Nonsteroidal anti-inflammatory drug-activated gene-1 plays a role in the impairing effects of cyclooxygenase inhibitors on gastric ulcer healing.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAID-activated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (DFU) (selective COX-2 inhibitor; 5 mg/kg), celecoxib (selective COX-2 inhibitor; 1 mg/kg), and valdecoxib (selective COX-2 inhibitor; 1 mg/kg), for 1, 3, or 7 days. Ulcerated tissues were processed to assess: 1) COX-1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA), and activated caspase-3 expression; 2) ulcer area; and 3) prostaglandin E(2) (PGE(2)) levels. COX-1 expression in ulcerated tissues was decreased, whereas COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE(2) levels were decreased by SC-560, DFU, celecoxib, valdecoxib, and indomethacin. NAG-1 was overexpressed in ulcerated tissues and further enhanced by indomethacin, DFU, and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing.

• Authors: Rocchina Colucci, Luca Antonioli, Nunzia Bernardini, Chiara Ippolito, Cristina Segnani, Oriana Awwad, Marco Tuccori, Corrado Blandizzi, Carmelo Scarpignato, Matteo Fornai
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 342 Issue 1 Pg. 140-9 (Jul 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22495067 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase Inhibitors
• Gdf15 protein, rat
• Growth Differentiation Factor 15
• Membrane Proteins
• Proliferating Cell Nuclear Antigen
• RNA, Messenger
• Cyclooxygenase 1
• Cyclooxygenase 2
• Ptgs1 protein, rat
• Caspase 3
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Caspase 3 (genetics, metabolism)
• Cyclooxygenase 1 (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase Inhibitors (pharmacology)
• Dinoprostone (genetics, metabolism)
• Gastric Mucosa (drug effects, metabolism)
• Growth Differentiation Factor 15 (genetics, metabolism)
• Inflammation (drug therapy, genetics, metabolism)
• Male
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Proliferating Cell Nuclear Antigen (genetics, metabolism)
• RNA, Messenger (genetics)
• Rats
• Rats, Sprague-Dawley
• Stomach Ulcer (drug therapy, genetics, metabolism)
• Wound Healing (drug effects)