseng aglycones (20(S)protopanaxadiol and 20(S)protopanaxatriol) and Rh(2) (a monoglucoside of 20(S)protopanaxadiol) with voltage-gated sodium channels in mouse brain. All compounds inhibited the binding of [(3)H]BTX-B and IC(50)s were established at 42 microM (20(S)protopanaxadiol), 79 microM (20(S)protopanaxatriol) and 162 microM (Rh(2)). Scatchard analysis confirmed that 20(S)protopanaxadiol and Rh-2 reduced the B(max) of [(3)H]BTX-B binding while Rh(2) also increased the K(d). At IC(50) concentrations and above, 20(S)protopanaxadiol and Rh(2) increased the dissociation of the [(3)H]BTX-B:sodium channel complex above that produced by a saturating concentration of veratridine, but failed to reduce the rate of association of [(3)H]BTX-B with sodium channels. Reversal of the inhibition of [(3)H]BTX-B binding by 20(S)protopanaxadiol and Rh(2) occurred slowly. We conclude that the 20(S)protopanaxadiol and the less potent inhibitor Rh(2) destabilize BTX-B-activated sodium channels through non-covalent allosteric modification of neurotoxin binding site 2.

Animals↗

20(S)-ginsenoside Rh2, a newly identified active ingredient of ginseng, inhibits NMDA receptors in cultured rat hippocampal neurons.

Most herbal medicines that are orally administrated have been known to be metabolized before they are absorbed from the gastrointestinal tract. We, therefore, examined the effects of 20(S)-ginsenosides Rb1, Rg1 and Rg3, the three most commonly studied ginsenosides in the central nervous system, and their main metabolites on NMDA receptors using fura-2-based digital imaging and perforated whole-cell patch-clamp techniques. Among the nine ginsenosides tested, 20(S)-ginsenoside Rh2 (20(S)-Rh2) along with 20(S)-ginsenoside Rg3 (20(S)-Rg3) produced the highest inhibitory effect in cultured hippocampal neurons. Although 20(S)-Rg3 and 20(S)-Rh2 selectively targeted NMDA receptors with similar potency, they produced additive effects and seemed to modulate different NMDA receptor regulatory sites. As a competitive antagonist, 20(S)-Rh2 seems to inhibit the receptor via its interaction with polyamine-binding sites, and 20(S)-Rg3 does so using glycine-binding sites. Therefore, these results suggest that the treatment of 20(S)-Rh2, a newly identified active ingredient of ginseng, might be a novel preventive candidate in treating neurodegenerative disorders.

Animals↗

Ginsenoside Re of Panax ginseng possesses significant antioxidant and antihyperlipidemic efficacies in streptozotocin-induced diabetic rats.

Diabetes mellitus is characterized by hyperglycemia and complications affecting the eye, kidney, nerve and blood vessel. We have previously demonstrated the occurrence of oxidative stress of streptozotocin-induced diabetic rats, preceded by a depletion in the tissue level of glutathione. In this study, when diabetic rats were treated with ginsenoside Re of Panax ginseng C.A. Meyer, there was a significant reduction in blood glucose, total cholesterol and triglyceride levels. On the other hand, oxidative stress has been implicated in the pathogenesis of diabetes and its complications. It was found that treatment by ginsenoside Re restored the levels of both glutathione and malondialdehyde in the eye and kidney to those found in the control rats. This is the first report demonstrating ginsenoside Re has significant antioxidant efficacy in diabetes, and prevents the onset of oxidative stress in some vascular tissues. Our results demonstrated that ginsenoside Re could lower blood glucose and lipid levels, and exerts protective actions against the occurrence of oxidative stress in the eye and kidney of diabetic rats. Our data also provide evidence that ginsenoside Re could be used as an effective antidiabetic agent particularly in the prevention of diabetic microvasculopathy.

Animals↗

Chronic pretreatment with American ginseng berry and its polyphenolic constituents attenuate oxidant stress in cardiomyocytes.

