Ulcer healing and mechanism(s) of action involved in the gastroprotective activity of fractions obtained from Syngonanthus arthrotrichus and Syngonanthus bisulcatus

BMC Complementary and Alternative Medicine

Alba Regina Monteiro Souza Brito⁴  Paulo Takeo Sano¹  Wagner Vilegas²  Clélia Akiko Hiruma-Lima²  Cláudia Helena Pellizzon³  Anderson Luiz Ferreira⁴  Tamara Regina Calvo⁴  Luciana De Pietro Magri⁴  Ana Beatriz Albino De Almeida⁴  Gedson Rodrigues De Morais Lima⁵  Leônia Maria Batista⁴ 

[1] Departamento de Botânica, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil;Departamento de Fisiologia, Instituto de Biociências, Universidade Estadual Paulista, Botucatu, SP, Brazil;Departamento de Morfologia, Instituto de Biociências, Universidade Estadual Paulista, Botucatu, SP, Brazil;Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil;Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Laboratório de Farmacologia do Trato Gastrintestinal, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brazil

关键词: Gastroprotective activity;    Healing;    Flavonoid;    Syngonanthus bisulcatus;    Syngonanthus arthrotrichus;    Eriocaulaceae;   

Others  :  1233208
DOI  :  10.1186/s12906-015-0923-x

 received in 2014-11-14, accepted in 2015-10-20,  发布年份 2015

【 摘 要 】

Background

Syngonanthus arthrotrichus and Syngonanthus bisulcatus, currently known for Comanthera aciphylla (Bong.) L.R.Parra & Giul. and Comanthera bisulcata (Koern.) L.R. Parra & Giul, popularly known in Brazil as “sempre-vivas,” are plants from the family Eriocaulaceae. They are found in the states of Minas Gerais and Bahia. The species are known to be rich in flavonoids to which their gastroprotective activity has been attributed. In this research, experimental protocols were performed to elucidate the associated mechanisms of action.

Methods

The activity was evaluated using induced gastric ulcer models (acetic acid and ethanol-induced gastric lesions in NEM or L-NAME pre-treated mice, and by ischemia/reperfusion). Antioxidant enzymes, serum somatostatin, and gastrin were also evaluated.

Results

In chronic gastric ulcers, a single daily oral dose of Sa-FRF or Sb-FRF (100 mg/kg body wt.) for 14 consecutive days accelerated ulcer healing to an extent similar to that seen with an equal dose of cimetidine. The pre-treatment of mice with NEM (N-ethylmaleimide) or L-NAME (N-nitro-L-arginine) abolished the protective activity of Sa-FRF, Sa-FDF, Sb-FDF and Sb-FRF or Sa-FRF and Sb-FRF, respectively, which indicates that antioxidant compounds and nitric oxide synthase activity are involved in the gastroprotective. Sa-FRF and Sb-FRF (100 mg/kg p.o) protected the gastric mucosa against ulceration that was induced by ischemia/reperfusion (72 and 76 %, respectively). It also decreased lipid peroxidation and restored total thiols in the gastric wall of mice that had been treated with ethanol. When administered to rats submitted to ethanol-induced gastric lesions, Sa-FRF and Sb-FRF (100 mg/kg, p.o.) increased the somatostatin serum levels, while the gastrin serum levels were proportionally decreased.

Conclusions

The results indicate significant healing effects and gastroprotective activity for the Sa-FRF and Sb-FRF, which probably involves the participation of SH groups, nitric oxide (NO), the antioxidant system, somatostatin, and gastrin. All are integral parts of the gastrointestinal mucosa’s cytoprotective mechanisms against aggressive factors.

