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Journal of Ethnopharmacology 113 (2007) 252–257

Evaluation of the antiulcerogenic activity of Maytenus robusta(Celastraceae) in different experimental ulcer models

Sergio Faloni de Andrade c,∗, Marivane Lemos a, Eros Comunello b, Vania Floriani Noldin a,Valdir Cechinel Filho c, Rivaldo Niero c

a Nucleo de Ciencia e Tecnologia, Area de Ciencias Biologicas e da Saude, Universidade do Oeste de Santa Catarina, Campus de Videira, SC, Brazilb Programa de Mestrado em Computacao Aplicada, Universidade do Vale do Itajaı (UNIVALI), Sao Jose, Santa Catarina, Brazil

c Programa de Mestrado em Ciencias Farmaceuticas, Nucleo de Investigacoes Quımico-Farmaceuticas (NIQFAR),Universidade do Vale do Itajaı (UNIVALI), Itajaı, Santa Catarina, Brazil

Received 30 November 2006; received in revised form 16 May 2007; accepted 2 June 2007Available online 13 June 2007

bstract

Maytenus robusta (Celastraceae) is used in folk medicine for the treatment of stomach ulcers and is very well adapted to the South ofrazil. Maytenus ilicifolia is the main species of the Celastraceae family, and is used in the treatment of gastric ulcers. However, Maytenus

licifolia is presently at the stage of extinction, due to indiscriminate use in Brazil. Thus, the use of Maytenus robusta in phytotherapeuticreparations, instead of Maytenus ilicifolia, is suggested. However, there have been no reports regarding the antiulcer activity of Maytenusobusta extract. Therefore, this study was carried out to evaluate the antiulcerogenic property of the hydroalcoholic extract of aerial parts ofaytenus robusta. The antiulcer assays were performed using the following protocols: nonsteroidal anti-inflammatory drug (NSAID)-induced

lcer, ethanol-induced ulcer, and stress-induced ulcer. The effects of the extract on gastric content volume, pH and total acidity, using the pylorusigated model, were also evaluated. In the ethanol-induced ulcer model, it was observed that the treatment with Maytenus robusta extract sig-ificantly reduced the lesion index in 75.1 ± 8.6, 85.0 ± 9.2, 86.6 ± 7.4 and 75.5 ± 5.3 for the groups treated with 50, 250 and 500 mg/kgf Maytenus robusta and positive control (omeprazole 30 mg/kg), respectively. Also were observed significant inhibition in lesion index inhe indomethacin-induced ulcer model, being the decrease of the 62.5 ± 7.1, 62.5 ± 6.1, 63.6 ± 5.5 and 96.2 ± 3.6 for groups treated with 50,50 and 500 mg/kg of Maytenus robusta and positive control (cimetidine 100 mg/kg), respectively. Results similar were observed in the stress-nduced ulcer model, where the inhibition of ulcer lesions were 71.3 ± 5.5, 72.7 ± 6.3, 76.5 ± 7.1 and 92.3 ± 7.5 for the groups treated with0, 250 and 500 mg/kg of Maytenus robusta and positive control (cimetidine 100 mg/kg), respectively. Regarding the model of gastric secre-ion, a reduction in the volume of gastric juice volume and total acidity was observed, as well as an increase in gastric pH. The results ofhe present study showed that Maytenus robusta hydroalcoholic extract displays gastroprotective activity. These results were similar to those

btained in studies carried out with Maytenus ilicifolia, which indicate that this species could be used in phytotherapeutic preparations as aubstitute for Maytenus ilicifolia. This work also corroborates the traditional indication of Maytenus robusta, contributing to its pharmacologicalalidation.

2007 Elsevier Ireland Ltd. All rights reserved.

eywords: Antiulcerogenic activity; Maytenus robusta; Gastric secretion; Celastraceae

. Introduction

The use of vegetal extracts in the treatment of diseasess widespread in Brazil. The country has a rich traditional

∗ Corresponding author. Tel.: +55 49 35511422; fax: +55 47 3341 7932.E-mail address: sfaloni@bol.com.br (S.F. de Andrade).

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378-8741/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.jep.2007.06.002

edicine, which can be partially explained by its multi-ethnicopulation (Farnsworth and Soejarto, 1991).

