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Gastroprotective activity of the ethanol extract from the innerbark ofCaesalpinia pyramidalis in rats

Ana Roseli S. Ribeiro a, Polyana B.F. Diniz a, Charles S.Estevam a, Malone S. Pinheiro b,Ricardo L.C. Albuquerque-Jnior c, Sara M. Thomazzi a,n

a Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitria, CEP 49100-000 So Cristvo, Sergipe, Brazilb Laboratrio de Biomedicina, Universidade Tiradentes, Av. Murilo Dantas, 300, CEP 49032-490 Aracaju, Sergipe, Brazilc Instituto de Tecnologia e PesquisaITP, Universidade Tiradentes, Av. Murilo Dantas, 300, CEP 49032-490 Aracaju, Sergipe, Brazil

a r t i c l e i n f o

Article history:

Received 20 December 2012

Received in revised form

31 January 2013

Accepted 10 March 2013Available online 16 March 2013

Keywords:

Antiulcer

Caesalpinia pyramidalis

Fabaceae

Gastroprotective

Helicobacter pylori

a b s t r a c t

Ethnopharmacological relevance: Caesalpinia pyramidalis Tul. (Fabaceae), known as catingueira, has

been used in folk medicine in the treatment of various disorders such as gastritis, heartburn, indigestion,and stomach ache. However, the gastroprotective properties of this species have not yet been studied.Materials and methods: The ethanol extract ofCaesalpinia pyramidalisinner bark was used in rats via oral

route, at the doses of 30, 100, and 300 mg/kg. The antiulcer assays were performed using the ethanol-

and nonsteroidal anti-inammatory drug-induced ulcer models. Gastric secretion parameters (volume,pH, and total acidity) were also evaluated by the pylorus ligated model, and the mucus in the gastriccontent was determined. The anti-Helicobacter pylori activity of the ethanol extract of Caesalpinia

pyramidalis was performed using the agar-well diffusion and broth microdilution methods.Results: The ethanol extract (30, 100, and 300 mg/kg) produced dose dependent inhibition ( Po0.01) on

the ulcer lesion index, the total lesion area, and the percentage of lesion area in the ethanol-inducedulcer model. The ethanol extract (30, 100, and 300 mg/kg) also reduced (Po0.001) the ulcer index in the

indomethacin-induced ulcer model. In the model ligature pylorus, the treatment with Caesalpiniapyramidalisethanol extract failed to signicantly change the gastric secretion parameters. However, after

treatment with the ethanol extract of Caesalpinia pyramidalis (30, 100, and 300 mg/kg), there was asignicant increase (Po0.05) in mucus production. The ethanol extract showed anti-Helicobacter pylori

activity, with inhibition halos of 12.071.7 mm at 10,000 g/mL. The minimum inhibitory concentration

(MIC) and minimal bactericidal concentration (MBC) values of the ethanol extract were of 625 and

10,000g/mL, respectively.Conclusions: Collectively, the present results suggest that the ethanol extract of Caesalpinia pyramidalis

displays gastroprotective actions, supporting the folkloric usage of the plant to treat various gastro-

intestinal disturbances.

& 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Peptic ulcer is an integrity disturbance of the gastric and/orduodenum mucosa, which causes local defect or excavation due toactive inammation (Syam et al., 2009). It is a recurrent chronic

illness that affects approximately 10% of the world population(Zapata-Colindres et al., 2006). However, current therapy of pepticulcers may fail due to hypersensitivity, gynecomastia, impotence,arrhythmia, and hematopoietic changes of drugs such as antacids,

anticholinergics, proton pump inhibitors, and H2-receptor antago-

nists (Bighetti et al., 2005; Lakshimi et al., 2010).

In recent years, considering the prominence of the disease,interest in the use of natural products as sources of new drugs forthe treatment of peptic ulcer has signicantly increased (Falco

et al., 2008). Plants belonging to the genusCaesalpinia (Fabaceae)have been used in folk medicine and its antiulcer activity has beendemonstrated (Bacchi et al., 1995; Sharma and Rajani, 2011).