【 授权许可】

   
2015 Batista et al.

【 参考文献 】

• [1]Li WF, Hao DJ, Fan T, Huang HM, Yao H, Niu X et al.. Protective effect of chelerythrine against ethanol-induced gastric ulcer in mice. Chem Biol Interact. 2014; 208:18-27.
• [2]Maity P, Biswas K, Roy S, Banerjee RK, Bandyopadhyay U. Smoking and the pathogenesis of gastroduodenal ulcer-recent mechanism update. Mol Cell Biochem. 2003; 253:329-338.
• [3]Wallace JL, Granger DN. The cellular and molecular basis of gastric mucosal defense. Faseb J. 1996; 10:731-740.
• [4]Mózsik G, Jávor T. A biochemical and pharmacological approach to the genesis of ulcer disease. I. A model study of ethanol-induced injury to gastric mucosa in rats. Dig Dis Sci. 1988; 33:92-105.
• [5]Malfertheiner P, Chan FKL, McColl KEL. Peptic ulcer disease. Lancet. 2009; 374:1449-1461.
• [6]Lin PC, Chang CH, Hsu PI, Tseng PL, Huang YB. The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta-analysis. Crit Care Med. 2010; 38:1197-1205.
• [7]Bansal VK, Goel RK. Gastroprotective effect of Acacia nilotica young seedless pod extract: role of polyphenolic constituents. Asian Pac J Trop Med. 2012; 5:523-528.
• [8]Henmann FD. Inhibition of peptic activity by carbenoxolone and glycerrhetinic acid. Gut. 1970; 11:344-351.
• [9]Baron JH. Effect of carbenoxolone sodium on human gastric acid secretion. Gut. 1977; 18:721-722.
• [10]Ali AM, Al-Alousi L, Sae-lem HA. Licorice: A possible anti-inflammatory and Anti-ulcer drug. AAPS Pharm Sci Tech. 2005; 6:74-82.
• [11]Shibata S. A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice [review]. Yakugaku Zasshi. 2000; 120:849-862.
• [12]Adami E, Marzzi-Uberti E, Turba C. Pharmacological research on gefarnate, a new synthetic isoprenoid with antiulcer action. Arch Int Pharmacol Therap. 1964; 147:113-145.
• [13]Best R, Lewis DA, Nasser N. The antiulcerogenic activity of unripe plantain banana (Musa spp.). Brit J Pharmacol. 1984; 82:107-116.
• [14]Goel RK, Gupta S, Shankar R, Sanyal AK. Anti-ulcerative effect of Banana powder (Musa sapientum var. paradisiacal) and its effect on mucosal resistance. J Ethnopharmacol. 1986; 18:33-44.
• [15]Giulietti AM, Pirani JR. Patterns of geographic distribution of some plant species from the Espinhaço Range, Minas Gerais and Bahia, Brazil. In: Proceedings of a Workshop on Neotropical Distribution Patterns. Heyer WR, Vanzolini PE, editors. Academia Brasileira de Ciências, Rio de Janeiro; 1988: p.39-69.
• [16]Giulietti AM, Hensold N. Padrões de distribuição geográfica dos gêneros de Eriocaulaceae. Acta Bot Bras. 1990; 4:133-158.
• [17]Lazzari LRP. Redelimitacão e revisão de Syngonanthus Sect. Eulepis (Bong. ex Koern.) Ruhland – Eriocaulaceae. PhD Thesis. Universidade de São Paulo, 2000.
• [18]Parra LR, Giulietti AM, Andrade MJG, Van Den Berg C. Reestablishment and new circumscription of Comanthera (Eriocaulaceae). Taxon. 2010; 59:1135-1146.
• [19]Batista LM. Atividade Antiulcerogênica de Extratos e Frações obtidas dos escapos das espécies Syngonanthus bisulcatus Rul. e Syngonanthus arthrotrichus Silveira em modelos animais. PhD Thesis. . Instituto de Biologia, Universidade de Campinas; 2003.
• [20]Agrawal PK. Carbon-13 NMR of flavonoids. Elsevier, Amsterdam; 1989.
