Influence of simultaneous inhibition of cyclooxygenase-2 and inducible nitric oxide synthase in experimental colitis in rats.
The inflamed mucosa in ulcerative colitis produces high amount of prostaglandin (PG) and nitric oxide (NO) through inducible enzymes: cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), respectively, implicating them as potential anti-inflammatory drug targets. COX-2 or iNOS-related treatments in different models of colitis have yielded ambiguous results ranging from exacerbation of disease to abolition of inflammation. iNOS and COX-2 induction is blocked by potent anti-inflammatory glucocorticoids, however, serious side effects including relapses limit their usefulness in colitis for long time. Simultaneous inhibition of iNOS and COX-2 was investigated in the current study in 2, 4, 6 trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Treatment group received rofecoxib, aminoguanidine hydrochloride or their combination at different doses at 48, 36, 24, 12 and 1 h prior to induction of colitis and 12 h later. Colonic myeloperoxidase (MPO), COX-2, nitrate and nitrite, tumor necrosis factor-alpha (TNF-alpha) and lipid peroxidation were maximally reduced by combination of 10 mg/kg rofecoxib and 30 mg/kg of aminoguanidine hydrochloride in TNBS-induced colitis in rats. However, maximum increase in SOD and catalase was noted by this combination. Rats treated with rofecoxib, aminoguanidine hydrochloride and their combinations reduced the inflammation, acute colonic damage produced by TNBS as verified by macroscopic changes in colon. Combination of rofecoxib (10 mg/kg) and aminoguanidine hydrochloride (30 mg/kg) has maximal protective effect on colonic injury induced by TNBS enema which is probably, via mechanism of local inhibition of iNOS and COX-2 activity in colonic mucosa and support the idea that simultaneous inhibition of iNOS and COX-2 inhibitors have a promising potential in the treatment of colitis.
Dudhgaonkar
S P
SP
Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Dist. - Bareilly, Pin - 243 122, UP India.
Tandan
S K
SK
Kumar
D
D
Raviprakash
V
V
Kataria
M
M
D000818:Animals; D002374:Catalase / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D007420:Intestine, Large / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D006146:Guanidines; D007783:Lactones; D009566:Nitrates; D009573:Nitrites; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C116926:rofecoxib; D014302:Trinitrobenzenesulfonic Acid; D002374:Catalase; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D013482:Superoxide Dismutase; C004479:pimagedine