Caesalpinia pyramidalis Tul., known as catingueira, i s a n

endemic medicinal plant species of the Northeast region of Brazil,mainly from the caatinga (Agra et al., 2007; Albuquerque et al.,2007). Bark, ower, leaf, root, and stem are traditionally used inthe form of drink and to wash the affected site in the treatment of

gastritis, heartburn, indigestion, stomach ache, stomach problems,cough, bronchitis, asthma, respiratory infection, inuenza, colic,

Contents lists available atSciVerse ScienceDirect

journal homepage: www.elsevier.com/locate/jep

Journal of Ethnopharmacology

0378-8741/$- see front matter& 2013 Elsevier Ireland Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.jep.2013.03.023

n Correspondence to: Department of Physiology, Center of Biological and Health

Sciences, Federal University of Sergipe, 49100-000 So Cristvo (SE), Brazil.

Tel.: 55 79 21056640; fax: 55 79 21056474.

E-mail addresses: [email protected],[email protected] (S.M. Thomazzi).

Journal of Ethnopharmacology 147 (2013) 383388
http://www.elsevier.com/locate/jephttp://www.elsevier.com/locate/jephttp://dx.doi.org/10.1016/j.jep.2013.03.023mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.jep.2013.03.023http://dx.doi.org/10.1016/j.jep.2013.03.023http://dx.doi.org/10.1016/j.jep.2013.03.023http://dx.doi.org/10.1016/j.jep.2013.03.023mailto:[email protected]:[email protected]://crossmark.dyndns.org/dialog/?doi=10.1016/j.jep.2013.03.023&domain=pdfhttp://crossmark.dyndns.org/dialog/?doi=10.1016/j.jep.2013.03.023&domain=pdfhttp://crossmark.dyndns.org/dialog/?doi=10.1016/j.jep.2013.03.023&domain=pdfhttp://dx.doi.org/10.1016/j.jep.2013.03.023http://dx.doi.org/10.1016/j.jep.2013.03.023http://dx.doi.org/10.1016/j.jep.2013.03.023http://www.elsevier.com/locate/jephttp://www.elsevier.com/locate/jep

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fever, atulence, diarrhea, collision, injury, diabetes, and as expec-torant and aphrodisiac (Albuquerque et al., 2007; Cartaxo et al.,2010).

Pharmacological studies ofCaesalpinia pyramidalishave shown

it to be useful in the treatment of diarrhea, inammation, and pain(Braga, 1960; Santana et al., 2012; Santos et al., 2011).

Therefore, the present study was carried out in order toevaluate the gastroprotective potential of the ethanol extract of

Caesalpinia pyramidalis inner bark.

2. Materials and methods

2.1. Plant collection and extraction of the ethanol extract

The inner bark ofCaesalpinia pyramidalis was collected in the

municipality of Canind de So Francisco-SE, Brazil, in September2008 (0916600S, 3717894W). The plant was authenticated byProfessor Ana Paula Prata, Department of Biology, FederalUniversity of Sergipe. A voucher specimen has been deposited at

the Herbarium of the Federal University of Sergipe (number ASE13,164). The inner bark was dried at 40 1C in a forced air oven fortwo days and subsequently powdered (2,840 g) and extracted bymaceration at room temperature with 90% ethanol for ve days.

The extract was ltered in vacuum, and the solvent was removedusing a rotary evaporator (45 1C). The percentage of yield of theethanol extract (EE) was 2.6% (73.8 g).

The EE of Caesalpinia pyramidalis was analyzed using high

performance liquid chromatography (Shimadzu, Prominencemodel, Kyoto, Japan) consisting of a vacuum degasser DGU-20A3model, SIL-10A autosampler, two high pressure pumps LC-6A, and

an SPDM20Avp photodiode array detector system coupled with aCBM 20A interface. Analysis was performed in an analyticalPhenomenex LUNA C18 column (2504.6 mm i.d., 5 mm ofparticle diameter, Torrance, CA, USA). Separation of compounds

was done by reverse mode gradient elution as previouslydescribed (Santana et al., 2012).

