Effects of ginseng saponins on receptor stimulation-responses

Ginseng, the root of Panax ginseng C. A. MEYER, is a wellknown and popular herbal medicine used in China for centuries and is now a world wide used natural medicine. Ginsenosides, the pharmacologically active components found in Ginseng, are also found in the leaf and stem of Panax ginseng C. A. MEYER, 1) and more than 30 different ginsenosides have been isolated from Ginseng. Ginsenosides exert various pharmacological effects on the central nervous, cardiovascular, endocrine, and immune systems.2-4) Notably, it is shown that Ginsenosides could reduce both Ca 2ϩ influx and catecholamine secretion in bovine adrenal chromaffin cells, 5,6) inhibit voltage-dependent Ca 2ϩ channels in sensory neurons as well as in chromaffin in cells, 7) and decrease the level of intracellular free calcium concentration ([Ca 2ϩ ] i ) in dog's myocardium suffered from ischemia-reperfusion injury 8) ; Ginsenosides could also stimulate endogenous product of nitric oxide (NO) in rat kidney 9) and in cardiovascular tissues, 10) evoke endothelium-dependent vascular relaxation in rat aorta. 11) Ca 2ϩ elevation has been known to be a critical signaling in the development of cardiac hypertrophy induced by various hypertrophic stimuli, 12) and NO, produced in virtually every cell type in the heart, shows potent antihypertrophic effects.13) Both effects of Ca 2ϩ -decrease and NO-release of ginsenosides indicate that ginsenosides may have a potential inhibitory effect on cardiac hypertrophy.The mechanism(s) at molecular level of pathological cardiac hypertrophy remains unclear. It has been reported that Ca 2ϩ elevation activates the calcineurin (CaN) pathway, and in turn enhances hypertrophy or apoptosis of cardiomyocytes.14) In addition, extracellular signal-regulated kinase-1/2 (ERK-1/2, the important members of mitogen-activated protein kinase (MAPK) family) likely occupies a central regulatory position in the signaling hierarchy of a cardiac myocyte given its unique ability to respond to virtually every characterized hypertrophic agonist and stress stimuli. 15) In the present study, we investigated whether total ginsenosides (TG) extracted from the leaf and stem of Panax ginseng C. A. MEYER have inhibitory effect on right ventricle hypertrophy (RVH) induced by injection of monocrotaline (MCT) which lead to pulmonary hypertension by causing injury of the lung vasculature, and examine the possible influences of TG on NO-release, CaN and ERK signaling pathways. MATERIALS AND METHODSMaterials TG (purity Ͼ93%), extracted from the leaf and stem of Panax ginseng C. A. MEYER, was presented by professor Rui Zhao (Beijing Naturally Occurring Drugs Research Institute, China), and was composed of Rb 1 (5.26%), Rg 1 (5.20%), Re (21.60%), Rd (13.65%), and other ginsenosides. MCT was purchased from Sigma Chemical Co. (U.S.A.). The antibodies against CnA, MKP-1, actin were obtained from Stressgen, Santa Cruz Company. Horseradish peroxidase conjugated goat anti-rabbit IgG were from Dako Cytomation Company. The reverse transcription kit and the primers o...

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Total Ginsenosides Inhibit the Right Ventricular Hypertrophy Induced by Monocrotaline in Rats

Qin

Gong

Wei³

et al. 2008

“…Thus, Rg 3 has been shown to inhibit brain Na ϩ channel activity, 3,4) and its effects are closely coupled to the inhibition of neurotransmitter release. 18) However, relatively little is known on the structure-activity relationships in Rg 3 -induced Na ϩ channel regulations.…”

Section: Discussionmentioning

confidence: 99%

Modifications of Aliphatic Side Chain of 20(S)-Ginsenoside Rg3 Cause an Enhancement or Loss of Brain Na+ Channel Current Inhibitions

