Agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ: A new compound with potent gastroprotective and ulcer healing properties

• Published in: Inflammopharmacology 2005-08, Vol.13 (1-3), p.317-330
• Main Authors: Brzozowski, Tomasz, Konturek, Peter C., Pajdo, Robert, Kwiecień, Slawomir, Konturek, Stanislaw, Targosz, Aneta, Burnat, Grzegorz, Cieszkowski, Jakub, Pawlik, Wieslaw W., Hahn, Eckhart G.
• Format: Article
• Language: English
• ISSN: 0925-4692; 1568-5608
• DOI: 10.1163/156856005774423908

Pioglitazone, a specific ligand for peroxisome proliferator-activated receptor gamma (PPAR- gamma ), was recently implicated in the control of inflammatory processes and in the modulation of the expression of various cytokines such as tumor necrosis factor alpha (TNF- alpha ), but its role in the mechanism of gastric mucosal integrity has not been studied extensively. This study was designed to determine the effect of pioglitazone on gastric mucosal lesions induced in rats by topical application of 100% ethanol and by 3.5 h of water immersion and restraint stress (WRS) with or without pretreatment with indomethacin (5 mg/kg i.p.) to inhibit cyclooxygenase-1 (COX-1) and COX-2 enzyme activities and L-NNA (20 mg/kg i.p.) to suppress nitric oxide (NO)-synthase. In addition, the effect of pioglitazone on ulcer healing in rats with chronic acetic acid ulcers (ulcer area 28 mm super(2)) was determined. Rats were killed 1 h and 3.5 h after ethanol administration or WRS exposure or at day 9 upon ulcer induction, and the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was determined by H sub(2)-gas clearance technique and the mucosal PGE sub(2) generation and gene expression and plasma concentration of TNF- alpha and IL-1 beta were also evaluated. Pre-treatment with pioglitazone dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID sub(50)) being 10 mg/kg and 7 mg/kg, respectively. The protective effect of pioglitazone was accompanied by the significant rise in the GBF, an increase in PGE sub(2) generation and the significant fall in the plasma TNF- alpha and IL-1 beta levels. Strong signals for IL-1 beta -and TNF- alpha mRNA were recorded in gastric mucosa exposed to ethanol or WRS, and these effects were significantly decreased by pioglitazone. Indomethacin which suppressed PG generation by about 90%, while augmenting WRS damage, and L-NNA, that suppressed NO-synthase activity, significantly attenuated the protective and hyperaemic activity of this PPAR- gamma ligand. In the chronic study, pioglitazone significantly reduced the area of gastric ulcers on day 9 and significantly raised the GBF at the ulcer margin. The acceleration of ulcer healing by PPAR- gamma ligand was accompanied by a significant increase in the expression of PECAM-1 protein, a marker of angiogenesis. We conclude that (1) pioglitazone exerts a potent gastroprotective and hyperaemic act