2.2. Drugs

The following substances were used: Alcin blue, carbenoxolone,cimetidine, indomethacin, and omeprazole (Sigma Chemical Co.,

St. Louis, MO). All the other reagents used were of analytical grade.All substances used were dissolved in 0.2% Tween 80 in 0.9% NaClsolution, with the exception of indomethacin which was dissolvedin 2% sodium bicarbonate.

2.3. Microorganism

Helicobacter pylori strain ATCC 43504 was obtained from the

Instituto Nacional de Controle de Qualidade em Sade

INCQS

Fundao Oswaldo CruzFiocruz/RJ, Brazil. Stock cultures weremaintained in Tryptic Soy broth at 20 1C.

2.4. Animals

Young adult Wistar rats (180300 g) of both sexes wereobtained from the Central Biotery of the Federal University of

Sergipe (So Cristvo, Brazil). Animals were maintained at con-trolled room temperature (2172 1C) with free access to food(Purina) and water, under a 12 h light/dark cycle. Twenty-fourhours before the experiments, they were transferred to the

laboratory and given only water, ad libitum. The experimentswere performed after approval of the protocol by the Institutional

Ethics Committee (CEPA/UFS 63/11) and were carried out in

accordance with the current guidelines for the care of laboratoryanimals.

2.5. Antiulcerogenic activity

2.5.1. Ethanol-induced ulcerThe experiment was carried out according to the method of

Robert et al. (1979). After 24 h of fasting, the rats (n8/group)

were pre-treated orally (p.o.) with the EE (30300 mg/kg),omeprazole (30 mg/kg), or vehicle (0.2% Tween 80, 10 mL/kg).One hour after treatment, all the rats received 4 mL/kg of absoluteethanol to induce gastric ulcer. One hour later, the animals wereanesthetized and euthanized by cervical dislocation, and their

stomachs were removed and opened along the greater curvature.The stomachs were gently rinsed with water to remove the gastriccontents and blood clots, for subsequent scanning. The imagesobtained were analyzed using a specic EARP software (devel-

oped by Dr. Eros Comunello, Universidade do Vale do Itaja,So Jos, SC, Brazil) measuring each lesion point. The ulcers wereclassied as level I, ulcer areao1 mm2; level II, ulcer area13 mm2; and level III, ulcer area43 mm2. The following para-

meters were determined: (i) Ulcerative Lesion Index (ULI) as 1

(number of ulcers level I)2 (number of ulcers level II)3(number of ulcers level III); (ii) curative ratio, which was deter-

mined as follows: %C100 (ULI treated 100/ULI vehicle); (iii)total area of lesion (mm2); and (iv) percentage of lesion area inrelation to total stomach area (Andrade et al., 2006).

For the histological analysis, the absolute ethanol-induced

ulcerative response in the stomachs was carried out after 1 h.The stomach samples were xed in 10% formalin and embedded inparafn. The samples (EE at 100 and 300 mg/kg, omeprazole, andvehicle) were cut in serial 5 m thick sections and stained in

hematoxylineosin. A microscopic score was determined for thefollowing parameters: (i) disruption of the supercial region of thegastric gland with epithelial cell loss, (ii) interstitial edema, and(iii) submucosal leukocytes inltration, using a scale ranging from

0 to 3 (0: none; 1: mild; 2: moderate; and 3: severe) for eachcriterion. The sections were assessed by an experienced patholo-gist without the knowledge of the treatments (four histologicalsections/animal, n8/group).

2.5.2. Nonsteroidal anti-inammatory drug (NSAID)-induced ulcer

The experiment was carried out according to the method ofDjahanguiri (1969)with a few modications. After 24 h of fasting,the rats (n8/group) were pre-treated orally with the EE (30300 mg/kg), cimetidine (100 mg/kg), or vehicle (0.2% Tween 80).