Lee

Choi

Lee

et al. 2008

Na ϩ channels are transmembrane proteins that consist of a pore-forming a subunit and auxiliary b1, b2 and b3 subunits. 1) The a subunit is composed of four homologous domains (I-IV), each composed of six a-helical transmembrane segments (S1-S6), and is responsible for voltage-dependent increases in Na ϩ -selective permeability. The inward Na ϩ current (I Na ) initiates axonal and somatic action potentials in nerve and muscle fibers, and may also be involved in axonal intraneuronal or interneuronal information transfer. 2) Na ϩ channels are one of the targets of cardiac-and neuroprotective treatments against pathologic conditions including arrhythmia and brain ischemia.Ginseng, the root of Panax ginseng C. A. MEYER, is well known in herbal medicine as a tonic and restorative agent. The main molecular ingredients responsible for the actions of ginseng are the ginsenosides (also called ginseng saponins), which are also amphiphilic molecules. 3) Ginsenosides consist of three major different parts; steroid-like backbone structure, carbohydrate portions, and aliphatic side chain [-CH 2 CH 2 CHϭC(CH 3 ) 2 ], which is coupled to the carbon-20 of backbone structure. Some subsets of ginsenosides also exist as stereoisomer of 20(R)-or 20(S)-form. We recently demonstrated that ginsenoside Rg 3 (20-S-protopanaxa-but not 20(R)-(Rg 3 ) inhibits voltage-dependent brain Na ϩ channel activity expressed in Xenopus laevis oocytes. 4,5) In the previous report, we also demonstrated that carbohydrate portion of 20(S)-Rg 3 play important roles in rat brain Na V 1.2 channel regulations. However, little is known about the role of aliphatic side chain coupled to the carbon-20 in 20(S)-Rg 3 -induced Na ϩ channel current inhibitions (Fig. 1).We herein identified the role of aliphatic side chain in 20(S)-Rg 3 -mediated Na ϩ channel regulation using a Xenopus oocyte gene expression system. This gene expression system has few endogenous ion channels, 6) and allows heterologous expression of ion channels for various biochemical studies. 4,7,8) We expressed rat brain Na ϩ channels by intraoocyte ], which is coupled to the carbon-20 of backbone structure. In the previous report, we demonstrated that 20(S)-but not 20(R)-Rg 3 and carbohydrate portion of Rg 3 play important roles in rat brain Na V 1.2 channel regulations. However, little is known about the role of aliphatic side chain coupled to the carbon-20 in brain Na ؉ channel regulations. In the present study, we prepared Rg 3 derivatives by modifying the aliphatic side chain of Rg 3 , remaining with backbone structure and carbohydrate portion intact, and examined the effects of Rg 3 derivatives on Na ؉ channel activity. We found that reduction of double bond in aliphatic side chain of Rg 3 exhibited agonistic actions in Na ؉ channel current inhibitions by shifting concentration-response curve to leftward by three-fold, whereas deletion, hydroxylation, or oxygenation of aliphatic side chain caused an attenuation or loss of Na ؉ channel current inhibitions. These results provide evidences that ...

“…9,10) Relatively, very little is known about the structure-activity relationships of ginsenosides in biological systems. In partic- The ( * ) indicates amino acid residues that were mutated in the present study.…”

Section: )mentioning

confidence: 99%

“…[6][7][8] In cells expressing nicotinic acetylcholine (nACh) receptors, such as bovine chromaffin cells, they inhibit acetylcholine-stimulated Na ϩ influx. 9,10) More directly, Choi et al 11,12) and Sala et al 13) showed that ginsenosides inhibit ACh-and 5-HT-induced inward currents in Xenopus oocytes expressing several subtypes of neuronal and abd . e muscle-type nACh and 5-HT 3A receptors, respectively.…”

Section: Recent Reports Show That the Mixture Of 20(r)-and 20(s)-ginsmentioning

confidence: 99%

Mutations of Arginine 222 in Pre-transmembrane Domain I of Mouse 5-HT3A Receptor Abolish 20(R)- But Not 20(S)-Ginsenoside Rg3 Inhibition of 5-HT-Mediated Ion Currents

Lee

Yoon

et al. 2007

Ginseng, the root of Panax ginseng C. A. MEYER, is well known as natural medicine with restorative and promoting health. In traditional herbal medicine, ginseng alone has been used for the alleviation of symptoms such as anorexia, dyspepsia, vomiting and pain.1) The main molecular components responsible for the actions of ginseng are ginsenosides, which are also known as ginseng saponins. Ginsenosides have a four-ring, steroid-like structure with sugar moieties attached, and about 30 different forms have been isolated and identified from the root of Panax ginseng. Each also has at least three side chains on carbon-3, -6, and -20, which are free, or bound to monomeric, dimeric, or trimeric sugars. They also exist as stereoisomers; 20(R)-ginsenoside and 20(S)-ginsenoside are epimers of each other depending on the position of the hydroxyl group on carbon-20 (Fig. 1). 2,3) Recent reports show that the mixture of 20(R)-and 20(S)-ginsenosides regulates voltage-dependent Ca 2ϩ channel activity and several types of ligand-gated ion channels. They inhibit high-threshold voltage-gated Ca 2ϩ channels in chromaffin cells 4,5) and sensory neurons. [6][7][8] In cells expressing nicotinic acetylcholine (nACh) receptors, such as bovine chromaffin cells, they inhibit acetylcholine-stimulated Na ϩ influx.9,10) More directly, Choi et al. 11,12) and Sala et al. 13)showed that ginsenosides inhibit ACh-and 5-HT-induced inward currents in Xenopus oocytes expressing several subtypes of neuronal and abd . e muscle-type nACh and 5-HT 3A receptors, respectively. Ginsenosides also inhibit NMDA receptor-mediated intracellular Ca 2ϩ increases and NMDAinduced currents in cultured rat hippocampal neurons.14) The effects of ginsenosides on voltage-dependent and ligandgated ion channels suggest that they may affect synaptic transmission by controlling neurotransmitter release. 9,10) Relatively, very little is known about the structure-activity relationships of ginsenosides in biological systems. In partic- The ( * ) indicates amino acid residues that were mutated in the present study.