Role of an Indole-Thiazolidine Molecule PPAR Pan-Agonist and COX Inhibitor on Inflammation and Microcirculatory Damage in Acute Gastric Lesions

Autor(es)

Santin, Jose Roberto ^[1] ; Machado, Isabel Daufenback ^[1] ; Rodrigues, Stephen F. P. ^[1] ; Teixeira, Simone ^[2] ; Muscara, Marcelo N. ^[2] ; Galdino, Suely Lins ^[3] ; Pitta, Ivan da Rocha ^[3] ; Farsky, Sandra H. P. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Lab Expt Toxicol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil

^[3] Univ Fed Pernambuco, Dept Chem, Recife, PE - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 8, n. 10 OCT 4 2013.
• Citações Web of Science: 14

Resumo

The present study aimed to show the in vivo mechanisms of action of an indole-thiazolidine molecule peroxisome-proliferator activated receptor pan-agonist (PPAR pan) and cyclooxygenase (COX) inhibitor, LYSO-7, in an ethanol/HCl-induced (Et/HCl) gastric lesion model. Swiss male mice were treated with vehicle, LYSO-7 or Bezafibrate (p.o.) 1 hour before oral administration of Et/HCl (60%/0.03M). In another set of assays, animals were injected i.p. with an anti-granulocyte antibody, GW9962 or L-NG-nitroarginine methyl ester (L-NAME) before treatment. One hour after Et/HCl administration, neutrophils were quantified in the blood and bone marrow and the gastric microcirculatory network was studied in situ. The gastric tissue was used to quantify the percentage of damaged area, as well as myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) protein and PPAR. protein and gene expression. Acid secretion was evaluated by the pylorus ligation model. LYSO-7 or Bezafibrate treatment reduced the necrotic area. LYSO-7 treatment enhanced PPAR. gene and protein expression in the stomach, and impaired local neutrophil influx and stasis of the microcirculatory network caused by Et/HCl administration. The effect seemed to be due to PPAR. agonist activity, as the LYSO-7 effect was abolished in GW9962 pre-treated mice. The reversal of microcirculatory stasis, but not neutrophil influx, was mediated by nitric oxide (NO), as L-NAME pre-treatment abolished the LYSO-7-mediated reestablishment of microcirculatory blood flow. This effect may depend on enhanced eNOS protein expression in injured gastric tissue. The pH and concentration of H+ in the stomach were not modified by LYSO-7 treatment. In addition, LYSO-7 may induce less toxicity, as 28 days of oral treatment did not induce weight loss, as detected in pioglitazone treated mice. Thus, we show that LYSO-7 may be an effective treatment for gastric lesions by controlling neutrophil influx and microcirculatory blood flow mediated by NO. (AU)

• Processo FAPESP: 10/17175-0 - Efeito do agonista PPAR Lyso-07 sobre a instalação e cicatrização de úlceras gástricas induzidas em camundongos
• Beneficiário: José Roberto Santin
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 11/01848-8 - Avaliação da atividade gastroprotetora do agonista PPAR Lyso-07 e do ácido clorogênico
• Beneficiário: Sandra Helena Poliselli Farsky
• Modalidade de apoio: Auxílio à Pesquisa - Regular