NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats

Although substance P (SP) has been implicated as a mediator of neurogenic i nflammation in the small intestine, little information is available regardi ng the role of SP in the pathogenesis of chronic ulcerative colitis. In thi s study, our aim was to investigate whether the intraperitoneal administrat ion of a nonpeptide neurokinin-1 (NK-1) antagonist, CP-96345, which antagon izes the binding of SP to its NK-1 receptor, results in the attenuation of colonic inflammation induced in rats by 5% dextran sodium sulfate (DSS) in drinking water for 10 days compared with an inactive enantiomer, CP-96344. Disease activity was assessed daily for 10 days, after which colonic tissue damage was scored and myeloperoxidase activity and colon and urinary 8-iso prostanes were measured. Animals receiving DSS exhibited marked physical si gns of colitis by day 5 compared with controls. Chronic administration of t he NK-1 antagonist significantly reduced the disease activity index, mucosa l myeloperoxidase activity, colonic tissue damage score, and mucosal and ur inary levels of 8-isoprostanes compared with inactive enantiomer- or vehicl e-injected (saline) animals receiving DSS alone. These data indicate that t he administration of an NK-1 antagonist can attenuate colonic inflammation and oxidative stress and suggest a novel therapeutic approach in the treatm ent of chronic ulcerative colitis.