Peptic ulcer is a benign lesion of the gastric or duodenalucosa, which occurs at a site where the mucosal epithelium

s exposed to acid and pepsin. Stress, smoking, nutritionaleficiencies and ingestion of nonsteroidal-anti-inflammatoryrugs (NSAIDs) can all increase the incidence of gastric ulcerBelaiche et al., 2002).

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The treatment of peptic ulcer is generally based on thenhibition of gastric acid secretion by H2-antagonists, such asmeprazol and antimuscarinics, as well as acid-independentreatment by sucralfate and bismuth (Bighetti et al., 2005).owever, one of the major problems in the treatment of gas-

roduodenal ulcer is that, despite a healing rate of 80–100%fter 4–8 weeks of therapy with H2-antagonists and protonump inhibitors, the rate of ulcer recurrence within 1 year afteruspending the treatment is between 40 and 80% (Miller andaragher, 1986). Furthermore, most of these drugs produce sev-ral adverse reactions (Ariyphisi et al., 1986). A search for newherapeutic antiulcer agents is therefore essential.

Plants belonging to the Celastraceae family are widespreadn tropical and subtropical regions (Spivey et al., 2002). Theeaves of some Celastraceae are used in traditional medicineue to their analgesic, anti-inflammatory and antiulcerogenicctivities, among others (Correa, 1984). Also, several speciesf that family have been cited as displaying antiulcer activ-ty, e.g., Maytenus ilicifolia (Jorge et al., 2004), Maytenusquifolium (Gonzalez et al., 2001), Maytenus truncata (Silvat al., 2005) and Austroplenckia populnea (Andrade et al.,006). Phytochemical studies carried out with plants belong-ng to the Maytenus genus have demonstrated the presencef many classes of constituents, including flavonoids (Leitet al., 2001; Tiberti et al., 2007), pentacyciclic triterpenesrincipally from the friedelane, oleanane, lupane and ursaneeries (Oliveira et al., 2006), sesquiterpenes, alkaloids (Bruningnd Wagner, 1978), and condensed tannins (Gonzalez et al.,982).

Maytenus ilicifolia is the principal species of the Celas-raceae family, and is used in the treatment of gastric ulcers.owever, Maytenus ilicifolia is presently at the extinction

tage due to indiscriminate use in Brazil (Niero et al., 2001).aytenus robusta is also used in folk medicine, to treat stom-

ch ulcers (Balbach, 1980), and very well adapted to the Southf Brazil (Niero et al., 2001). Thus, its uses suggested inhytotherapeutic preparations, as a substitute for Maytenus ili-ifolia. However, there have been no reports regarding thentiulcer activity of Maytenus robusta extract. Therefore, thistudy was carried out to evaluate the antiulcerogenic prop-rty of the hydroalcoholic extract of Maytenus robusta aerialarts.

. Materials and methods

.1. Plant material and preparation of extract

Maytenus robusta was collected at the Morro do Bau Ecolog-cal Park, Ilhota, Santa Catarina, and identified by Dr. Ademireis (Department of Botany, Universidade Federal de Santaatarina). A voucher specimen was deposited at the Barbosaodrigues Herbarium (Itajaı-SC) under number V.C. Filho16.

The leaves of Maytenus robusta were dried under air circu-ation (40 ◦C). The dried leaves (500 g) were ground in a knife

ill, and macerated with aqueous ethanol 70% (v/v) at roomemperature for 7 days. The macerated leaves were filtered and

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harmacology 113 (2007) 252–257 253

oncentrated under reduced pressure, yielding 38.0 g (7.6%) ofrude hydroalcoholic extract.

.2. Drugs, reagents and solvents

Indomethacin, cimetidine and omeprazol were purchasedrom Sigma–Aldrich (St. Louis, MD, USA). All other usedeagents and solvents were of analytical grade.

.3. Animals

Male Wistar rats, weighing 200–250 g, were provided by theentral Animal House of the West University of Santa Cata-

ina (UNOESC), Videira Campus. The animals were housedn groups of five, in standard cages, at room temperature25 ± 3 ◦C), with 12 h dark/12 h light cycles, and food and waterd libitum. Twelve hours prior to the experiments they wereransferred to the laboratory and given only water ad libitum.he animals used in the present study were housed and cared

or in accordance with the Federal Government legislation onnimal care. Also, the experiments were authorized by the Eth-cal Committee for Animal Care of the University of the Westf Santa Catarina, Brazil.

