Anoja S. Attele

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-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.

Voltage-dependent inhibition of brain Na^+ channels by American ginseng

American ginseng (Panax quinquefolius) is a major species of ginseng that has many pharmacological effects. Studies have demonstrated that constituents of ginseng have neuroprotective effects during ischemia. Neuronal damage during ischemic episodes has been associated with abnormal Na(+) fluxes. Drugs that block voltage-dependent Na(+) channels provide cytoprotection during cerebral ischemia. We thus hypothesized that American ginseng may block Na(+) channels. In this study, effects of an American ginseng aqueous extract was evaluated in tsA201 cells transfected with cDNA expressing alpha subunits of the Brain(2a) Na(+) channel using the whole-cell patch clamp technique. We found that American ginseng extract tonically and reversibly blocked the channel in a concentration- and voltage-dependent manner. It shifted the voltage-dependence of inactivation by 14 mV (3 mg/ml) in the hyperpolarizing direction and delayed recovery from inactivation, whereas activation of the channel was unaffected. Ginsenoside Rb(1), a major constituent of the American ginseng extract, produced similar effects. The data were compared with the actions of lidocaine, a Na(+) channel blocker. Our results suggest that Na(+) channel block by American ginseng extract and Rb(1) was primarily due to interaction with the inactive state of the channel. Inhibition of the Na(+) channel activity by American ginseng extract may contribute to its neuroprotective effect during ischemia.

Leptin, gut, and food intake

Hyperphagia (overeating) is often associated with energy over-storage and obesity, which may lead to a myriad of serious health problems, including heart disease, hypertension, and type 2 diabetes. Thus, understanding the complex pathological mechanisms underlying hyperphagia and obesity has an important clinical significance. Leptin, or ob protein, is a key element in the long-term regulation of food intake and body weight homeostasis. It circulates in the blood at levels correlated with body fat mass. Leptin binds to specific receptors in the hypothalamus to mediate events that regulate feeding behavior. In light of new evidence, the initial view that leptin is an adipocyte-derived signal, which acts centrally to decrease body weight, has been modified. It has been shown that leptin may also have specific functions in the gastrointestinal tract, suggesting that feeding and energy homeostasis is regulated by both central and peripheral signals. Evidence supports the view that leptin integrates short-term, meal-related signals from the gut into long-term regulation of energy balance. In addition, the gastric leptin level is altered by the nutritional state and the administration of cholecystokinin. This commentary aims to review the evidence of the role of leptin as a peripherally acting signal in the gut in the regulation of nutrient intake, adiposity, and body weight. Based on currently available data, some potential future studies are suggested.

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.

Effects of quercetin on the release of endothelin, prostacyclin and tissue plasminogen activator from human endothelial cells in culture

Quercetin and related flavonoids are naturally occurring polyphenolic compounds with multiple pharmacological activities. Using cultured human umbilical vein endothelial cells, we investigated the effects of quercetin on endothelin (ET-1) and tissue plasminogen activator (t-PA) release induced by thrombin. We observed that when endothelial cells pretreated with 5 or 50 microM of quercetin were incubated for 4 and 24 h with thrombin, ET-1 concentration-dependently decreased (n = 6, P < 0.01, at 4 h IC50 = 1.54 microM, at 24 h IC50 = 2.78 microM). Under the same experimental conditions, quercetin significantly increased t-PA (n = 6, P < 0.01, at 4 h EC50 = 0.71 microM and at 24 hrs EC50 = 0.74 microM). In the same preparation, we evaluated prostacyclin (PGI2) release, induced by thrombin activated platelets, as determined by a 6-Keto-PGF1alpha radioimmunoassay. Following the treatment of cultured endothelial cells with activated platelets, the concentration of 6-Keto-PGF1alpha was significantly increased (P < 0.01). Quercetin (1, 5, and 20 microM) inhibited PGI2, in a concentration-dependent manner (n = 6, P < 0.05). Our data indicate that quercetin modulates the release of ET-1, t-PA, and PGI2 from vascular endothelial cells.

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.

Leptin Reduces Body Weight Gain in Neonatal Rats

Leptin (OB protein) elicits a neuroendocrine response to starvation and states of nutritional abundance to stabilize the proportion of body fat. Leptin has dramatic effects on food intake and energy expenditure in adult and juvenile rodents. However, whether the neonatal period is associated with the development of an effective leptin feedback system is still not known. In this study, we evaluated the effects of peripherally administered leptin on body weight changes in neonatal rats during the early suckling period (from birth to 10 d). Our results show that daily i.p. injections of leptin (0.3 μg/g and 1.0 μg/g) to neonatal rats led to a significant reduction in weight gain over 10 d compared with the control group (p < 0.01 and p < 0.01, respectively). Concomitant with a reduction in weight gain, retroperitoneal fat pad weight also significantly decreased in the leptin-treated group. Our data indicate that the potential for energy balance regulation by leptin occurs in the first day after birth. In addition, we also observed that 3 d after discontinuing leptin treatment, the body weight as well as the fat pad weight of leptin-treated pups returned to the control level. Our results demonstrate that leptin reduces body weight gain in neonatal rats.Committee on Clinical Pharmacology [C.-S.Y.] and Department of Anesthesia and Critical Care [A.S.A., L.Z., J.P.L., J.-T.X.], The Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637, U.S.A.; and Department of Pharmacology, Amgen, Thousand Oaks, California 91320, U.S.A. [Z.Q.S.]