title: Role of an indole-thiazolidine molecule PPAR pan-agonist and COX inhibitor on inflammation and microcirculatory damage in acute gastric lesions.
abstract: 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 PPARγ 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 PPARγ 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 PPARγ 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.
authors.affiliation: Laboratory of Experimental Toxicology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: José Roberto
authors.initials: JR
authors.lastname: Santin
authors.forename: Isabel
authors.initials: I
authors.lastname: Daufenback Machado
authors.forename: Stephen F P
authors.initials: SF
authors.lastname: Rodrigues
authors.forename: Simone
authors.initials: S
authors.lastname: Teixeira
authors.forename: Marcelo N
authors.initials: MN
authors.lastname: Muscará
authors.forename: Suely
authors.initials: S
authors.lastname: Lins Galdino
authors.forename: Ivan
authors.initials: I
authors.lastname: da Rocha Pitta
authors.forename: Sandra H P
authors.initials: SH
authors.lastname: Farsky
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000431:Ethanol / Q000009:adverse effects; D005744:Gastric Acid / Q000378:metabolism; D005756:Gastritis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006851:Hydrochloric Acid / Q000009:adverse effects; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C583084:5-((5-bromo-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)thiazolidine-2,4-dione; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D009569:Nitric Oxide; D000431:Ethanol; D006851:Hydrochloric Acid