Gastroprotections of escins Ia, Ib, IIa, and IIb on ethanol-induced gastric mucosal lesions in rats

doi:10.1016/S0014-2999(99)00249-6

European Journal of Pharmacology

Volume 373, Issue 1, 28 May 1999, Pages 63-70

https://doi.org/10.1016/S0014-2999(99)00249-6 Get rights and content

Abstract

Effects of escins Ia, Ib, IIa, and IIb isolated from horse chestnuts on ethanol-induced gastric mucosal lesions and the roles of capsaicin-sensitive afferent neurons, endogenous nitric oxide (NO), sulfhydryls, prostaglandins, as well as gastric secretion and the sympathetic nervous system, were investigated in rats. Test samples were given orally to fasted rats 1 h before ethanol (1.5 ml/rat, p.o.) treatment or ligation of the pylorus. Escins Ia–IIb (10–50 mg/kg) potently inhibited ethanol-induced gastric mucosal lesions, whereas desacylescins I and II (50 mg/kg) showed no such effect. These active saponins (10 and 20 mg/kg) did not decrease the gastric secretion. The gastroprotections of escins Ia–IIb were attenuated by the pretreatment with capsaicin, N^G-nitro-l-arginine methyl ester, and indomethacin, but not by N-ethylmaleimide. The effects of escins Ia–IIb were also attenuated in streptozotocin-induced diabetic rats, in which the activity of the sympathetic nervous system was abnormal. These results suggest that the gastroprotections of escins Ia–IIb on ethanol-induced gastric mucosal lesions are acid-independent, whereas endogenous prostaglandins, NO, capsaicin-sensitive afferent neurons, and the sympathetic nervous system participate.

Introduction

`Escin', one of the most important saponin constituents, is known as a mixture of saponins occurring in horse chestnut, the seed of Aesculus hippocastanum L. (Hippocastanaceae). The saponin mixture `escin' is reported to have a potent anti-inflammatory activity against different types of edema (Di Rosa et al., 1971) and a great capacity to raise the vascular tone, and also to help in the regulation of the microcirculation (Antoni et al., 1979). This effect is attributable to the formation of prostaglandin F_2α in the vascular tissue and can be suppressed by non-steroid anti-inflammatory drugs (Longiave et al., 1979). Experimentally, `escin' prevented the development of gastric lesions in various ulcers (Marhuenda et al., 1993), and reduced gastric secretion (Marhuenda et al., 1994). Recently, we isolated 12 acylated polyhydroxyolean-12-ene 3-O-monodesmosides, escins Ia, Ib, IIa, IIb, IIIa, IIIb, IV, V, and VI and isoescins Ia, Ib, and V, from horse chestnuts and determined their chemical structures (Yoshikawa et al., 1994, Yoshikawa et al., 1996, Yoshikawa et al., 1998). We have also reported on both the inhibitory activity of escins Ia–IIb on the increase of blood glucose or ethanol concentration in oral glucose- or ethanol-loaded rats (Yoshikawa et al., 1994, Yoshikawa et al., 1996) and their anti-inflammatory effects (Matsuda et al., 1997). Furthermore, investigation of the modes of action using principal escins for the hypoglycemic activity revealed that they potently inhibited gastric emptying in rats, and additionally, they showed weak inhibitory activity on glucose uptake in the small intestine in vitro (Matsuda et al., 1998). We now describe the effects of escins Ia–IIb and their desacyl derivatives (desacylescins I and II) on ethanol-induced gastric mucosal lesions in rats. We also discuss the roles of capsaicin-sensitive afferent neurons, endogenous nitric oxide (NO), sulfhydryls, prostaglandins, as well as gastric secretion and the sympathetic nervous system in the gastroprotection by escins Ia–IIb in conscious rats.

Section snippets

Chemicals

Escins Ia, Ib, IIa, and IIb were isolated from the seeds of European Aesculus hippocastanum, and desacylescins I and II were obtained by alkaline hydrolysis of escins Ia and IIa according to our previous report (Fig. 1) (Yoshikawa et al., 1996). Omeprazole was obtained from Fujisawa Pharmaceutical, Japan. Other reagents were purchased from Wako Pure Chemical, Japan.