.4. Antiulcer activity

The antiulcer assays were performed using the following pro-ocols: nonsteroidal anti-inflammatory drug (NSAID)-inducedlcer, ethanol-induced ulcer, and stress-induced ulcer. Since tra-itional uses of this plant is based on oral administration of aecoction prepared from 20.0 g of dry and pulverized leaf inpproximately 1 L of water, taken by people four times by dayTeske and Trentini, 2001), for a person with 80 kg body weight,his administration represents approximately 250 mg/kg/day.ased on this traditional preparation and use, the extract wasdministered by oral route at 50, 250 and 500 mg/kg.

.4.1. Ethanol-induced ulcerThe experiment was performed according to the method of

orimoto et al. (1991). After 12 h of fasting, the rats wereandomly divided into five groups of six animals each. Therst group was given 1 mL of vehicle (1% Tween-80 aqueousolution), and the second group was treated with omeprazol30 mg/kg). The remaining three groups received 50, 250 and00 mg/kg of Maytenus robusta extract, respectively. All thereatments were administered orally. One hour after treatment,ll the rats received 1 mL of 99.5% ethanol to induce gastriclcer. One hour later, the animals were sacrificed by cervicalislocation, and the stomachs removed and opened along thereater curvature. The stomachs were gently rinsed with water toemove the gastric contents and blood clots, for subsequent scan-ing. The images obtained were analyzed using specific “EARP”oftware to measure each lesion point. The ulcers were classi-

ed as level I, ulcer area <1 mm2; level II, ulcer area 1–3 mm2;nd level III, ulcer area >3 mm2. The following parameters wereetermined: (i) Ulcerative Lesion Index (ULI) as 1 × (numberf ulcers level I) + 2 × (number of ulcers level II) + 3 × (number

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f ulcers level III); (ii) cure ratio, which was determined as fol-ows: % C = 100 − (IUtreated × 100/IUcontrol); (iii) total area ofesion; (iv) percentage of lesion area in relation to total stomachrea.

.4.2. Nonsteroidal anti-inflammatory drugNSAID)-induced ulcer

The experiment was performed according to the methodf Nwafor et al. (2000), with a few modifications. After2 h of fasting, the rats were randomly divided into fiveroups of six animals each. The first group was given 1 mLf vehicle (1% Tween-80 aqueous solution), and the sec-nd group was treated with cimetidine (100 mg/kg). Theemaining three groups received 50, 250 and 500 mg/kg of

aytenus robusta extract, respectively. All the treatmentsere administered orally. One hour after treatment, all the

ats received indomethacin (100 mg/kg) to induce gastriclcer. Four hours after treatment with indomethacin, the ani-als were sacrificed by cervical dislocation. The stomachsere removed, and opened along the greater curvature. The

tomachs were gently rinsed with water to remove the gas-ric contents and blood clots, for subsequent scanning. Themages obtained were analyzed using the parameters previouslyescribed.

.4.3. Stress-induced ulcerThe method described by Basile et al. (1990) was used

n this assay. Groups of six animals were treated as previ-usly described, and 30 min later, each animal was placed intube and immersed vertically until the water reached the neck

egion in a tank with current water at 25 ◦C for 17 h. Afterhis period, the rats were sacrificed by cervical dislocation.he stomachs were removed and opened along the greater cur-ature, followed by gentle washing with water to remove theastric contents and blood clots, for subsequent scanning. Themages obtained were analyzed using the parameters describedbove.