• [21]Harbone JB. The Flavonoids advances in research since 1986. Chapman, Hall, London; 1996.
• [22]Coelho RG. Estudo químico de Sempre-Vivas brasileiras: Syngonanthus bisulcatus (Eriocaulaceae). Dissertação (Mestrado) Instituto de Química, Universidade Paulista, Araraquara; 2000.
• [23]Rinaldi V. Estudo químico de plantas da família Eriocaulaceae. 2000. Monografia(Conclusão de curso). Instituto de Química, Universidade Estadual Paulista, Araraquara; 2000.
• [24]De Morais Lima GR, de Albuquerque Montenegro C, de Almeida CL, de Athayde-Filho PF, Barbosa-Filho JM, Batista LM. Database survey of anti-inflammatory plants in South America: A review. Int J Mol Sci. 2011; 12:2692-2749.
• [25]De Morais Lima GR, de Sales IR, Caldas Filho MR, de Jesus NZ, de Sousa FH, Barbosa-Filho JM et al.. Bioactivities of the genus Combretum (Combretaceae): a review. Molecules. 2012; 17:9142-9206.
• [26]Lima GRM, Montenegro CA, Falcão HS, Jesus NZT, Cabral AG, Gomes IF et al.. Gastroprotective activity of the ethanolic extract and hexane phase of Combretum duarteanum Cambess. (Combretaceae). J Nat Med. 2013; 67:492-502.
• [27]Falcão HS, Maia GL, Bonamin F, Kushima H, Moraes TM, Hiruma Lima CA et al.. Gastroprotective mechanisms of the chloroform and ethyl acetate phases of Praxelis clematidea (Griseb.) R.M.King & H.Robinson (Asteraceae). J Nat Med. 2013; 67:480-491.
• [28]De Sousa Falcão H, Leite JA, Barbosa-Filho JM, de Athayde-Filho PF, de Oliveira Chaves MC, Moura MD et al.. Gastric and duodenal antiulcer activity of alkaloids: a review. Molecules. 2008; 13:3198-3223.
• [29]Jesus NZ, Falcão HS, Lima GR, Caldas Filho MR, Sales IR, Gomes IF et al.. Hyptis suaveolens (L.) Poit (Lamiaceae), a medicinal plant protects the stomach against several gastric ulcer models. J Ethnopharmacol. 2013; 150:982-988.
• [30]Mota KS, Dias GE, Pinto ME, Luiz-Ferreira A, Souza-Brito AR, Hiruma-Lima CA et al.. Flavonoids with gastroprotective activity. Molecules. 2009; 14:979-1012.
• [31]Batista LM, de Almeida AB, de Pietro ML, Toma W, Calvo TR, Vilegas W et al.. Gastric antiulcer activity of Syngonanthus arthrotrichus Silveira. Biol Pharm Bull. 2004; 27:328-332.
• [32]Batista LM, de Almeida ABA, de Morais Lima R, de Sousa Falcão H, Ferreira AL, de Pietro Magri L et al.. Gastroprotective Effect of the Ethanolic Extract and Fractions obtained from Syngonanthus bisulcatus Rul. Rec Nat Prod. 2013; 7:35-44.
• [33]Batista LM, de Almeida AB, Lima GR, Falcão Hde S, Magri Lde P, Luiz-Ferreira A et al.. Gastroprotective effects (in rodents) of a flavonoid rich fraction obtained from Syngonanthus macrolepsis. J Pharm Pharmacol. 2014; 66:445-452.
• [34]Takagi K, Okabe S, Saziki R. A new method for the production of chronic gastric ulcer in rats and the effect of several drugs on its healing. Jap J Pharmac. 1969; 19:418-426.
• [35]Matsuda H, Li Y, Yoshikawa M. Gastroprotections of escins Ia, Ib, Iia, and Iib on ethanol-induced gastric mucosal lesions in rats. Eur J Pharmacol. 1999; 373:63-70.
• [36]Szelenyi I, Thiemer K. Distention ulcer as a model for testing of drugs for ulcerogenic side effects. Arch Toxicol. 1978; 41:99-105.