Animals

Male Sprague–Dawley rats were purchased from Kiwa Laboratory Animal, Japan. The animals were maintained at a constant temperature

Effects on gastric lesions induced by ethanol in rats

Ethanol-induced gastric mucosal lesions and the effects of escins Ia, Ib, IIa, and IIb and desacylescins I and II in rats are shown in Fig. 2. When ethanol (1.5 ml/rat) was administered to control animals, marked gastric mucosal lesions were induced. These lesions were characterized by multiple hemorrhage red bands (patches) of different sizes lesions macroscopically, and vasocongestion of the mucosa and submucosal hemorrhage histologically, along the long axis of the glandular stomach. Oral

Discussion

Necrotizing agents such as ethanol, 0.6 N HCl, 0.2 N NaOH, etc. given intragastrically in the rat produce severe gastric hemorrhagic erosions (Robert et al., 1979; Szabo et al., 1981). In this study, comparing to reference drug omeprazole, escins Ia–IIb (10–50 mg/kg, p.o.) showed potent protective effects against ethanol-induced gastric mucosal lesions.

Gastric acid is not a primary cause but plays a permissive role in gastric mucosal damage induced by ethanol (Tarnawski et al., 1983). Previous

Conclusion

These results suggest that capsaicin-sensitive afferent neurons, endogenous NO, and prostaglandins participate in the protections of escins Ia–IIb against ethanol-induced gastric mucosal lesions. The mechanisms of sympathetic nervous system and the secretion of pancreatic β-cells in the gastroprotection by escins Ia–IIb should be studied further.