One hour after treatment, all the rats received indomethacin(100 mg/kg, p.o.) to induce gastric ulcer. Six hours after treatmentwith indomethacin, the animals were anesthetized and eutha-nized by cervical dislocation. The stomachs were removed, and

opened along the greater curvature. The stomachs were gentlyrinsed with water to remove the gastric contents and blood clots.For determination of the ulcer index, scores were attributed asfollows: (i) score 1 each, loss of mucosal folding, mucosal dis-coloration, edema, or hemorrhage; (ii) score 2, less than 10

petechiae; and (iii) score 3, more than 10 petechiae ( Gamberiniet al., 1991).

2.6. Evaluation of mucosal protective factors

2.6.1. Determination of the gastric juice parameterspyloric ligatureThe assay was performed using the method ofShay et al. (1945)

with a few modications. After 24 h of fasting, the animals were

anesthetized with tyopental sodium (10 mg/kg, i.p.), the abdomen

was incised and the pylorus ligated. Immediately after pylorus

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production, compared with the group treated with vehicle (Table 5).Carbenoxolone (200 mg/kg) also increased the mucus production

(Po0.05,Table 5).The EE showed anti-Helicobacter pyloriactivity, with inhibition

halos of 12.071.7 mm at 10,000 g/mL. Tetracycline (30 g/mL),

used as the standard drug in the assay, presented inhibition halos

of 40.070.5 mm.The MIC and MBC values obtained in the broth microdilution

method of the EE were 625 and 10,000 g/mL, respectively.

Fig. 1. Photomicrographs of gastric mucosa (HE; magnication 100 for a, d, g, and j; 400 for b, c, e, f, h, i, k, and l). (ac) Vehicle group showing disruption of the epithelial

structure (des), pronounced interstitial edema of the submucosa (ed3), and inammatory inltrate (arrows). (df) Omeprazole group showing gastric epithelium (ge) and submucosa

with normal characteristics. The EE of Caesalpinia pyramidalisgroups, at 100 (gi) and 300 mg/kg (jl), showing the gastric epithelium (ge) preserved and discreet interstitial edema ofthe submucosa (ed1). get: gastric epithelial tissue; sct: submucosal connective tissue; pml: peripheral muscle layer (four histological sections of each animal, n8/group).

Table 2

Effect of the ethanol extract of Caesalpinia pyramidalis (EE) on ethanol-induced

microscopic damage in gastric mucosa.

Treatment

(p.o.)

Dose

(mg/kg)

Epithelial cell loss

(score 03)

Edema

(score 03)

Inammatory

cells (score 03)

Vehicle 3.0 (2.03.0) 3.0 (2.03. 0) 1.0 (0.01.0)

Omeprazole 30 1.0 (1.02.0) nnn 1.0 (0.02.0) nnn 0.5 (0.01.0)

EE 100 1.0 (0.03.0) nnn 1.0 (0.02.0) nnn 0.0 (0.02.0) nnn

300 1.0 (0.02.0) nnn 1.0 (0.02.0) nnn 0.0 (0.00.0)

Data shown are medians with minimum and maximal scores in brackets. Kruskal

Wallis followed by Dunn's test vs. vehicle group (four histological sections of each

animal,n8/group).nnn Po0.001.

Table 3

Effect of the ethanol extract of Caesalpinia pyramidalis (EE) on indomethacin-

induced ulcers in rats.

Tr eat ment ( p. o. ) Dose ( mg/kg) Ulcer index Inhibition ( %)

Vehicle 3.0770.25

Cimetidine 100 0.4070.21 nnn 86.97

EE 30 0.6770.28 nnn 78.18

100 0.4070.27 nnn 86.97

300 0.7370.30 nnn 76.22

Results as mean7SEM (n8/group). Statistical comparison was performed using

Kruskal-Wallis followed by Dunn's test vs. vehicle group.nnn Po0.001.


