Cyclooxygenase-2 inhibition and experimental colitis: Beneficial effects of phosphorothioated antisense oligonucleotide and meloxicam

Abstract

Background: The effects of cyclooxygenase-2 (cox-2) inhibition by a cox-2 selective antisense phosphorothioated oligonucleotide (AS) and meloxicam were examined in experimental colitis. Methods: Colitis was induced by trinitrobenzenesulphonic acid (TNBS) and acetic acid (Hac) separately in male Sprague-Dawley rats. Both groups of animals were treated daily intraperitoneally with AS and a mismatched control oligo (CO) (3 mg/kg), and orally with meloxicam (7.5 mg/kg) 1 h before induction of colitis. The animals were killed on day 4 (Hac) and on day 5 (TNBS). Tissue samples from colon, ileum, liver, kidney and spleen were collected for mRNA, myeloperoxidase activity (MPO), prostaglandin E 2 (PGE 2) estimation and for histology, and blood samples for PGE 2, thromboxane B 2 (TxB 2) and TNF-α. Results: Both TNBS and Hac increased colonic MPO activity, PGE 2 concentrations and infiltration of colonic wall by inflammatory cells. Serum levels of TNF-α were increased in both models, whereas PGE 2 was increased only in TNBS colitis. Only meloxicam suppressed the level of PGE 2 significantly below the basal level. The animals in both models also showed splenomegaly. The colitis-induced changes were significantly suppressed by the treatment of the test compounds but not by the CO. Cox-2 mRNA but not cox-1 was decreased by the AS, but not by meloxicam or in CO-treated colitic animals. Conclusion: The findings demonstrate comparable beneficial effects of the cox-2 selective antisense oligonucleotide and meloxicam, which seem to be mediated by a combined inhibition of both PGE 2 and TNF-α in the present models of colitis.