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Pharmacokinetics of escin Ia in rats after intravenous administration
2014, Journal of Ethnopharmacology
Citation Excerpt :
To date, about 20 individual compounds have been identified in escin (Yoshikawa et al., 1994, 1998; Sirtori, 2001; Wei et al., 2005). Amongst these, escin Ia (Fig. 1) is the main bioactive component of escin that, according to previous studies, exerted a high potency in anti-diabetic and anti-ischemic effects, anti-inflammation and gastroprotection (Matsuda et al., 1997, 1999), and thus has been frequently referred as a representative of escin. In China, escin Ia has been assigned as the marker compound for horse chestnut seeds in the 2005 Chinese Pharmacopoeia.
Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration.
Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC–MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany).
After intravenous administration, the C_max and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t_1/2 was significantly longer with increased intravenous doses, while other parameters such as CL and V_d also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5–2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia.
The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5–2.0 mg/kg after intravenous administration. Escin Ia is isomerized to isoescin Ia rapidly and extensively regardless of the doses.
The effect of a minor constituent of essential oil from Citrus aurantium: The role of β-myrcene in preventing peptic ulcer disease
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The monoterpene β-myrcene has been widely used in cosmetics, food and beverages, and it is normally found in essential oil from citrus fruit. The aim of this study was to investigate the anti-ulcer effects of β-myrcene on experimental models of ulcers that are induced by ethanol, NSAIDs (non-steroidal anti-inflammatory drugs), stress, Helicobacter pylori, ischaemia–reperfusion injury (I/R) and cysteamine in order to compare with the essential oil of Citrus aurantium and its major compound limonene. The results indicate that the oral administration of β-myrcene at a dose of 7.50 mg/kg has important anti-ulcer activity with significantly decreased gastric and duodenal lesions as well as increased gastric mucus production. The results showed treatment with β-myrcene caused a significant increase in mucosal malondialdehyde level (MDA), an important index of oxidative tissue damage. The β-myrcene was also endowed with marked enhancement of antioxidant enzyme activity from GR system as evidenced by the decreased activity of superoxide dismutase (SOD) and increased levels of glutathione peroxidase (GPx), glutathione reductase (GR), and total glutathione in gastric tissue. Our results also shown that treatment with β-myrcene is not involved with thioredoxin reductase (TrxR) activity. Our results reveal, for the first time, the importance of β-myrcene as an inhibitor of gastric and duodenal ulcers and demonstrate that an increase in the levels of gastric mucosa defence factors is involved in the anti-ulcer activity of β-myrcene.
Comparative pharmacokinetics and the bioavailability of escin Ib and isoescin Ib following the administration of escin, pure escin Ib and isoescin Ib in rats
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Citation Excerpt :
Although α-escin has a lower pharmacological activity than β-escin, the commercially available preparations in China, Germany and other countries contain both α- and β-escin (Ikhlas et al., 2009). In addition, the pharmacological activity of escin monomers, including escin Ia and escin Ib, was compared to that of the complete saponin extract, demonstrating that the single saponin exhibits a higher potency than the complete saponin extract in mice (Matsuda et al., 1997, 1999). These results also indicate that it would be beneficial to develop individual isomers of escin as pure drugs.
Adequate pharmacokinetic data of escin, a natural mixture of triterpene saponins used for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema, is of special interest in view of the growing use of escin agent in clinical medicine. However, pharmacokinetic data are inadequate to support their clinical indication. Escin Ib and isoescin Ib are the chief active ingredients in escin, pharmacokinetics study of them would be helpful for improving the practice of escin application. The goals of this study are to determine the plasma concentration of escin Ib and isoescin Ib using an established liquid chromatography tandem mass spectrometry (LC–MS/MS) method and to compare the pharmacokinetics and bioavailability of these compounds in rats when administered as pure isomers or as sodium escinate.
Five groups of Wistar rats (n=6 per group) were treated with either an intravenous (IV) dose (2.78 mg/kg) of sodium escinate (corresponding to 0.5 mg/kg of escin Ib and 0.5 mg/kg of isoescin Ib), an IV dose (0.5 mg/kg) and an oral dose (4 mg/kg) of pure escin Ib or isoescin Ib. The concentrations of escin Ib and isoescin Ib in rat plasma were determined by LC–MS/MS at various times following the administration of the drugs. The pharmacokinetic parameters were estimated by a non-compartmental analysis and then subjected to statistical analysis.
The administration of sodium escinate, which contains the two isomers, gave rise to higher terminal phase half-life (t_1/2) and mean residence time (MRT) values for both escin Ib and isoescin Ib compared to the corresponding compounds administered alone. The absorption of escin Ib and isoescin Ib was very poor, with the oral bioavailability (F) values of <2% observed for both compounds. The two compounds were found to isomerize in vivo, wherein the conversion of escin Ib to isoescin Ib was much easier than that of isoescin Ib to escin Ib.
A comparison of the pharmacokinetics of escin Ib and isoescin Ib administered alone and together in rats suggests that the administration of herbal preparations of escin in a clinical setting may result in a longer duration of action than the administration of each isomer alone. The interconversion of escin Ib and isoescin Ib when administered alone indicates that the administration of one isomer results in exposure to the other isomer.
Evaluation of genotoxic and antioxidant activity of an Aesculus hippocastanum L. (Sapindaceae) phytotherapeutic agent
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Citation Excerpt :
Ensuring the safety of herbs and phytomedicinal products has been an urgent approach adopted by governments throughout the world. In the present work, we have investigated the citotoxic, genotoxic, mutagenic, and antioxidant properties of AH, which has been traded in tablets as a phytotherapeutical medicine, and indicated mainly for treatment of chronic venous insufficient [14,31–33]. The in vitro plasmid DNA test, which detects breaks in the DNA molecule caused by interaction with genotoxic products, has been shown to be a useful tool to evaluate this effect promoted by plant extracts [4,34–36].