.5. Determination of gastric secretion

The assay was performed using the method of Shay et al.1945) with a few modifications. The animals were divided intoroups (n = 6), according to the treatment used, as previouslyescribed. After 24 h of fasting, the animals were anesthetizedith tyopental sodium (10 mg/kg, i.p.), the abdomen was incised

nd the pylorus was ligated. Immediately after pylorus ligature,aytenus robusta extract was administered at doses of 50, 250

nd 500 mg/kg, respectively. Cimetidine (100 mg/kg) was useds positive control, and 1 mL of vehicle (1% Tween-80 aqueousolution) was administered as negative control. All the samplesere administered intraduodenally. Four hours later, the animalsere sacrificed by cervical dislocation; the abdomen was opened

nd another ligature was placed at the oesophageal end. The

tomachs were removed and the gastric content collected andentrifuged at 3000 rpm (8000 × g, 25 ◦C, 10 min). The amountf gastric acid (mL) and the pH values were determined. Theotal acid secretion in the gastric hen was determined in the

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harmacology 113 (2007) 252–257

upernatant volume by titration to pH 7.0 using a 0.01 mol−1

aOH solution, and phenolphthalein as indicator.

.6. Statistical analysis

Data are reported as mean ± standard error of the meanS.E.M.) and were compared using one-way analysis of vari-nce (ANOVA), followed by Dunnet’s pairwise test, and p values0.05 were considered significant.

. Results

In the ethanol-induced ulcer model, it was observed thathe treatment with Maytenus robusta extract (50, 250 and00 mg/kg) and omeprazol (30 mg/kg) significantly reduced theesion index, the total lesion area and the percentage of lesion,n comparison with negative control group (p < 0.05). The per-entages of inhibition of ulcers were 75.1 ± 8.6, 85.0 ± 9.2,6.6 ± 7.4 and 75.5 ± 5.3 for the treated groups with 50, 250 and00 mg/kg of Maytenus robusta and positive control (omepra-ole), respectively.

The treatment with Maytenus robusta extract (50, 250 and00 mg/kg) and cimetidine (100 mg/kg) reduced significantlyll the evaluated parameters in comparison with control groupp < 0.05) in the indomethacin-induced ulcer model. In thisodel, the percentages of inhibition of ulcers were 62.5 ± 7.1,

2.5 ± 6.1, 63.6 ± 5.5 and 96.2 ± 3.6 for groups treated with 50,50 and 500 mg/kg of Maytenus robusta and positive controlcimetidine), respectively.

Regarding the stress-induced ulcer model, it was observed aignificant reduction in lesion index, total lesion area and in theercentage of lesion in animals treated with Maytenus robustaxtract (50, 250 and 500 mg/kg) and cimetidine (100 mg/kg),n comparison with negative control group (p < 0.05). The per-entages of inhibition of ulcers were 71.3 ± 5.5, 72.7 ± 6.3,6.5 ± 7.1 and 92.3 ± 7.5 for the groups treated with 50, 250nd 500 mg/kg of Maytenus robusta and positive control (cime-idine), respectively. These results are summarized in Figs. 1–3.

In the gastric secretion determination model, using ligatedylorus, treatment with Maytenus robusta extract (50, 250 and00 mg/kg) and cimetidine (100 mg/kg), respectively, reducedhe volume of gastric juice, total acidity and raised gastric pHignificantly (p < 0.05) in comparison with the control groupTable 1).

. Discussion

There are several factors that may induce ulcer in humaneings, such as: stress, chronic use of anti-inflammatory drugsnd continuous alcohol ingestion, among others (Barocelli etl., 1997). Although in most cases the aetiology of ulcer isnknown, it is generally accepted that it is the result of an imbal-

nce between aggressive factors and maintenance of the mucosalntegrity through the endogenous defence mechanism (Pipernd Stiel, 1986). The candidate for an effective drug againsteptic ulcer should basically act either by reducing the aggres-

S.F. de Andrade et al. / Journal of Ethnopharmacology 113 (2007) 252–257 255

Fig. 1. Effect of Maytenus robusta hydroalcoholic extract on ulcer index (UI),total area of lesion, percentage of lesion and inhibition of ulcers in ethanol-induced ulcer model. The results are mean ± S.E.M. for six rats. Statisticalcomparison was performed using ANOVA followed by the Dunnet’s test.*p < 0.05 in comparison with the control group.

