title: Gastroprotective effects of goniothalamin against ethanol and indomethacin-induced gastric lesions in rats: Role of prostaglandins, nitric oxide and sulfhydryl compounds.
abstract: 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.
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Rua Josué de Castro s/n, Cidade Universitária Zeferino Vaz, CP 6154, Campinas, SP 13081-970, Brazil; Chemical, Biological and Agricultural Pluridisciplinary Research Center, CPQBA, University of Campinas, Rua Alexandre Cazelatto, 999, Vila Betel, Paulínia, SP 13148-218, Brazil. Electronic address: vendramini.debora@gmail.com.
authors.forename: Débora Barbosa
authors.initials: DB
authors.lastname: Vendramini-Costa
authors.affiliation: Chemical, Biological and Agricultural Pluridisciplinary Research Center, CPQBA, University of Campinas, Rua Alexandre Cazelatto, 999, Vila Betel, Paulínia, SP 13148-218, Brazil.
authors.forename: Karin Maia
authors.initials: KM
authors.lastname: Monteiro
authors.affiliation: Chemical, Biological and Agricultural Pluridisciplinary Research Center, CPQBA, University of Campinas, Rua Alexandre Cazelatto, 999, Vila Betel, Paulínia, SP 13148-218, Brazil; Department of Pharmacology, Anaesthesiology and Therapeutics, Faculty of Dentistry, University of Campinas, Av. Limeira, 901, Piracicaba, SP 13414-903, Brazil.
authors.forename: Leilane Hespporte
authors.initials: LH
authors.lastname: Iwamoto
authors.affiliation: Chemical, Biological and Agricultural Pluridisciplinary Research Center, CPQBA, University of Campinas, Rua Alexandre Cazelatto, 999, Vila Betel, Paulínia, SP 13148-218, Brazil.
authors.forename: Michelle Pedroza
authors.initials: MP
authors.lastname: Jorge
authors.affiliation: Chemical, Biological and Agricultural Pluridisciplinary Research Center, CPQBA, University of Campinas, Rua Alexandre Cazelatto, 999, Vila Betel, Paulínia, SP 13148-218, Brazil.
authors.forename: Sirlene Valério
authors.initials: SV
authors.lastname: Tinti
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Rua Josué de Castro s/n, Cidade Universitária Zeferino Vaz, CP 6154, Campinas, SP 13081-970, Brazil.
authors.forename: Ronaldo Aloise
authors.initials: RA
authors.lastname: Pilli
authors.affiliation: Chemical, Biological and Agricultural Pluridisciplinary Research Center, CPQBA, University of Campinas, Rua Alexandre Cazelatto, 999, Vila Betel, Paulínia, SP 13148-218, Brazil; Department of Pharmacology, Anaesthesiology and Therapeutics, Faculty of Dentistry, University of Campinas, Av. Limeira, 901, Piracicaba, SP 13414-903, Brazil; Faculty of Pharmaceutical Sciences, University of Campinas, Cidade Universitária Zeferino Vaz, Campinas, SP 13081-970, Brazil.
authors.forename: João Ernesto
authors.initials: JE
authors.lastname: de Carvalho
mesh_terms: D000818:Animals; D000431:Ethanol; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011453:Prostaglandins / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D011753:Pyrones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control*; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D011453:Prostaglandins; D020011:Protective Agents; D011753:Pyrones; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; C103280:goniothalamin; D000431:Ethanol; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin
keywords: Gastric ulcers; Goniothalamin; Michael acceptor; Rats; Styryl-lactones; Sulfhydryl compounds