The acute anti-oxidant and protective effect of American ginseng berry extract (AGBE) has been demonstrated in cultured cardiomyocytes in our previous study. In the current study we evaluated if a chronic pretreatment of cultured cardiomyocytes with AGBE can alter the cellular antioxidant potential. Chick embryo cardiomyocytes were treated with AGBE (0.5-2.5 mg/ml) for up to 72 h. The treated cells were then exposed to exogenously added hydrogen peroxide (H(2)O(2); 500 microM). The oxidant-mediated injury was measured using a fluorescent probe 2',7'-dichlorofluorescin diacetate (DCFH/DA) while cell death was measured using propidium iodide (PI) staining. The non-treated (control) cells exposed to H(2)O(2) showed significant increase in DCF- and PI-mediated fluorescence suggesting significant oxidative injury and cell death. Pretreatment with AGBE demonstrated a significant attenuation of DCF fluorescence (p<0.005) with AGBE 0.5 mg/ml showing a 17% decrease, AGBE 1.0 mg/ml showing a 26% decrease, and AGBE 2.5 mg/ml showing a 49% decrease from control DCF fluorescence following a 72 h pretreatment. Cell death caused by H(2)O(2) was also significantly attenuated in AGBE-pretreated cells in a concentration- and time-dependent manner (p<0.005). We also demonstrated that active polyphenolic constituents in AGBE, caffeic acid and chlorogenic acid, appear to contribute significantly to AGBE's protective effects. Finally, catalase inhibition resulted in a significantly increased fluorescence in AGBE-treated cells compared to the control. The results suggest that pretreatment with AGBE upregulates peroxide detoxifying mechanisms, which could affect intracellular oxidant dynamics in cardiomyocytes.

Animals↗

Antimutagenic effect of polysaccharide ginsan extracted from Panax ginseng.

Ginsan is a polysaccharide extracted from the roots of Panax ginseng, and it has earlier been reported to have an immunostimulatory effect. In the present study, the frequency of micronucleated polychromatic erythrocytes (MNPCE) was assessed in the bone marrow of C57BL/6 male mice treated with ginsan [100, 200 or 300 mg/kg body weight (b.w.)] or amifostine (200mg/kg b.w.) 30 min before as well as 15 min after 1.5 Gy of gamma-irradiation. Ginsan and amifostine did not alter the frequency of MNPCE of control mice (P>0.05), showing that they are non-mutagenic per se; gamma-irradiation induced a statistically significant (P<0.001) increase of MNPCE and decrease of PCE/NCE ratio (P<0.001) compared to control group. However, ginsan applied 30 min before or 15 min after irradiation reduced MNPCE in a dose-dependent manner. Amifostine (200mg/kg b.w.) did not reduce radiation-induced MNPCE, but stimulated erythropoiesis, when administered before irradiation. Based on the above results, radioprotective effect of ginsan can be partially attributed to reduction of radiation-induced genotoxicity.

Amifostine↗

Role of Korean red ginseng total saponins in rat infertility induced by polycystic ovaries.

OBJECTIVE: To investigate the effect of Korean red ginseng total saponins (GTS) on ovarian morphology and nerve growth factor (NGF) expression in the ovaries, pituitary, and hippocampus. DESIGN: Polycystic ovary (PCO) rat model induced by estradiol valerate (EV). SETTING: University research laboratory. PATIENT(S): Thirty sexually mature female Sprague-Dawley rats weighing 190-210 g. INTERVENTION(S): Female Sprague-Dawley rats (190-210 g) were separated into three groups: EV control (n = 10), EV plus GTS (n = 10), and oil control (n = 10). MAIN OUTCOME MEASURE(S): Ovarian morphology and NGF protein expression. RESULT(S): Polycystic ovary was fully developed in rats with a single intramuscular injection of EV. Increased expression of NGF was noted in the ovaries and the brain of rats with PCO. GTS administration attenuated NGF expression in the ovaries but not in the brain. CONCLUSION(S): Our findings suggest a role for GTS in the regulation of NGF expression in female rats with PCO.

Animals↗

Physicochemical characteristics and bioavailability of a novel intestinal metabolite of ginseng saponin (IH901) complexed with beta-cyclodextrin.

