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

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• 作者：Marcin Magierowski^a ; Katarzyna Jasnos^a ; Danuta Drozdowicz^a ; Malgorzata Strzalka^a ; Kyle L. Flannigan^b ; Slawomir Kwiecien^a ; John L. Wallace^b ; Tomasz Brzozowski^a
• 刊名：Nitric Oxide
• 出版年：30 May 2014
• 年：2014
• 卷：39
• 期：supp_S
• 页码：S46
• 全文大小：39 K

文摘

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 < 0.05). In contrast, naproxen in equimolar dose of 20 mg/kg i.g., and celecoxib significantly increased WRS-induced lesions (p < 0.002), the effect accompanied by the significant fall in the GBF, the suppression of PGE₂ generation and the significant rise in the mucosal MDA and MPO content and plasma TNF-alpha and IL-1beta levels. Naproxen and celecoxib significantly enhanced the expression of mRNA for TNF-alpha and IL-1beta and downregulated SOD and GPx mRNAs in the presence of WRS and these effects were significantly attenuated by ATB-346. We conclude that (1) naproxen and celecoxib aggravate WRS-damage due to an impairment of GBF, suppression of SOD and GPx and enhanced expression and release of IL-1beta and TNF-alpha, and (2) these effects against WRS ulcerogenesis are counteracted by H₂S causing cGMP-mediated vasodilatation and gastric mucosal hyperemia that compensates for PG deficiency induced by this NSAID and COX-2 inhibitor.