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4. Discussion

The present study demonstrates that the oral administration of

the EE ofCaesalpinia pyramidalispossesses gastroprotective activity,as evidenced by its inhibition of the development of ulcers induced

by chemical agents and increase of mucosal protective factor afterthe intraduodenal administration.

The functional integrity of gastric mucosa depends on a balancebetween protective mechanisms and aggressive factors. Thus, thesuccess of gastric pharmacological treatment relies not only on theblockage of acid secretion, but also on the augmentation of the

protective factors of the gastric mucosa (Dajani and Klamut, 2000).Ethanol-induced ulcer model was rst performed to assess the

gastroprotective effects of the EE ofCaesalpinia pyramidalis. It iswell established that, ethanol is considered one of the agents that

induce more intense gastric ulcers because it promotes seriousdisturbances in the gastric mucosa (Hiruma-Lima et al., 2009).Ethanol acts by exerting a direct toxic effect on the epithelium,leading to the formation of characteristic necrotic lesions due to a

reduction in the mucus production and bicarbonate secretion(Massignani et al., 2009). In addition, it induces reduction ofgastric blood ow, the solubilization of components of the mucusof the stomach, and oxidative stress, increase of xanthine oxidase

activity and levels of malondialdehyde with reduction in levels ofglutathione (Marrotta et al., 1999).

Here, we clearly demonstrated that the vehicle group, treatedorally with absolute ethanol, produced the expected characteristic

zone of necrotizing mucosal lesions with severe macroscopic andmicroscopic gastric mucosal damage (epithelial cell loss, edema,and inammatory cell inltrate). On the other hand, Caesalpinia

pyramidalis EE-treated groups signicantly decreased the ulcerlesion index, the total lesion area, and the percentage of lesion as

well as the epithelial cell loss, edema, and inammatory cell

inltrate. These results indicate that Caesalpinia pyramidalis EE

displays an antiulcerogenic effect related to cytoprotective activity,since it signicantly reduced the ethanol-induced ulcer.

In order to provide more evidence concerning the gastroprotec-tive effect of Caesalpinia pyramidalisEE, we investigated its action on

indomethacin-induced ulcer model. NSAID are considered anotherwell established and common cause of peptic ulcers in humans(Bjarnason et al., 2007). These drugs are known to induce ulcersduring the course of anti-inammatory therapy, by inhibiting pros-

taglandin synthetase through the inhibition of cyclo-oxygenase(COX)-1 and COX-2 activities, and direct cytotoxic effects on theepithelium (Moleiro et al., 2009; Rainsford, 1987). Prostaglandinsplay an important protective role by stimulating the secretion of

bicarbonate and mucus, maintaining the bloodow of the mucosa,and they are responsible for regulating mucosal cell renewal. Ourresults demonstrated that the EE ofCaesalpinia pyramidalispresentsgastroprotective potential in NSAID-induced ulcer model. This action

denotes that the EE ofCaesalpinia pyramidaliscould be administeredtogether with NSAID with the aim of minimizing this side effect onthe gastric mucosa.

Previous study suggests that natural compound may provide a

cytoprotective effect by the induction of COX-2 expression ingastric mucosa and maintenance of basal prostaglandin E2 levelindependent of action of NSAID in gastric mucosa (Moleiro et al.,2009). However, prostaglandin inhibition seems not to be the

exclusive mechanism of NSAID-induced gastric lesion. Othermechanisms such as induction of oxidative damage throughincreased lipid peroxidation, thiol depletion, and inactivation ofgastric mucosal peroxidase are also involved (Prez et al., 2013;

