RESUMO
We determined the effects of subchronic exposure to aqueous extract of leaves from Achillea millefolium (AE) on enzyme- and non-enzyme-dependent antioxidant systems in rats. Seven days treatment with AE (1 g/kg/twice a day, p.o.) altered the reduced glutathione (GSH) levels and antioxidant enzyme activities in several organs of the animals. Amount of GSH in uterus was increased (73%) while in kidneys it was decreased (23%). Besides, NAD(P)H quinone oxidoreductase 1 (NQO1) activity was increased in forestomach (26%) and in liver (64%), while glutathione S-transferase activity was decreased in the forestomach (32%) and increased in the liver (41%), kidney (35%) and uterus (37%). In preliminary experiments targeting the interaction of AE with acetaminophen (600 mg/kg, p.o.), we observed augmentation of acetaminophen-induced increase of the plasmatic alanine aminotransaminase, aspartate aminotransaminase and lactate dehydrogenase. Overall, the results indicate a potential toxic interaction of AE compounds with xenobiotics that use the glutathione pathway.
Assuntos
Achillea/química , Antioxidantes/metabolismo , Extratos Vegetais/farmacologia , Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Animais , Feminino , Glutationa/metabolismo , Rim/enzimologia , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Extratos Vegetais/toxicidade , Folhas de Planta/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Útero/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Maytenus ilicifolia Mart. ex. Reissek (Celastraceae) is widely used in Brazilian folk medicine to treat gastric disturbances. AIM OF THE STUDY: This work intended to characterize the effects of Maytenus ilicifolia on gastrointestinal motility. MATERIALS AND METHODS: Gastric emptying and intestinal transit were measured in the same animal. Mice received a semisolid marked with phenol red, half an hour after treatment with extracts. The amount of marker in the stomach and the distance reached in the intestine after 15 min were measured as index of gastrointestinal emptying and intestinal transit, respectively. RESULTS: Intraperitoneal administration of a flavonoid-rich extract potently reduced the gastric emptying (ED(50)=89 mg/kg) and the intestinal transit (ED(50)=31 mg/kg) of mice. Bio-guided purification of the flavonoid-rich extract by chemical partition with solvents of decreasing polarity yielded fraction insF with about 12-14 times higher activity than the initial flavonoid extract in both the gastric emptying and the intestinal transit. The inhibitory effects of the insF (9.7 mg/kg, i.p.) on gastric emptying and intestinal transit were reversed by co-administration of bethanechol (10 mg/kg, s.c.) but not by co-administration of metoclopramide (30 mg/kg, p.o.) indicating muscarinic but not dopaminergic interaction of the compounds of Maytenus. Chemical investigation of the insF fraction by HPLC-MS allowed the identification of 4 free flavonoids (catechin, epicatechin, quercetin and kaempferol), 29 flavonol glycosides and 8 tannins. The flavonol glycosides ranged from 1 to 4 monosaccharide units, having mainly quercetin and kaempferol as aglycone moieties, and the tannins were composed by catechin/epicatechin and/or afzelechin/epiafzelechin. CONCLUSIONS: Overall, the results indicate that the components of Maytenus ilicifolia have a potential use in the treatment of gastrointestinal motility disturbances such as diarrhea.
Assuntos
Colinérgicos/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Maytenus , Extratos Vegetais/farmacologia , Animais , Betanecol/farmacologia , Colinérgicos/administração & dosagem , Colinérgicos/química , Feminino , Flavonoides/farmacologia , Flavonóis/farmacologia , Glicosídeos/farmacologia , Injeções Intraperitoneais , Maytenus/química , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Taninos/farmacologiaRESUMO
Maytenus ilicifolia Mart. ex. Reissek (Celastraceae), a medicinal plant known in Brazil as "espinheira-santa" is commonly used to treat gastric disorders. The effect of the flavonoid-rich fraction separated from the leaves was evaluated for its gastroprotective properties and the mechanism(s) involved in this activity. Intraperitoneal administration of the flavonoid-rich fraction potently protected rats from experimentally induced chronic (ED(50)=79 mg/kg) and acute gastric lesions by ethanol (ED(50)=25mg/kg) and indomethacin (ED(50)=4 mg/kg) without altering the decreased amount of cytoprotective glutathione and mucus amount in the injured gastric mucosa. A potent reduction of gastric acid hypersecretion (ED(50)=7 mg/kg, i.p.) was accompanied by a reduction of nitric oxide release (ED(50)=1.6 mg/kg, i.p.) in the gastric secretion of 2h pylorus ligated rats which suggests an important role for nitric oxide-dependent mechanisms. Inhibition of gastric acid secretion in vivo was correlated with the in vitro inhibition of rabbit gastric H(+),K(+)-ATPase activity (IC(50)=41 microg/mL). Chemical investigation of the fraction showed galactitol (25%), epicatechin (3.1%) and catechin (2%) as the majoritary components. Collectively, the results show that the flavonoid-rich fraction of Maytenus ilicifolia potently protects animals from gastric lesions with high potency through inhibition of gastric acid secretion.