• [37]Sikirić P, Seiwerth S, Grabarević Z, Rucman R, Petek M, Jagić V et al.. The influence of a novel pentadecapeptide, BPC 157, on NG-nitro-L-arginine methylester and L-arginine effect on stomach mucosa integrity and blood pressure. Eur J Pharmacol. 1997; 332:23-33.
• [38]Ueda S, Yoshikawa T, Takahashi S, Ichikawa H, Yasuda M, Oyamada H et al.. Role of free radicals and lipid peroxidation in gastric mucosal injury induced by ischemia-reperfusion in rats. Scand J Gastroenterol. 1989; 162:55-58.
• [39]Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxidation in animal tissues by thiobarbituric acid reaction. Anal Bichem. 1979; 95:351-358.
• [40]Faure P, Lafond JL. Measurement of plasma sulfhydryl and carbonyl groups as a possible indicator of protein oxidation. In: Analysis of free radicals in biological systems. Favier AE, editor. Verlag, Boston; 1995: p.237-248.
• [41]Morimoto Y, Shimohara K, Oshima S, Sukamoto T. Effects of the new anti-ulcer agent KB-5492 on experimental gastric mucosal lesion and gastric mucosal defensive factors, as compared to those of teprenone and cimetidine. Japan J Pharmacol. 1991; 57:495-505.
• [42]Arimura A, Lundqvist G, Rothman J, Chang R, Fernandez-Durango R, Elde R et al.. Radioimmunoassay of somatostatin. Metabolism. 1978; 27:1139-1144.
• [43]Slingerland DW, Cardarelli JA, Burrows BA, Miller A. The utilty of serum gastrin levels in assessing the significence of low serum B12 levels. Arch Intern Med. 1984; 144:1167-1168.
• [44]Hiruma-Lima CA, Calvo TR, Rodrigues CM, Andrade FD, Vilegas W, Brito AR. Antiulcerogenic activity of Alchornea castaneaefolia: effects on somatostatin, gastrin and prostaglandin. J Ethnopharmacol. 2006; 104:215-224.
• [45]Bonamin F, Moraes TM, Kushima H, Silva MA, Rozza AL, Pellizzon CH et al.. Can a Strychnos species be used as antiulcer agent? Ulcer healing action from alkaloid fraction of Strychnos pseudoquina St. Hil. (Loganiaceae). J Ethnopharmacol. 2011; 138:47-52.
• [46]Luiz-Ferreira A, Cola M, Barbastefano V, De-Faria FM, Almeida AB, Farias-Silva E et al.. Healing, Antioxidant and Cytoprotective Properties of Indigofera truxillensis in Different Models of Gastric Ulcer in Rats. Int J Mol Sci. 2012; 13:14973-14991.
• [47]Okabe S, Amagase K. An overview of acetic acid ulcer models--the history and state of the art of peptic ulcer research. Biol Pharm Bull. 2005; 28:1321-1341.
• [48]Wallace JL, Devchand PR. Emerging roles for COX-2 in gastrointestinal mucosal defense-review. Br J Pharmacol. 2005; 145:275-282.
• [49]Tarnawski A. Cellular and molecular mechanisms of gastrointestinal ulcer healing. Digestion and Disease Science. 2005; 50:S24-S33.
• [50]Tarnawski A, Douglass TG, Stachura J, Krause WJ. Quality of gastric ulcer healing: histological and ultrastructural assessment. Alimentary Pharmacology and Therapeutic. 1991; 5:79-90.
• [51]Ito M, Segami T, Inagguma K, Suzuki Y. Cimetidine and omeprazole accelerate gastric ulcer healing by an increase in gastrin secretion. Eur J Pharmacol. 1994; 263:251-259.
• [52]Shirin H, Pinto JT, Liu LU, Merzianu M, Sordillo EM, Moss SF. Helicobacter pylori decreases gastric mucosal glutathione. Cancer Lett. 2001; 164:127-133.