Aesculus hippocastanum L. (Sapindaceae), vulgarly known as horse chestnut, is a native European plant, but widely distributed all over the world. The parts used in medicine are the seeds and the bark of young branches. The seed extract has been marketed as a phytotherapeutic product and it is extensively recommended for treatment of chronic venous insufficiency, traumatic edema, hemorrhoid and postoperative edema. Most of the beneficial effects of horse chestnut are attributed to its principal component aescin. The present study aims to evaluate the citotoxic, genotoxic, mutagenic, and antioxidant activity of this seed extract by performing a set of bacterial and cell-free tests. Phytochemical screening and thin layer chromatography confirmed the presence of aescin as well as others chemical constituents in the studied extract. Negative results were obtained for the occurrence of double-strand breaks in pBCKS plasmid DNA. Two different effects were detected in Escherichia coli strains CC104 and CC104mutMmutY: mutagenic (non-oxidative lesions) and antioxidant. The mutagenic effect was confirmed by Kado assay, where the extract was considered weakly mutagenic towards frameshift mutations. Moreover, the extract demonstrated to protect bacterial cells from lesions induced by mitomycin C, suggesting an antioxidative potential. A. hippocastanum seed extract demonstrated to be genotoxic and weakly mutagenic, as well as antioxidative.
Hymenaea stigonocarpa Mart. ex Hayne: A Brazilian medicinal plant with gastric and duodenal anti-ulcer and antidiarrheal effects in experimental rodent models
2012, Journal of Ethnopharmacology
Citation Excerpt :
For each sample, the absorbance at 598 nm was measured in a spectrophotometer, and the results are expressed as μg of Alcian blue/g of tissue. Ethanol-induced gastric lesions in l-NAME- and NEM-pretreated rats—The procedure was performed according to the methods described by Matsuda et al. (1999). Gastric mucosal lesions were induced in male Wistar rats (n=7).
Hymenaea stigonocarpa Mart. ex Hayne (Fabaceae) is a medicinal species commonly found in the Brazilian savannah. The stem bark of this medicinal plant, popularly known as “jatobá-do-cerrado”, is widely used in tea form to treat gastric pain, ulcers, diarrhoea and inflammation, whereas its fruits pulp is edible.
The aim of this study was to investigate the antidiarrheal and anti-ulcer effects of a methanolic extract derived from the stem bark (MHs) and diet with fruit pulp of H. stigonocarpa.
The antidiarrheal action of MHs was measured against the intestinal motility and diarrhoea induced by castor oil in mice. The preventive action of MHs (50, 100, 150 and 200 mg/Kg, by oral route (p.o.)) against peptic ulcers was evaluated in experimental rodent models challenged with absolute ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia–reperfusion (I/R) (200 mg/Kg, p.o.) and cysteamine (200 mg/Kg, p.o.). The main anti-ulcer mechanisms of action of MHs were analysed as follows: evaluation of the gastric juice parameters, assessment of mucus adherence to the gastric wall, determination of the role of nitric oxide (NO) and sulfhydryl compounds (SH), glutathione (GSH) levels and myeloperoxidase (MPO) activity. The healing effects from MHs (200 mg/Kg) and diet with fruit pulp (10%) against gastric and duodenal ulcers induced by acetic acid were also evaluated by treating rats over 7 or 14 consecutive days of treatment.
The phytochemical profile of MHs and fruit pulp indicated the presence of phenolic compounds (mainly flavonoids and condensed tannins). MHs (200 mg/Kg, p.o.) displayed an antidiarrheal effect and were able to protect gastric mucosa against absolute ethanol (68% protection) and also against the injurious effect of NSAIDs (86% protection) when compared to the group treated with vehicle. These results were accompanied by the prevention of GSH depletion and an inhibition of MPO activity when compared to animals treated with vehicle (P<0.05). MHs markedly protected duodenal mucosa against injuries caused by cysteamine (98%) and also against I/R induced gastric ulceration (80%) when compared to the group treated with vehicle. Furthermore, MHs also prevented the GSH depletion of gastric mucosa relative to the control group treated with vehicle. NO appeared to be involved in this gastroprotective effect. MHs and diet with fruit pulp clearly demonstrated gastric healing actions after treatment for 7 (MHs – 53% inhibition) or 14 days (MHs – 60% inhibition and fruit pulp – 61% inhibition). Treatment with diet with fruit pulp for 7 days demonstrates a significant duodenal healing effect (71% inhibition) without any signs of toxicity.
MHs clearly demonstrate antidiarrheal, gastroprotective and cicatrising effects in experimental gastric and duodenal ulcers, and the diet with fruit pulp displays duodenal healing effects. The observed effects may be associated with the antioxidant effect, which may be due the presence of condensed tannins and flavonoids in the bark and fruit of H. stigonocarpa.
Byrsonima intermedia A. Juss.: Gastric and duodenal anti-ulcer, antimicrobial and antidiarrheal effects in experimental rodent models
2012, Journal of Ethnopharmacology
Citation Excerpt :
For each sample, the absorbance at 598 nm was measured in a spectrophotometer, and the results are expressed as μg of Alcian blue/g of tissue. Ethanol-induced gastric lesions in l-NAME-, NEM-, and Ruthenium Red-pretreated rats – The procedure was performed according to the methods of Pongpiriyadacha et al. (2003), Matsuda et al. (1999) and Morimoto et al. (1991). Gastric mucosal lesions were induced in male Wistar rats.
An ethnopharmacological survey indicated that the leaves of Byrsonima intermedia A. Juss. (Malpighiaceae), a medicinal species commonly found in the Brazilian Cerrado, can be used against gastroduodenal disorders, such as gastric ulcers and diarrhea.
The objective of this study was to evaluate the effects of a methanolic extract of Byrsonima intermedia (MBI) leaves on gastric and duodenal ulcers and to assess the antimicrobial and antidiarrheal effects of this extract.
The anti-ulcerogenic effect of MBI was investigated with different ulcerogenic agents in rodents (mice and rats), including non-steroidal anti-inflammatory drug (NSAID), HCl/ethanol, pyloric ligature, absolute ethanol, cysteamine and ischemia–reperfusion. The gastroprotective effect of MBI was assessed by analysing the volume of gastric juice, pH, total acidity, mucus, NO, sulfhydryl compound, vanilloid receptor, glutathione (GSH) levels, and myeloperoxidase (MPO) activity in the gastric and duodenal mucosa. The gastric and duodenal healing effects of MBI were also evaluated during 7 or 14 days of treatment. The antidiarrheal action (measured by intestinal motility and diarrhea induced by castor oil) and anti-bacterial action of MBI against Staphylococcus aureus, Escherichia coli and Helicobacter pylori were also evaluated by microdilution methods.
The phytochemical profile from MBI indicated the presence of phenolic acids, flavan-3-ols, oligomeric proanthocyanidins, and flavonoids. MBI (500 mg/kg, p.o.) significantly inhibited totally gastric and duodenal lesions (69%) and healed gastric (49% on 14 days) and duodenal lesions (45% on 7 and 14 days). The MBI exert gastroprotective action by participation of endogenous sulfhydryl compounds, vanilloid receptors and increase in GSH level to effective gastric and duodenal protection. MBI also displayed curative (42%) and preventive (49%) antidiarrheal effects by involvement of opiate receptors and also antimicrobial effects in vitro.
Byrsonima intermedia leaves present gastroprotective, healing and antidiarrheal activities, supporting previous claims that its traditional use can treat gastrointestinal disorders.