Assuntos
Flavonoides/uso terapêutico , Mucosa Gástrica/efeitos dos fármacos , Maytenus/química , Substâncias Protetoras/uso terapêutico , Inibidores da Bomba de Prótons , Úlcera Gástrica/tratamento farmacológico , Ácido Acético , Animais , Feminino , Ácido Gástrico/metabolismo , Suco Gástrico/química , Mucosa Gástrica/metabolismo , Glutationa/metabolismo , Indometacina , Muco/metabolismo , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Folhas de Planta/química , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismoRESUMO
The freeze-dried aqueous extract (AE) from the aerial parts of Scoparia dulcis was tested for its effects on experimental gastric hypersecretion and ulcer in rodents. Administration of AE to animals with 4h pylorus ligature potently reduced the gastric secretion with ED(50)s of 195 mg/kg (rats) and 306 mg/kg (mice). The AE also inhibited the histamine- or bethanechol-stimulated gastric secretion in pylorus-ligated mice with similar potency suggesting inhibition of the proton pump. Bio-guided purification of the AE yielded a flavonoid-rich fraction (BuF), with a specific activity 4-8 times higher than the AE in the pylorus ligature model. BuF also inhibited the hydrolysis of ATP by H(+),K(+)-ATPase with an IC(50) of 500 microg/ml, indicating that the inhibition of gastric acid secretion of Scoparia dulcis is related to the inhibition of the proton pump. Furthermore, the AE inhibited the establishment of acute gastric lesions induced in rats by indomethacin (ED(50)=313 mg/kg, p.o.) and ethanol (ED(50)=490 mg/kg, p.o.). No influence of the AE on gastrointestinal transit allowed discarding a possible CNS or a cholinergic interaction in the inhibition of gastric secretion by the AE. Collectively, the present data pharmacologically validates the popular use of Scoparia dulcis in gastric disturbances.
Assuntos
Ácido Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Scoparia/química , Água/química , Animais , Antiulcerosos/farmacologia , Cruzamentos Genéticos , Avaliação Pré-Clínica de Medicamentos , Feminino , Determinação da Acidez Gástrica , Mucosa Gástrica/metabolismo , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fitoterapia , Piloro/cirurgia , Ratos , Ratos Wistar , Estômago/efeitos dos fármacosRESUMO
Achillea millefolium L. (Asteraceae), popularly known as yarrow, has been used in folk medicine to treat complaints such as inflammation, pain, wounds, hemorrhages and gastrointestinal disturbances. The aim of the present study was to assess the safety and efficacy of the aqueous extract (AE) of the plant after chronic exposure. Indeed, the AE was effective in protecting the gastric mucosa against acute gastric lesions induced by ethanol and indomethacin and in healing chronic gastric lesions induced by acetic acid with (ED(50)=32 mg/kg, p.o.). Safety studies were performed in female and male Wistar rats treated daily with AE (0.3-1.2 g/kg, p.o./day) or vehicle (water, 10 ml/kg/day) for 28 or 90 consecutive days. Satellite groups consisted of animals sacrificed 30 days after the end of these treatments. Clinical observations, body and organ weight measurements, gross autopsy, hematology, clinical biochemical and histopathological examinations were performed. Slight changes in liver weight, cholesterol, HDL-cholesterol and glucose were observed in male and female animals. These changes were not correlated with dose or time of exposure of the animals to the AE. Overall, the results show the antiulcer potential of the aerial parts of the Achillea millefolium which is accompanied by no signs of relevant toxicity even at very long chronic exposure.
Assuntos
Achillea/química , Antiulcerosos , Úlcera Gástrica/tratamento farmacológico , Administração Oral , Animais , Antiulcerosos/efeitos adversos , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Contagem de Células Sanguíneas , Coagulação Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Feminino , Masculino , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Medicinal plants are commonly used in Latin American folk medicine for the treatment of gastric problems. In order to understand the properties of some of their chemical constituents, four natural xanthones, an acetylated derivative, two coumarins (mammea A/BA and mammea C/OA) isolated from Calophyllum brasiliense Cambess and two flavonoids (minimiflorin and mundulin) isolated from Lonchocarpus oaxacensis Pittier, and the chalcone lonchocarpin isolated from Lonchocarpus guatemalensis Benth were tested for their activities on gastric H+,K+-ATPase isolated from dog stomach. All the compounds tested inhibited H+,K+-ATPase activity with varied potency. The xanthones inhibited the H+,K+-ATPase with IC50 values ranging from 47 microM to 1.6 mM. Coumarins inhibited H+,K+-ATPase with IC50 values of 110 and 638 microM. IC50 values for the flavonoids ranged from 9.6 to 510 microM among which minimiflorin was the most potent. The results suggest that H+,K+-ATPase is sensitive to inhibition by several types of structurally different natural compounds. The potency of the effects on gastric H+,K+-ATPase depends on the presence, position and number of hydroxyls groups in the molecule. Collectively, these results suggest a potential for important pharmacological and toxicological interactions by these types of natural products at the level of H+,K+-ATPase which may explain, at least in part, the gastroprotective properties, indicated by traditional medicine, of the plants from which these compounds were isolated.
