Gastroprotective Mechanisms of Indole Alkaloids from Himatanthus lancifolius

Abstract

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 (ED₅₀ = 30 mg/kg, p. o.) and reduced gastric acid hypersecretion induced by pylorus ligature (ED₅₀ = 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 (NO₃ + NO₂) 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 (EC₅₀ = 212 µg/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.

Key words

Alkaloids - uleine - demethoxyaspidormine - antiulcer - medicinal plant - Himatanthus

References

• 1 Coimbra R. Manual de Fitoterapia. 2nd edn Belem; CEJUP 1994: pp 22-3
• 2 Perdue G P, Blomster R N. South-American plants 3. Isolation of fulvoplumierin from Himatanthus sucuuba (M-Arg) Woodson (Apocynaceae).  J Pharm Sci. 1978;  67 1322-3
• 3 Souza C P, Azevedo M LL, Lopes J LC, Sarti J, Santos-Filho D D, Lopes J NC. et al . Molluscicidal activity of natural products.  Ana Acad Brasil Science. 1984;  56 333-8
• 4 Endo Y, Hayashi H, Sato T, Maruno M, Ohta T, Nozoe S. Confluentic acid and 2′-O-methylperlatolic acid, monoamine-oxidase-B inhibitors in a Brazilian plant, Himatanthus sucuuba .  Chem Pharm Bull. 1994;  42 1198-201
• 5 de Miranda A LP, Silva J RA, Rezende C M, Neves J S, Parrini S C, Pinheiro M LB. et al . Anti-inflammatory and analgesic activities of the latex containing triterpenes from H. sucuuba .  Planta Med. 2000;  66 284-6
• 6 Vanderlei M F, Souza-Brito A RM. Spasmodic effects of Himatanthus phagedaenica (Mart) Woodson.  J Braz Chem Soc. 1991;  2 51
• 7 França Jr O O, Santos C AM, Brown R T. Uleine and demethoxyaspidospermine from the barks of Plumeria lancifolia .  Fitoterapia. 2000;  71 208-10
• 8 Joule J A, Djerassi C. Alkaloid studies XLIV. Mass spectrometry in structural and stereochemical problems. XLII. Some aspects of the chemistry and mass spectrometry of uleine. J Chem Soc 1964: 2777-90
• 9 Gaskell J, Joule J A. The structure of uleine - relative stereochemistry.  Chem Ind. 1967;  23 1089-90
• 10 Robert A, Nezamis J E, Lancaster C, Hanchar A J. Cytoprotection by prostaglandin in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl and thermal injury.  Gastroenterology. 1979;  77 433-43
• 11 Vela S M, Souccar C, Lima-Landman M TR, Lapa A J. Inhibition of gastric acid secretion by the aqueous extract and purified extracts of Stachytarpheta cayennensis .  Planta Med. 1997;  63 36-9
• 12 Shay H, Komarov S A, Fels S S, Meranze D, Gruenstein M, Siplet H. A simple method for the uniform production of gastric ulceration in rat.  Gastroenterology. 1945;  5 43-61
• 13 Kubo K, Uehara A, Kubota T, Nozu T, Moriya M, Watanabe Y. et al . Effects of ranitidine on gastric vesicles containing H⁺/K⁺-adenosine triphosphatase in rats.  Scand J Gastroenterol. 1995;  30 944-51
• 14 Murakami S, Arai I, Muramatsu M, Otomos S, Baba K, Kido T. et al . Inhibition of gastric H⁺/K⁺-ATPase and acid secretion by cassigarol A: a polyphenol from Cassia garrettiana Craib.  Biochem Pharmacol. 1992;  44 33-7
• 15 Fiske C H, Subbarow Y. The colorimetric determination of phosphorus.  J Biol Chem. 1925;  66 375-400
• 16 Jaiswal A K, McBride O W, Adesnik M, Nebert D W. Human dioxin-inducible cytosolic NAD(P)H: menadione oxidoreductase. CDNA sequence and localization of gene to chromosome.  J Biol Chem. 1988;  263 13 572-8
• 17 Habig W H, Pabst M J, Jakoby W B. Glutathione S-transferases: the first enzymatic step in mercapturic acid formation.  J Biol Chem. 1974;  249 7130-9
• 18 Sedlak J, Lindsay R H. Estimation of total protein bound and nonprotein sulfhydril groups in tissues with Ellman’s reagent.  Ann Biochem. 1988;  25 192-205
• 19 Granger D L, Hibbs J B, Perfect J R, Durack D T. Metabolic fate of L-arginine in relation to microbiostatic capability of murine macrophages.  J Clin Invest. 1990;  85 264-73
• 20 Stickney J C, Northup D W. Effect of gastric emptying upon propulsive motility of small intestine in rat.  Exp Biol Med. 1959;  101 582
• 21 Szabo S, Trier J, Brown A, Schnoor J. Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat.  Gastroenterology. 1985;  88 228-36
• 22 Cnubben N HP, Rietjens I MCM, Wortelboer H, van Zanden J, van Bladeren P J. The interplay of glutathione related processes in antioxidant defense.  Environ Toxicol Pharmacol. 2001;  10 141-52
• 23 Tzeon-Jye C A, Woan-Fang T B. The roles of glutathione and antioxidant enzymes in menadione-induced oxidative stress.  Toxicology. 2000;  154 75-84
• 24 Cadenas E. Antioxidant and prooxidant functions of DT-Diaphorase in quinone metabolism.  Biochem Pharmacol. 1995;  49 127-140
• 25 Terano A, Hiraishi H, Ota S, Shiga J, Sugimoto T. Role of superoxide and hydroxyl radicals in rat gastric mucosal injury induced by ethanol.  Gastroenterol Jpn. 1989;  24 488-93
• 26 Szelenyi I, Brune K. Possible role of oxygen free radicals in ethanol-induced gastric mucosal damage in rats.  Dig Dis Sci. 1988;  33 865-71
• 27 Pihan G, Regillo B A, Szabo S. Free radicals and lipid peroxidation in ethanol- or aspirin-induced gastric mucosal injury.  Dig Dis Sci. 1987;  32 1395-401
• 28 Repetto M, Maria A, Guzman J, Giordano O, Llesuy S. Protective effect of Artemisia douglasiana Besser extracts in gastric mucosal injury.  J Pharm Pharmacol. 2003;  55 551-7
• 29 Calatayud S M, Barranchina D, Esplugues J V. Nitric oxide: relation to integrity, injury and healing of the gastric mucosa.  Microsc Res Tech. 2001;  53 325-35
• 30 Whittle B J, Lopez-Belmonte J. Actions and interactions of endothelins, prostacyclin and nitric oxide in the gastric mucosa.  J Physiol Pharmacol. 1993;  44 91-107
• 31 Whittle B J, Lopez-Belmonte J, Moncada S. Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat.  Braz J Pharmacol. 1990;  99 607-11
• 32 Kisakurek M, Leewenberg A JM, Hesse M. Alkaloids: Chemical and Biological Perspective. Pelletier SW, editor New York; John Wiley and Sons 1983: p 17
• 33 Jasztold-Howorko R, Croisy A, Carrez D, Jaroszewicz I, Nasulewicz A, Pelczynska M. et al . Synthesis, structure, and cytostatic properties of new olivacine derivatives.  Arch Pharm. 2004;  337 599-604
• 34 Borris R P, Lanki D C, Cordell G A. Studies of the uleine alkaloids I. Carbon ¹³NMR studies on 21-uleine, 20-epiuleine and (4S)-uleine Nb-oxide.  J Nat Prod. 1983;  46 200-5