Rao et al., 2004).The next step of this study was the evaluation of the effect of

the EE of Caesalpinia pyramidalis on gastric juice parametersthrough the pylorus ligature model. In this model, the digestive

effect of accumulated gastric juices and interference in gastricblood ow are responsible for inducing ulceration (Patel et al.,2000). The intraduodenal administration of the EE ofCaesalpinia

pyramidaliswas not able to change the volume, acidity, and pH ofthe gastric juice. Therefore, the EE ofCaesalpinia pyramidalis did

not act as an antacid or as buffer solution in contact with gastricmucosa, as indicated by the lack of antisecretory effects in the

gastric juice.Another parameter measured in this study was the amount of

gastric mucus in pylorus-ligated rats. Gastric mucus is the rst lineof defense against acid and adheres together with bicarbonate

secreted by the epithelium to serve as a barrier against self-digestion (Allen and Flemstrn, 2005). We observed that theamount of adhered gastric mucus was augmented by treatmentwith the EE of Caesalpinia pyramidalis when compared to the

animals treated with vehicle. These results indicate an increase inthe amount of mucus as a potential mechanism of action for thegastroprotective effect of the EE ofCaesalpinia pyramidalis.

Considering that the EE ofCaesalpinia pyramidalis has gastro-

protective actions, additional assays were carried out in order toevaluate its anti-Helicobacter pyloriactivity. Our ndings show thatthe EE ofCaesalpinia pyramidalispresents a MIC value of 625 g/mL.Natural products with concentrations above 500 g/mL have weak

antimicrobial activity, their use being difcult to treat bacterial orfungal infections (Holetz et al., 2002).

Generally, the major components are found to reect quite wellthe biophysical and biological features of the extracts from which

they were isolated. Our previous study conrmed the presence ofavonoids in the EE of Caesalpinia pyramidalis inner bark, anddemonstrated the presence of rutin (Santana et al., 2012). Theliterature shows that some potent antiulcer plants containphenolic compounds, namely, baicalein, cinnamic acid, oleuropein,

rutin, quercetin, and tephrosin, as active constituents (Sumbul

et al., 2011).

Table 4

Effect of the ethanol extract of Caesalpinia pyramidalis (EE), administered intra-

duodenally, on the biochemical parameters of gastric juice obtained from pylorus

ligature in rats.

Treatment

(p.o.)

Dose (mg/kg) Volume (mL) pH [H]mEq/L/4 h

Vehicle 1.0470.19 3.6070.18 48.8672.82

Cimetidine 100 0.4270.05 nn 4.9670.33 nnn 28.0972.45 nn

EE 30 0.7370.07 3.5070.13 49.1073.76100 0.6870.09 3.4870.18 45.0973.50

300 0.7070.07 3.2570.14 51.1273.57


ANOVA followed by Tukey's test vs. vehicle group.nn Po0.01.nnn Po0.001.

Table 5

Effect of the ethanol extract ofCaesalpinia pyramidalis (EE) on Alcian blue binding

to free gastric mucus from pylorus ligature in rats.

Treatment (p.o.) Dose (mg/kg) Alcian blue bound (mg/g tissue)

Vehicle 1.0070.13

Carbenoxolone 200 1.4370.07 n

Indomethacin 100 0.9170.07EE 30 1.4470.05 n

100 1.4470.11 n

300 1.6170.09 nnn


ANOVA followed by Tukey's test vs. vehicle group.n Po0.05.nnn Po0.001.

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5. Conclusion

In summary, the present results provide convincing evidencethat the EE from Caesalpinia pyramidalis displays pronounced

gastroprotective activity, as evidenced by the signicant inhibitionof the formation of ulcers induced by different agents and increasein the amount of mucus, supporting the folkloric usage of the plantto treat various gastrointestinal disorders. This ethanol extract is of

great interest as a source of novel molecules for developingstrategies more appropriate in treating ulcer. In order to identifythe active compounds present in the EE ofCaesalpinia pyramidalis,pharmacological and chemical studies are in progress.

Acknowledgments

The authors are grateful to Coordenao de Aperfeioamentode Pessoal de Nvel Superior (CAPES) and Conselho Nacional deDesenvolvimento Cientco e Tecnolgico (CNPq). SMT is recipientof CNPq productivity grants.

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Glossary

COX: cyclo-oxygenase;EE: ethanol extract;MBC: minimal bactericidal concentration;MIC: minimum inhibitory concentration;NSAID: nonsteroidal anti-inammatory drugs.

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