Abstract
The present study was designed to evaluate the anti-ulcerogenic properties of an alkaloid chromane, rohitukine from Dysoxylum binectariferum. Anti-ulcer potential of rohitukine was assessed in cold restrained, pyloric ligated and ethanol induced ulcers in rats. In addition, rohitukine was tested in vitro for H+ K+-ATPase inhibitory activity in gastric microsomes. Moreover, we studied the role of rohitukine on the cytosolic concentration of Ca2+ in parietal cell-enriched cell suspension in order to ascertain its mechanism of action. Cytoprotective activity was evaluated through PGE2 level. Rohitukine significantly attenuated the ulcers in cold restraint ulcer (CRU) model in a dose-related manner. Moreover, it significantly lowered the free acidity and pepsin activity in pyloric ligated rats while improved the depleted level of mucin. Furthermore, rohitukine significantly reversed the cold restrained-induced increase in gastrin level. Our in vitro study revealed that rohitukine moderately inhibited the microsomal H+ K+-ATPase activity with respect to positive control omeprazole. Furthermore, rohitukine potently antagonized the gastrin-elicited increase in cytosolic Ca2+ level in parietal cell-enriched suspension. In ethanol-induced gastric lesions in rats, rohitukine significantly inhibited the formation of erosions and increased PGE2 content showing more potency than reference drug sucralfate. Our results thus suggest that rohitukine possess significant anti-ulcer and anti-gastrinic activity in rats. It is likely that gastro-protective influences of rohitukine are dependent partly on its acid-lowering potential and partly on cytoprotective property. The acid-reducing effect of rohitukine might be attributed to its lowering effect on gastrin production and/or antagonism of gastrin-evoked functional responses of parietal cells. Thus, rohitukine represent a useful agent in the treatment of peptic ulcer disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anoop A, Jegadeesan M (2003) Biochemical studies on the anti-ulcerogenic potential of Hemidesmus indicus R.Br. var. indicus. J Ethnopharmacol 84:149–156
Berglindh T (1990) Gastric glands and cells: preparation and in vitro methods. Methods Enzymol 192:93–107
Carlson B, Lahusen T, Singh S, Loaiza-Perez A, Worland PJ, Pestell R, Albanese C, Sausville EA, Senderowicz AM (1999) Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res 59:4634–4641
Code CF (1965) Histamine and gastric secretion: a later look. Fed Proc 24:1311–1321
Crowther RS, Wetmore RF (1987) Fluorometric assay of O-linked glycoproteins by reaction with 2-cyanoacetamide. Anal Biochem 163:170–174
Debas HT, Carvajal SH (1994) Vagal regulation of acid secretion and gastrin release. Yale J Biol Med 67:145–151
Debnath PK, Gode KD, Das DG, Sanyal AK (1974) Effects of propranolol on gastric secretion in albino rats. Br J Pharmacol 51:213–216
Erin N, Ercan F, Yegen BC, Arbak S, Okar I, Oktay S (2000) Role of capsaicin-sensitive nerves in gastric and hepatic injury induced by cold-restraint stress. Dig Dis Sci 45:1889–1899
Finney DJ (1952) A statistical treatment of the sigmoidal response curve. Cambridge University Press, New York, p. 318
Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450
Harmon AD, Weiss U, Silverton JV (1979) The structure of rohitukine, the main alkaloid of Amoora rohituka (Syn.) Aphanamixis polystachya (meliaceae). Tetrahedron Lett 20:721–724
Harty RF, Maico DG, McGuigan JE (1981) Role of calcium in antral gastrin release. Gastroenterology 80:491–497
Harty RF, Maico DG, Brown CM, McGuigan JE (1984) Effects of calcium on cholinergic-stimulated gastrin release in the rat. Mol Cell Endocrinol 37:133–138
Kahlson G, Rosengren E (1972) Histamine: entering physiology. Experientia 28:993–1002
