Ji An Wu

GINSENG PHARMACOLOGY: MULTIPLE CONSTITUENTS AND MULTIPLE ACTIONS

Ginseng is a highly valued herb in the Far East and has gained popularity in the West during the last decade. There is extensive literature on the beneficial effects of ginseng and its constituents. The major active components of ginseng are ginsenosides, a diverse group of steroidal saponins, which demonstrate the ability to target a myriad of tissues, producing an array of pharmacological responses. However, many mechanisms of ginsenoside activity still remain unknown. Since ginsenosides and other constituents of ginseng produce effects that are different from one another, and a single ginsenoside initiates multiple actions in the same tissue, the overall pharmacology of ginseng is complex. The ability of ginsenosides to independently target multireceptor systems at the plasma membrane, as well as to activate intracellular steroid receptors, may explain some pharmacological effects. This commentary aims to review selected effects of ginseng and ginsenosides and describe their possible modes of action. Structural variability of ginsenosides, structural and functional relationship to steroids, and potential targets of action are discussed.

Anti-hyperglycemic effects of ginseng: Comparison between root and berry

Previous studies demonstrated that both ginseng root and ginseng berry possess anti-diabetic activity. However, a direct comparison between the root and the berry under the same experimental conditions has not been conducted. In the present study, we compared anti-hyperglycemic effect between Panax ginseng root and Panax ginseng berry in ob/ob mice, which exhibit profound obesity and hyperglycemia that phenotypically resemble human type-2 diabetes. We observed that ob/ob mice had high baseline glucose levels (195 mg/dl). Ginseng root extract (150 mg/kg body wt.) and ginseng berry extract (150 mg/kg body wt.) significantly decreased fasting blood glucose to 143 +/- 9.3 mg/dl and 150 +/- 9.5 mg/dl on day 5, respectively (both P < 0.01 compared with the vehicle). On day 12, although fasting blood glucose level did not continue to decrease in the root group (155 +/- 12.7 mg/dl), the berry group became normoglycemic (129 +/- 7.3 mg/dl; P < 0.01). We further evaluated glucose tolerance using the intraperitoneal glucose tolerance test. On day 0, basal hyperglycemia was exacerbated by intraperitoneal glucose load, and failed to return to baseline after 120 min. After 12 days of treatment with ginseng root extract (150 mg/kg body wt.), the area under the curve (AUC) showed some decrease (9.6%). However, after 12 days of treatment with ginseng berry extract (150 mg/kg body wt.), overall glucose exposure improved significantly, and the AUC decreased 31.0% (P < 0.01). In addition, we observed that body weight did not change significantly after ginseng root extract (150 mg/kg body wt.) treatment, but the same concentration of ginseng berry extract significantly decreased body weight (P < 0.01). These data suggest that, compared to ginseng root, ginseng berry exhibits more potent anti-hyperglycemic activity, and only ginseng berry shows marked anti-obesity effects in ob/ob mice.

Anti-HIV Activity of Medicinal Herbs: Usage and Potential Development

The acquired immunodeficiency syndrome (AIDS) is a result of human immunodeficiency virus (HIV) infection which subsequently leads to significant suppression of immune functions. AIDS is a significant threat to the health of mankind, and the search for effective therapies to treat AIDS is of paramount importance. Several chemical anti-HIV agents have been developed. However, besides the high cost, there are adverse effects and limitations associated with using chemotherapy for the treatment of HIV infection. Thus, herbal medicines have frequently been used as an alternative medical therapy by HIV positive individuals and AIDS patients. The aim of this review is to summarize research findings for herbal medicines, which are endowed with the ability to inhibit HIV. In this article, we will emphasize a Chinese herbal medicine, Scutellaria baicalensis Georgi and its identified components (i.e., baicalein and baicalin), which have been shown to inhibit infectivity and replication of HIV. Potential development of anti-AIDS compounds using molecular modeling methods will also be discussed.

Ginseng berry reduces blood glucose and body weight in db/db mice

In this study, we observed anti-diabetic and anti-obesity effects of Panax ginseng berry in adult C57BL/Ks db/db mice and their lean littermates. Animals received daily intraperitoneal injections of Panax ginseng berry extract at 150 mg/kg body wt. for 12 consecutive days. On Day 5, the extract-treated db/db mice had significantly lower fasting blood glucose levels as compared to vehicle-treated mice (180.5+/-10.2 mg/dl vs. 226.0+/-15.3 mg/dl, P < 0.01). On day 12, the extract-treated db/db mice were normoglycemic (134.3+/-7.3 mg/dl) as compared to vehicle-treated mice (254.8+/-24.1 mg/dl; P < 0.01). Fasting blood glucose levels of lean mice did not decrease significantly after treatment with extract. After 12 days of treatment with the extract, glucose tolerance increased significantly, and overall blood glucose exposure calculated as area under the curve (AUC) decreased 53.4% (P < 0.01) in db/db mice. Furthermore, db/db mice treated with extract (150 mg/kg body wt.) showed weight loss from 51.0+/-1.9 g on Day 0, to 46.6+/-1.7 g on Day 5, and to 45.2+/-1.4 g on Day 12 (P < 0.05 and P < 0.01 compared to Day 0, respectively). The body weight of lean littermates also decreased at the same dose of extract. These data suggest that Panax ginseng berry extract may have therapeutic value in treating diabetic and obese patients.