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Gastroprotections of escins Ia, Ib, IIa, and IIb on ethanol-induced gastric mucosal lesions in rats

Abstract

Introduction

Section snippets

Chemicals

Animals

Effects on gastric lesions induced by ethanol in rats

Discussion

Conclusion

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

Prostaglandins, Leukotrienes Essent. Fatty Acids

Gastroenterology

Diabetes Res. Clin. Pract.

Eur. J. Pharmacol.

Gastroenterology

Gastroenterology

Gen. Pharmacol.

Bioorg. Med. Chem.

Eur. J. Pharmacol.

Gastroenterology

Gastroenterology

Lancet

The role of nitric oxide and sulfhydryls in gastric mucosal protection induced by sodium cromoglycate in rats

J. Pharm. Pharmacol.

The estimation of pepsin, trypsin, papain and cathepsin with hemoglobin

J. Gen. Physiol.

Venotonic activity of aescine on the human saphenous vein

Arzneim.-Forsch.

Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice

Proc. Natl. Acad. Sci. USA

Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK and F93479 and oxmetidine and omeprazole

Toxicol. Pathol.

Nitric oxide generators and cGMP stimulate mucus secretion by rat gastric mucosal cells

Am. J. Physiol.

A review of the effects of long-term acid inhibition in animals

Scand. J. Gastroenterol.

Pharmacology and toxicology of omeprazole—with special reference to the effects on the gastric mucosa

Scand. J. Gastroenterol.

Prevention by mild irritants of gastric necrosis produced in rats by sodium taurocholate

Dig. Dis. Sci.

Studies of the mediators acute inflammatory response induced in rats in different sites of turpentine

J. Pathol.

Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H₂-antagonists SK and F93479 and oxmetidine and omeprazole