Kasuya Y, Urushidani T, Okabe S (1979) Effects of various drugs and vagotomy on indomethacin-induced gastric ulcers in the rat. Jpn J Pharmacol 29:670–673
Kitagawa H, Fujiwara M, Osumi Y (1979) Effects of water-immersion stress on gastric secretion and mucosal blood flow in rats. Gastroenterology 77:298–302
Konturek SJ, Brzozowski T, Bielanski W, Schally AV (1995) Role of endogenous gastrin in gastroprotection. Eur J Pharmacol 278:203–212
Lakshmi V, Pandey K, Kapil A, Singh N, Samant M, Dube A (2007) In vitro and in vivo leishmanicidal activity of Dysoxylum binectariferum and its fractions against Leishmania donovani. Phytomedicine 14:36–42
Larsson H, Carlsson E, Junggren U, Olbe L, Sjostrand SE, Skanberg I, Sundell G (1983) Inhibition of gastric acid secretion by omeprazole in the dog and rat. Gastroenterology 85:900–907
Letari O, Mennuni L, Revel L, Colombo S, Makovec F (1996) Cytosolic Ca2+ evaluation in rabbit parietal cells: a novel method to screen gastrin receptor antagonists. Eur J Pharmacol 306:325–333
Lippmann W (1974) Inhibition of indomethacin-induced gastric ulceration in the rat by perorally-administered synthetic and natural prostaglandin analogues. Prostaglandins 7:1–10
MacIntosh FC (1938) Histamine as a normal stimulant of gastric secretion. Q J Exp Physiol 28:87–89
McEwen CR, Stallard RW, Juhos ET (1968) Separation of biological particles by centrifugal elutriation. Anal Biochem 23:369–377
Naik RG, Ramachandra G, Kattige SL, Bhat Z, Alreja B, De Souza NJ, Rupp RH (1988) An antiinflammatory cum immunomodulatory piperidinylbenzopyranone from Dysoxylum binectariferum: isolation, structure and total synthesis. Tetrahedron 44:2081–2086
Poynter D, Pick CR, Harcourt RA, Selway SA, Ainge G, Harman IW, Spurling NW, Fluck PA, Cook JL (1985) Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat. Gut 26:1284–1295
Reenstra WW, Forte JG (1990) Isolation of H+, K(+)-ATPase-containing membranes from the gastric oxyntic cell. Methods Enzymol 192:151–165
Sanui H (1974) Measurement of inorganic orthophosphate in biological materials: extraction properties of butyl acetate. Anal Biochem 60:489–504
Shay H, Komarov SA, Fels SS, Meranze D, Gruenstein H, Siplet H (1945) A simple method for the uniform production of gastric ulceration in the rat. Gastroenterology 5:43–61
Soll AH (1978) The actions of secretagogues on oxygen uptake by isolated mammalian parietal cells. J Clin Invest 61:370–380
Srivastava SK, Nath C, Gupta MB, Vrat S, Sinha JN, Dhawan KN, Gupta GP (1991) Protection against gastric ulcer by verapamil. Pharmacol Res 23:81–86
Suleyman H, Demirezer LO, Buyukokuroglu ME, Akcay MF, Gepdiremen A, Banoglu ZN, Gocer F (2001) Antiulcerogenic effect of Hippophae rhamnoides L. Phytother Res 15:625–627
Suleyman H, Demirezer LO, Kuruuzum-Uz A (2004) Effects of Rumex patientia root extract on indomethacine and ethanol induced gastric damage in rats. Pharmazie 59:147–149
Takeuchi K, Ueki S, Okabe S (1986) Importance of gastric motility in the pathogenesis of indomethacin-induced gastric lesions in rats. Dig Dis Sci 31:1114–1122
Wormsley KG (1986) Ulcer disease: medical treatment. Curr Opin Gastroenterol 2:855–868
Acknowledgments
Authors gratefully acknowledge ICMR and CSIR, New Delhi, India for providing financial support. Mrs. Shibani Sengupta is acknowledged for her technical assistance.
Author information
Authors and Affiliations
Corresponding author
Additional information
N. Singh and P. Singh contributed equally to this work.
The Communication Number allotted to this paper is 8158.
Rights and permissions
About this article
Cite this article
Singh, N., Singh, P., Shrivastva, S. et al. Gastroprotective effect of anti-cancer compound rohitukine: possible role of gastrin antagonism and H+ K+-ATPase inhibition. Naunyn-Schmiedeberg's Arch Pharmacol 385, 277–286 (2012). https://doi.org/10.1007/s00210-011-0711-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-011-0711-1