Effects of American Ginseng Berry Extract on Blood Glucose Levels in ob/ob Mice

In this study, we evaluated antihyperglycemic effects of American ginseng berry extract in diabetic ob/ob mice. Animals received daily intraperitoneal (IP) injections of the extract 150 mg/kg for 12 days. On days 5 and 12, the extract-treated ob/ob mice had significantly lower fasting blood glucose levels compared to day 0 (both p < 0.05). Glucose tolerance improved significantly, which was shown by overall glucose excursion, calculated as area under the curve (AUC) during the two-hour IP glucose tolerance test. The AUC decreased by 31.8% on day 12 compared to day 0 (p < 0.01). In addition, after 12 days of the berry extract treatment, a significant reduction in body weight (p < 0.01 compared to day 0) and a significant increase in body temperature (p < 0.01 compared to day 0) was noticeable. Our results support in vivo antihyperglycemic and antiobese activity of American ginseng berry extract that may prove to be of clinical importance in the prevention and treatment of Type 2 diabetes.

Anti-hyperglycemic effect of the polysaccharides fraction from American ginseng berry extract in ob/ob mice

In this study, we evaluated the anti-hyperglycemic effect of a polysaccharides fraction from American ginseng berry extract in diabetic ob/ob mice. All animals received daily intraperitoneal injections of polysaccharides at 150 mg/kg body wt. (n = 5), polysaccharides at 50 mg/kg body wt. (n = 5), or vehicle (n = 5) for 10 consecutive days. On Day 5, as compared to the vehicle-treated mice (230.5 +/- 13.5 mg/dl, mean +/- S.E), mice from both treated groups showed significantly lower fasting blood glucose levels (187.4 +/- 20.5 mg/dl and 187.4 +/- 17.1 mg/dl), respectively (both P < 0.05). On Day 10, compared to the vehicle group (240.1 +/- 12.3 mg/dl), the 50 mg/kg dose group were at 188.4 +/- 12.6 mg/dl (P < 0.05), and the 150 mg/kg dose group were normoglycemic (148.8 +/- 17.6 mg/dl, P < 0.01). Those ob/ob mice treated with vehicle did not, however, show significant changes in fasting blood glucose levels. Data from the intraperitoneal glucose tolerance test (IPGTT) showed that, compared to Day 0, there was a significant improvement in glucose tolerance in animals who received the 50 and 150 mg/kg polysaccharide doses, and the area under the curve (AUC) decreased 15.5% (P < 0.05) and 28.2% (P < 0.01), respectively. Interestingly, after cessation of polysaccharide treatment, the fasting blood glucose levels stayed lower, and returned to control concentration on Day 30. We also observed that the polysaccharides fraction did not affect body weight changes in ob/ob mice. Our data suggest that the polysaccharides fraction from American ginseng berry extract has a potential clinical utility in treating diabetic patients.

Gut and brain effects of American ginseng root on brainstem neuronal activities in rats.

Brainstem neurons receiving subdiaphragmatic vagal inputs were recorded in an in vitro neonatal rat brainstem-gastric preparation. Aqueous extracts of American ginseng root (Panax quinquefolium L.) were applied to the gastric compartment or the brainstem compartment of the bath chamber to evaluate the peripheral gut and central brain effects of the extracts on brainstem unitary activity. After Panax quinquefolium L. application to the gastric or brainstem compartment, a concentration-related inhibition in neuronal discharge frequency in the brainstem unitary activity was observed, suggesting that Panax quinquefolium L. may play an important role in regulating the digestive process and modulating brain function. In this study, pharmacological effects of American-cultivated Panax quinquefolium L. and Chinese-cultivated Panax quinquefolium L. were also compared. Our results suggest that American-cultivated Panax quinquefolium L. possesses a significantly stronger gastric modulating effect on brain neuronal activity.

