P101 Comparative study with hydrogen sulfide (H2S)-releasing derivative of naproxen ATB-346, naproxen and cyclooxygenase (COX)-2 inhibitor in the mechanisms of gastric mucosa injury induced by stress

Abstract

Naproxen belongs to commonly used NSAIDs associated with less cardiovascular toxicity than selective COX-2 inhibitors and other NSAIDs but its use is limited due to serious gastrointestinal (GI)-tract adverse effects. Novel H2S-releasing derivative of naproxen (ATB-346) was shown to inhibit COX-1 and prostaglandins (PGs) generation without causing mucosal damage unlike parent drug but whether ATB-346 can affect stress-induced gastric damage remains unknown. We compared ATB-346 vs naproxen and celecoxib and determined the role of reactive oxygen species and cytokines in the action of these NSAIDs against water immersion restraint stress (WRS)-induced gastric lesions in rats. WRS exposed animals were pretreated with (1) naproxen, (2) ATB-346 (0.5–40 m/kg i.g.), and (3) celecoxib (10 mg/kg i.g.) with or without ODQ (5 mg/kg i.p.), selective guanylate cyclase inhibitor or BCA (10 mg/kg i.p.), the inhibitor of H2S-synthesizing enzyme CSE. The number of gastric lesions was assessed by planimetry, the gastric blood flow (GBF) by H2-gas clearance technique, the malonyldialdehyde (MDA) concentration, MPO and PGE2 generation, the plasma level of IL-1beta and TNF-alpha and the expression of SOD and glutathione peroxidase (GPx) were determined by ELISA and RT-PCR. Pretreatment with ATB-346 dose-dependently reduced WRS-induced gastric lesions; the dose inhibiting these lesions by 50% being 29 mg/kg, caused significant rise in GBF and fall in MPO and MDA content. These effects of ATB-346 were reversed by cotreatment with ODQ but not BCA (p