Assuntos
Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Plantas Medicinais/química , Inibidores da Bomba de Prótons , Estômago/enzimologia , Xantonas/farmacologia , Animais , Calophyllum/química , Cumarínicos/isolamento & purificação , Derris/química , Cães , Inibidores Enzimáticos/isolamento & purificação , Feminino , Flavonoides/isolamento & purificação , Xantonas/isolamento & purificaçãoRESUMO
The indole alkaloids mixture (AlkF) obtained from the barks of Himatanthus lancifolius (Muell. Arg.) Woodson was evaluated for gastroprotective properties in rodents. The AlkF potently protected rats from experimentally induced gastric lesions by ethanol (ED (50) = 30 mg/kg, p. o.) and reduced gastric acid hypersecretion induced by pylorus ligature (ED (50) = 82 mg/kg, i. d.). Protective effects of the AlkF in the ethanol and hypersecretion models included increase of GSH levels of gastric mucosa indicating activation of GSH-dependent cytoprotective mechanisms. Also, an increase of the antioxidant capacity as measured through glutathione S-transferase activity was observed in the hypersecretory but not in the ulcerative model. Furthermore, the amount of nitric oxide derivatives (NO (3) + NO (2)) in the forestomach was increased while the amount released into the gastric juice during pylorus ligature was decreased by the AlkF suggesting an alteration of NO-related mechanisms. Reduction of gastric acid hypersecretion induced by pylorus ligature seems to correlate with the blockade of H (+),K (+)-ATPase activity as determined in vitro by the capacity of the AlkF mix to decrease the hydrolysis of ATP by the ATPase isolated from dog gastric mucosa (EC (50) = 212 microg/mL). Cholinergic mechanisms can be excluded since intestinal transit was not modified with doses up to 100 mg/kg ( p. o.). GC-MS investigation of components of the AlkF resulted in the identification of 3 main indole alkaloids, uleine (53 %), its isomer (13 %), demethoxyaspidormine (23.8 %) and traces of at least other five alkaloids. Collectively, the results show the novel gastroprotective properties of the indole AlkF of H. lancifolius through a variety of mechanisms.
Assuntos
Antiulcerosos/farmacologia , Apocynaceae , Fitoterapia , Extratos Vegetais/farmacologia , Úlcera Gástrica/prevenção & controle , Administração Oral , Animais , Antiulcerosos/administração & dosagem , Antiulcerosos/uso terapêutico , Relação Dose-Resposta a Droga , Etanol , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Ácido Gástrico/metabolismo , Motilidade Gastrointestinal , Alcaloides Indólicos/administração & dosagem , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/uso terapêutico , Ligadura , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamenteRESUMO
Himatanthus lancifolius, popularly known as "agoniada" in Brazil, is largely used in folk medicine against asthma, dysmenorrhea and as an emenagogue and abortive. This study reveals the effects of an alkaloid rich fraction (AlkF) obtained from the bark of Himatanthus lancifolius in vascular and non-vascular smooth muscle responsiveness. Incubation of AlkF (3-30 microg/ml) during 15 min generates a concentration-related and fully reversible reduction in maximal contractile responses evoked by acetylcholine and phenylephrine in rat jejune and aorta preparations, respectively. Exposition of endothelium-denuded pre-contracted rat aorta rings to AlkF results in a complete relaxation, with EC(50) of 22.2 (16.2-28.2 microg/ml). AlkF is also able to induce a concentration-related rightward shift of cumulative concentration curves for calcium in uterus and aorta rings maintained in depolarizing nutritive solution. Moreover, addition of AlkF in calcium-free solution also reduces, in a concentration-dependent manner, the ability of caffeine and phenylephrine to contract aorta rings. This study reveals that the bark of Himatanthus lancifolius possesses one or more indole alkaloids able to alter non-vascular and vascular smooth muscle responsiveness, an event that may involve the blocking of calcium entry or changes on intracellular calcium utilization or mobilization.