Gastroprotective effects of goniothalamin against ethanol and indomethacin-induced gastric lesions in rats: Role of prostaglandins, nitric oxide and sulfhydryl compounds

• Published in: Chemico-biological interactions Vol. 224; pp. 206 - 212
• Main Authors: Vendramini-Costa, Débora Barbosa, Monteiro, Karin Maia, Iwamoto, Leilane Hespporte, Jorge, Michelle Pedroza, Tinti, Sirlene Valério, Pilli, Ronaldo Aloise, de Carvalho, João Ernesto
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 05.12.2014
• Subjects: Animals; Ethanol; Gastric Mucosa - drug effects; Gastric Mucosa - secretion; Gastric ulcers; Goniothalamin; Indomethacin; Male; Michael acceptor; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Prostaglandins - metabolism; Protective Agents - administration & dosage; Protective Agents - chemical synthesis; Protective Agents - therapeutic use; Pyrones - administration & dosage; Pyrones - chemical synthesis; Pyrones - therapeutic use; Rats; Rats, Wistar; Stomach Ulcer - chemically induced; Stomach Ulcer - prevention & control; Styryl-lactones; Sulfhydryl compounds; Sulfhydryl Compounds - metabolism; GTN; NO; Sulfhydryl compounds; Keap 1; Michael acceptor; l-NAME; PPI; Rats; cox; ULI; NPSH; NOS; ARE; SH; Nrf2; NSAIDs; Gastric ulcers; NEM; PG; ROS; DNTB; Styryl-lactones; ED50; Goniothalamin
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2014.10.025

•The gastroprotective action of goniothalamin (GTN) on chemical-induced gastric ulcers models in rats is described.•GTN has a potent gastroprotective effect on ethanol-induced ulcers (ED50=18mg/kg).•This activity is dependent on sulfhydryl compounds and prostaglandins generation.•On the other hand, is independent of NO, gastric secretion and mucus production.•We hypothesize that GTN acts as a mild irritant, promoting an adaptive cytoprotection. Goniothalamin (GTN), a styryl-lactone, is a secondary metabolite naturally found in its enantiomeric form (R) in plants of the genus Goniothalamus (Annonaceae). The antiproliferative activity against human tumor cell lines reported in several studies suggest that the α,β-unsaturated δ-lactone moiety emerges as a key Michael acceptor for cysteine residues or other nucleophilic biological molecules. Our group reported on the in vivo activity of (R)- and (S)-GTN as well as its racemic form (rac-GTN) in both Ehrlich solid tumor and carrageenan-induced paw edema in mice, without side effects in the effective doses. Despite the rich body of data on the in vitro GTN biological activity, much less is known about its in vivo pharmacological action. Herein we describe the gastroprotective activity of rac-GTN on chemical-induced gastric ulcers models in rats. GTN has a potent gastroprotective effect on ethanol-induced ulcers (effective dose50=18mg/kg) and this activity is dependent on sulfhydryl compounds and prostaglandins generation, but independent of nitric oxide (NO), gastric secretion and mucus production. We hypothesize that goniothalamin may act as a mild irritant, inducing the production of sulfhydryl compounds and prostaglandins, in a process known as adaptive cytoprotection. This hypothesis is supported by the fact that Michael acceptors are the most potent inducers of antioxidant response (as activation of Nrf2 pathway) through generation of mild oxidative stress and that gastroprotective activity of goniothalamin is inhibited after pre-treatment with NEM (N-ethylmaleimide) and NSAID (non-steroidal anti-inflammatory drugs), highlighting the importance of sulfhydryl compounds and prostaglandins on GTN activity.