Peripheral gastric leptin modulates brain stem neuronal activity in neonates

Afferent sensory fibers are the primary neuroanatomic link between nutrient-related events in the gastrointestinal tract and the central neural substrates that modulate ingestion. In this study, we evaluated the peripheral gastric effects of leptin (OB protein) on brain stem neuronal activities using an in vitro neonatal rat preparation. We also tested gastric leptin effects as a function of age in neonates. For approximately 33% of the nucleus tractus solitarius units observed, gastric leptin (10 nM) produced a significant activation of 188.2 +/- 8.6% (mean +/- SE) compared with the control level of 100% (P < 0.01). Concentration-dependent leptin effects have also been shown. The remaining neurons (67%) had no significant response to gastric leptin application. Next, we evaluated the peripheral gastric effects of leptin (10 nM) on brain stem unitary activity in three different age groups (1-2 days old, 3-5 days old, and 7-8 days old) of neonatal rats. In the 1- to 2-day-old and the 3- to 5-day-old groups, we observed that response ratios and activity levels were similar. However, there was a significant difference between the 7- to 8-day-old group and the two younger age groups in both the response ratios and the activation levels. The percentage of activation responses increased from approximately 26% in the 1- to 2-day-old and the 4- to 5-day-old age groups to 70% in the 7- to 8-day-old group (P < 0.05). The level of activation increased from 168.3 +/- 2.7% (compared with the control level) in the 1- to 2-day-old and the 4- to 5-day-old age groups to 231.4 +/- 11.9% in the 7- to 8-day-old group (P < 0.01). Our data demonstrate that peripheral gastric leptin modulates brain stem neuronal activity and suggest that gastric leptin has a significantly stronger effect in the 7- to 8-day-old animals than in the younger neonates.Afferent sensory fibers are the primary neuroanatomic link between nutrient-related events in the gastrointestinal tract and the central neural substrates that modulate ingestion. In this study, we evaluated the peripheral gastric effects of leptin (OB protein) on brain stem neuronal activities using an in vitro neonatal rat preparation. We also tested gastric leptin effects as a function of age in neonates. For ∼33% of the nucleus tractus solitarius units observed, gastric leptin (10 nM) produced a significant activation of 188.2 ± 8.6% (mean ± SE) compared with the control level of 100% ( P < 0.01). Concentration-dependent leptin effects have also been shown. The remaining neurons (67%) had no significant response to gastric leptin application. Next, we evaluated the peripheral gastric effects of leptin (10 nM) on brain stem unitary activity in three different age groups (1-2 days old, 3-5 days old, and 7-8 days old) of neonatal rats. In the 1- to 2-day-old and the 3- to 5-day-old groups, we observed that response ratios and activity levels were similar. However, there was a significant difference between the 7- to 8-day-old group and the two younger age groups in both the response ratios and the activation levels. The percentage of activation responses increased from ∼26% in the 1- to 2-day-old and the 4- to 5-day-old age groups to 70% in the 7- to 8-day-old group ( P < 0.05). The level of activation increased from 168.3 ± 2.7% (compared with the control level) in the 1- to 2-day-old and the 4- to 5-day-old age groups to 231.4 ± 11.9% in the 7- to 8-day-old group ( P < 0.01). Our data demonstrate that peripheral gastric leptin modulates brain stem neuronal activity and suggest that gastric leptin has a significantly stronger effect in the 7- to 8-day-old animals than in the younger neonates.

Dose‐related effects of oral acetaminophen on cold‐induced pain: A double‐blind, randomized, placebo‐controlled trial

The cold‐pressor test is a widely used pain‐induction model in humans. This method has been shown to be a sensitive measure for detecting opioid analgesia. However, nonsteroidal anti‐inflammatory drugs have not produced consistent analgesic effects with use of this model. The analgesic effect of acetaminophen (INN, paracetamol) on cold pressor‐induced pain has not been reported by other investigators. In this study, a double‐blind, randomized, placebo‐controlled design was used to evaluate the dose‐related effects of oral acetaminophen on cold pressor‐induced pain in 18 normal healthy human subjects. We observed dose‐related analgesic activity of oral acetaminophen using the cold pressor‐induced pain model in these subjects. There were statistically significant main effects of both dose and time (pain and bothersomeness ratings decreased with increasing drug dose and increased over time). In pairwise comparisons only the contrast between the highest dose of acetaminophen (1000 mg) and placebo reached statistical significance. Results from our study suggest that the cold‐pressor method may have clinical value in evaluating nonopioid analgesic agents.

Modulation of American ginseng on brainstem GABAergic effects in rats

Single neurons in the region of the medial nucleus tractus solitarius (NTS), responding or not responding to gastric vagal branch stimulation, were recorded in an in vitro neonatal rat brainstem-gastric preparation. The spontaneous activity of the majority of these two types of NTS units was inhibited by GABA(A) receptor agonist, muscimol (30 microM), and this inhibition (approximately 52% compared to 100% of the control level) could be antagonized by selective GABA(A) receptor antagonist, bicuculline (10 microM). Application of Panax quinquefolium L. extracts (3.0 microg/ml) into the brainstem compartment of the preparation also significantly reduced the discharge rate of these NTS neurons (approximately 27% compared to the control level), but this reduction could not be reversed by bicuculline (10 microM). Pretreatment with Panax quinquefolium L. (3.0 microg/ml) significantly decreased the NTS inhibitory effects induced by muscimol (30 microM), approximately from 51 to 33%. Our results demonstrated the interactions of Panax quinquefolium L. with ligand-bindings of GABA(A) receptors, and the modulation of the brainstem GABAergic mechanism by Panax quinquefolium L. Our data suggest that the regulation of GABAergic neurotransmission may be an important action of Panax quinquefolium L.