Fig. 2. Effect of Maytenus robusta hydroalcoholic extract on ulcer index (UI),total area of lesion, percentage of lesion and inhibition of ulcers in indomethacin-ic*

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Fig. 3. Effect of Maytenus robusta hydroalcoholic extract on ulcer index (UI),total area of lesion, percentage of lesion and inhibition of ulcers in stress-inducedulcer model. The results are mean ± S.E.M. for six rats. Statistical compari-sc

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nduced ulcer model. The results are mean ± S.E.M. for six rats. Statisticalomparison was performed using ANOVA followed by the Dunnet’s test.p < 0.05 in comparison with the control group.

ive factors on gastroduodenal mucosa or by increasing mucosalesistance against them.

Several species of plants belonging to that family Celas-

raceae have been cited as possessing antiulcer activityGonzalez et al., 2001; Jorge et al., 2004; Silva et al., 2005;ndrade et al., 2006). The Maytenus ilicifolia is main species

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able 1ffect of Maytenus robusta hydroalcoholic extract, administered intraduodenally, on

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reatments Dose (mg/kg) pH

ontrol – 1.58 ± 0.14imetidine 100 3.49 ± 0.33*aytenus robusta extract 50 2.79 ± 0.17*

250 2.96 ± 0.07*500 2.92 ± 0.15*

he results are mean ± S.E.M. for six rats. Statistical comparison was performed usontrol group.

on was performed using ANOVA followed by the Dunnet’s test. *p < 0.05 inomparison with the control group. CMT, cimetidine.

f this family used for treatment of gastric ulcers. Due to this,aytenus ilicifolia is presently at the extinction stage due to

ndiscriminate use in Brazil (Niero et al., 2001). Therefore, con-idering that Maytenus robusta is used in folk medicine to treattomach ulcers (Balbach, 1980), and is very well adapted tohe South of Brazil (Niero et al., 2001), this research was car-ied out to evaluate the antiulcer activity of Maytenus robustaydroalcoholic extract. For this purpose, the antiulcer activityas evaluated using ethanol, indomethacin and stress-inducedlcer models, the most commonly used experimental modelsor the evaluation of antiulcer activity in animal models. Also,he effect of Maytenus robusta extract on gastric secretion wasvaluated using the ligated pylorus model.

Exposure to ethanol increases the extension of cellular dam-ge in a dose-dependent way (Mutoh et al., 1990). Ethanols metabolised in the body and releases superoxide anion andydroperoxy free radicals. It has been found that oxygen-derivedree radicals are involved in the mechanism of acute and chroniclceration in the gastric mucosa (Pihan et al., 1987). Further-ore, disturbances in gastric secretion, damage to the gastricucosa, alterations in permeability, gastric mucus depletion and

ree-radical production are observed after the administration of

thanol (Salim, 1990). These data suggest that antioxidant com-ounds could be active in this experimental model, producingntiulcerogenic effects. This effect is known as cytoprotection.

the biochemical parameters of gastric juice obtained from pylorus ligature in

Gastric juice volume (mL) [H+] mequiv./I/4 h)

3.14 ± 0.52 121.45 ± 12.790.76 ± 0.16* 48.40 ± 7.86*0.92 ± 0.15* 61.49 ± 4.06*0.87 ± 0.07* 56.27 ± 4.53*0.78 ± 0.05* 56.90 ± 3.67*

ing ANOVA followed by the Dunnet’s test. *p < 0.05 in comparison with the

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In the present study, the control group treated orally withthanol clearly produced the expected characteristic zone ofecrotizing mucosal lesions. On the other hand, the treat-ents with Maytenus robusta extract significantly decreased the

esion index, the total lesion area and the percentage of lesion.hese results indicate that Maytenus robusta extract displays anntiulcerogenic effect related to cytoprotective activity, since itignificantly reduced the ethanol-induced ulcer.

Nonsteroidal anti-inflammatory drugs (NSAIDS), likespirin and indomethacin, are known to induce ulcers dur-ng the course of anti-inflammatory therapy, by inhibitingrostaglandin synthetase through the cycloxygenase pathwayRainsford, 1987). In the stomach, prostaglandins play a vitalrotective role, stimulating the secretion of bicarbonate anducus, maintaining mucosal blood flow, and regulating mucosal

ell turnover and repair (Hayllar and Bjarnason, 1995). Thus,he suppression of prostaglandin synthesis by NSAIDS resultsn increased susceptibility to mucosal injury and gastroduode-al ulceration. It was observed that Maytenus robusta extractisplayed significant reduction of the mucosal damage in thendomethacin-induced ulcer model. These results suggest theossible involvement of prostaglandins and/or mucus in thentiulcer effect of the extract.

