Cyclooxygenase-2 inhibition and experimental colitis: beneficial effects of phosphorothioated antisense...

The effects of cyclooxygenase-2 (cox-2) inhibition by a cox-2 selective antisense phosphorothioated oligonucleotide (AS) and meloxicam were examined in experimental colitis.

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 E2 (PGE2) estimation and for histology, and blood samples for PGE2, thromboxane B2 (TxB2) and TNF-alpha.

Both TNBS and Hac increased colonic MPO activity, PGE2 concentrations and infiltration of colonic wall by inflammatory cells. Serum levels of TNF-alpha were increased in both models, whereas PGE2 was increased only in TNBS colitis. Only meloxicam suppressed the level of PGE2 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.

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 PGE2 and TNF-alpha in the present models of colitis.