In an effort to improve the bioavailability (BA) of the insoluble compound 20-O-(beta-d-glucopyranosyl)-20(S)-protopanaxadiol (IH901), we prepared beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) inclusion complexes containing IH901. IH901 is a major metabolite formed by intestinal bacteria from protopanaxadiol ginseng saponins. We developed and validated an HPLC-based method to measure IH901 levels from samples prepared in vitro. The phase solubility profiles with both cyclodextrins (CDs) were classified as AL-type, indicating the formation of a 1:1 stoichiometric inclusion complex. Stability constants (Ks) calculated from the phase solubility diagrams showed that the betaCD complex was more stable than the HPbetaCD complex. Consequently, complexes of IH901 and betaCD were prepared by a freeze-drying method and were analyzed by fourier transformation-infrared spectroscopy (FT-IR), X-ray diffraction, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). From these physicochemical characterizations, we confirmed the presence of a new solid phase in the freeze-dried samples. The IH901 released from the complex in a pH 1.2 solution, the pH range of gastric fluids, was considerably lower than the amount released in the other solutions. The IH901 released from the complex in pH 6.8 solution, the range of intestinal fluids, was 9.0-fold greater than pure IH901 powder. However, the amount of IH901 released from the complex in pH 4.0-8.0 was less than 20%. After oral administration of the IH901-betaCD inclusion complex (30 mg/kg IH901) into rats, plasma concentrations were determined by LC/MS/MS. The peak concentration (Cmax) for the inclusion complex was 2.8-fold higher than that for pure IH901 powder. The BA, calculated from the ratio of the AUCoral to the AUCi.v., for the pure IH901 powder, the IH901-betaCD physical mixture, and the inclusion complex was 3.52, 4.34, and 6.57%, respectively. These results indicate that the BA for the inclusion complex was 1.9-fold higher than that for the pure IH901 powder.

Administration, Oral↗

Stability of angiogenic agents, ginsenoside Rg1 and Re, isolated from Panax ginseng: in vitro and in vivo studies.

The study was designed to investigate the stability of ginsenoside Rg(1) (Rg(1)) and Re (Re), two natural herbal compounds isolated from Panax ginseng, based on their activity to promote angiogenesis in vitro and in vivo. After being treated at different temperatures, pHs, and solvent species for distinct durations, the remaining activities of Rg(1) and Re on human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation were examined in vitro. Additionally, the remaining activity of each treated test agent, mixed in a growth factor-reduced Matrigel, in stimulating angiogenesis was evaluated subcutaneously in a mouse model. Basic fibroblast growth factor (bFGF) was used as a control. It was found in vitro that HUVEC proliferation, migration in a Transwell plate, and tube formation on Matrigel were all significantly enhanced in the presence of bFGF, Rg(1), or Re. However, after being treated at different temperatures, pHs, or solvent species, the remaining activity of bFGF on HUVEC behaviors reduced significantly. This observation was more significant with increasing the duration of treatment. In contrast, the activities of Rg(1) and Re remained unchanged throughout the entire course of the study. The in vivo results observed on day 7 after implantation showed that the blank control (Matrigel alone) was slightly vascularized. In contrast, the density of neo-vessels in the Matrigel plug mixed with bFGF, Rg(1), or Re was significantly enhanced. However, after being treated, the density of neo-vessels was significantly reduced in the Matrigel plug mixed with bFGF, while those of Rg(1) and Re remained unchanged. The aforementioned results suggested that Rg(1) and Re could be a novel group of nonpeptide angiogenic agents with a superior stability and may be used for the management of tissue regeneration.

Angiogenesis Inducing Agents↗

Mass production of somatic embryos expressing Escherichia coli heat-labile enterotoxin B subunit in Siberian ginseng.

The B subunit of Escherichia coli heat-labile toxin (LTB) is a potent mucosal immunogen and immunoadjuvant for co-administered antigens. In order to produce large scale of LTB for the development of edible vaccine, we used transgenic somatic embryos of Siberian ginseng, which is known as medicinal plant. When transgenic somatic embryos were cultured in 130L air-lift type bioreactor, they were developed to mature somatic embryos through somatic embryogenesis and contained approximately 0.36% LTB of the total soluble protein. Enzyme-linked immunosorbent assay indicated that the somatic embryo-synthesized LTB protein bound specifically to GM1-ganglioside, suggesting the LTB subunits formed active pentamers. Therefore, the use of the bioreactor system for expression of LTB proteins in somatic embryos allows for continuous mass production in a short-term period.

Adjuvants, Immunologic↗