Gastric stress ulceration is probably mediated by the releasef histamine. It not only enhances the gastric secretion, oftenalled the aggressive factor, but also causes disturbances of theastric mucosal microcirculation and abnormal motility, andeduces mucus production, known as the defensive factor. More-ver, stress-induced ulcer in animal models may be partially orntirely prevented by vagotomy, since increased vagal activityas been suggested as the main factor in stress-induced ulcera-ion (Singh and Majumdar, 1999). In the current study, Maytenusobusta extract inhibited the production of stress-induced ulcers.his finding indicates that Maytenus robusta may enhance gas-

ric mucosal defensive factors.In this work, we also evaluated the activity of Maytenus

obusta extract on gastric secretion in the ligature pylorus model.significant decrease in gastric fluid volume, and a decrease in

cid output with an elevation in gastric pH, were observed afterntraduodenal administration of Maytenus robusta extract, whenompared with the respective control, indicating that it possessntisecretory potency. Moreover, these results showed that thentiulcer activity of this extract was not only related to a localeutralization of gastric content, but also that it was effectivefter the absorption of the extract, indicating a systemic effect.his effect is also indicative of antihistaminic activity.

The phytochemical profile, carried out with samples fromaytenus robusta extract used in this study, indicated the pres-

nce of triterpenes (Niero et al., 2001, 2006). A review onntiulcer drugs of plant origin shows that triterpenes, becausef their ability to strengthen defensive factors such as stimu-ation of mucus synthesis or maintenance of the prostaglandinontents of gastric mucosa at high levels, are compounds with

otential antiulcerogenic activity (Lewis and Hanson, 1991). Onhe other hand, studies carried out by Queiroga et al. (2000)ave revealed that the triterpenes friedelin and friedelanol doot display antiulcer activity. However, other triterpenes, such

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harmacology 113 (2007) 252–257

s populnoic acid, which was isolated from Maytenus ilicifo-ia, Maytenus senegalensis (Itokawa et al., 1991; Sosa et al.,007) and other species belonging to the Celastraceae family,id present antiulcer activity (Andrade et al., 2006). Moreover,he presence of flavonoids was ascribed to the Maytenus speciesVilegas et al., 1999; Jorge et al., 2004; Tiberti et al., 2007). It isell known that many flavonoids display antisecretory and cyto-rotective properties in different experimental models of gastriclcer (Martin et al., 1998; Zayachkivska et al., 2005).

In addition, oxidative damage is considered to be a commonactor in the pathogenesis of ulcers by different experimen-al and clinical models (Sairam et al., 2002). This antioxidantctivity has been described for several triterpenes, such as: �-nd �-amirins, oleanolic acid, ursolic acid, lupeol and glycir-etinic acid, among other related compounds (Andrikopoulost al., 2003). Furthermore, antioxidant activity was observed inxtracts containing flavonoids (Larson, 1998; Ohshima et al.,998; Gonzalez and Di Stasi, 2002). Therefore, the antiulcerctivity of Maytenus robusta extract may be partially due to itselative antioxidant activity.

It is also important to take into consideration that theesults obtained in this study show that the activity antiulcer of

aytenus robusta was similar to that observed in studies carriedut with Maytenus ilicifolia (Jorge et al., 2004), using equivalentoses.

In conclusion, the results of the present study show thataytenus robusta hydroalcoholic extract displays gastroprotec-

ive activity, as demonstrated by its significant inhibition of theormation of ulcers induced using different models, as well as itsbility to decrease gastric secretion. These results were similaro the results observed in the studies undertaken with Maytenuslicifolia. Thus, considering that Maytenus ilicifolia is presentlyt the extinction stage owing to indiscriminate use in Brazil,nd that Maytenus robusta is very well adapted to the Southf Brazil, the results indicate that this species could be usedn phytotherapeutic preparations as a substitute for Maytenuslicifolia. Besides, this work corroborates the traditional indica-ion of Maytenus robusta, contributing for its pharmacologicalalidation.

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