• [53]Avila JR, de la Lastra CA, Martin MJ, Motilva V, Luque I, Delgado D et al.. Role of endogenous sulphydryls and neutrophil infiltration in the pathogenesis of gastric mucosal injury induced by piroxicam in rats. Inflamm Res. 1996; 45:83-88.
• [54]Wallace JL, Miller MJ. Nitric oxide in mucosal defense: A little goes a long way. Gastroenterology. 2000; 119:512-520.
• [55]Chandranath SI, Bastaki SM, Singh J. A comparative study on the activity of lansoprazole, omeprazole and PD-136450 on acidified ethanol and indomethacin-induced gastric lesions in the rat. Clinical Experimental Pharmacology and Physiology. 2002; 29:173-180.
• [56]Li Y, Zhang JF, Zhang YM, Ma XB. The protective effect of genistein post conditioning on hypoxia/reoxygenation-induced injury in human gastric epithelial cells. Acta Pharmacol. 2009; 30:576-581.
• [57]Andrews FJ, Malcontenti C, O’Brien PE. Sequence of gastric mucosal injury following ischemia and reperfusion. Role of reactive oxygen metabolites. Dig Dis Sci. 1992; 37:1356-1361.
• [58]Wada K, Kamisaki Y, Ohkura T, Kanda G, Nakamoto K, Kishimoto Y et al.. Direct measurement of nitric oxide release in gastric mucosa during ischemia–reperfusion in rats. Am J Physiol. 1998; 274:G465-G471.
• [59]Chamoun F, Burne M, O’Donnell M, Rabb H. Pathophysiologic role of selectins and their ligands in ischemia/reperfusion injury. Front Biosci. 2000; 5:E103-E109.
• [60]Piper HM, Meuter K, Schäfer C. Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg. 2003; 75:S644-S648.
• [61]Rao CV, Vijayakumar M. Protective effect of (+)-catechin against gastric mucosal injury induced by ischaemia-reperfusion in rats. J Pharm Pharmacol. 2007; 59:1103-1107.
• [62]Smith GS, Mercer DW, Cross JM, Barreto JC, Miller TA. Gastric injury induced by ethanol and ischemia-reperfusion in the rat. Differing roles for lipid peroxidation and oxygen radicals. Dig Dis Sci. 1996; 41:1157-1164.
• [63]Makoto S, Takashi J. Oxidative stress and ischemia–reperfusion injury in gastrointestinal tract and antioxidante, protective agents. J Clin Biochem Nutr. 2007; 40:1-12.
• [64]Brzozowski T et al.. Prostaglandin/cyclooxygenase pathway in ghrelin-induced gastroprotection against ischemia–reperfusion injury. Pharmacol Exp Ther. 2006; 319:477-487.
• [65]Sener G, Sert G, Ozer Sehirli A, Arbak S, Uslu B, Gedik N et al.. Pressure ulcer-induced oxidative organ injury is ameliorated by beta-glucan treatment in rats. Int Immunopharmacol. 2006; 6:724-732.
• [66]Karmeli F, Eliakim R, Okon E, Rachmilewitz D. Gastric and mucosal damage by ethanol is mediated by substance P and prevented by ketotifen, a mast cell stabilizer. Gastroenterology. 1994; 10:1206-1216.
• [67]Sun FP, Song YG, Cheng W, Zhao T, Yao YL. Gastrin, somatostatin, G and D cells of gastric ulcer in rats. World J Gastroenterol. 2002; 8:375-378.
• [68]Konturek SJ, Radecki T, Brzozowski T, Drozdowicz D, Piastucki I, Muramatsu M et al.. Antiulcer and gastroprotective effects of solon, a synthetic flavonoid derivative of sophoradin- Role of endogenous prostaglandins. Eur J Pharmacol. 1996; 125:185-192.
• [69]Kutchai HC. Gastrointestinal secretions. In: Principles of Physiology. 2nd ed. Berne RM, Levy MN, editors. Mosby-Year Book, St. Louis; 1996: p.516-589.