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.

Endothelial nitric oxide synthase in the microcirculation

“…The expression and activity of eNOS compared to iNOS is a factor in the development and outcome of inflammation 113, 114 . During gastric ulcers, inflammatory processes are related to an imbalance between NO derived from eNOS and iNOS: eNOS expression was reduced during inflammation, and iNOS expression increased 115, 116, 117, 118 .…”

New PPARα/γ/δ Optimal Activator Rationally Designed by Computational Methods

“…Besides chiglitazar, LYSO-07 designed initially as a PPARγ agonist also presented PPARα and PPARδ activation, this PPAR pan agonism boosted its research. 38,39 Other molecules like ZBH and CNX-013-B2 also were researched for a PPAR pan agonism which is considered by the researchers a characteristic that may represent a promising adverse effect profile in in vivo studies. 40,41 Candidate 1 herein presented is a molecule similar to LY465608, used as a lead structure in PPAR pan agonists design.…”

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

“…Mourão et al (2005) published a study on the synthesis of 5-benzylidene and 5-acridinylidene derivatives, both of which were N-3 substituted; these compounds showed hypoglycemic activity in mice. Many other authors have used similar approaches with promising outcomes (da Costa Leite et al, 2007;Barros et al, 2010;Araújo et al, 2011;Amato et al, DMD # 79012 5 2012;Santin et al, 2013a;Santin et al, 2013b;Cesar et al, 2015;Rudnicki et al, 2016;Silva et al, 2016).…”