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

Abstract

Although substance P (SP) has been implicated as a mediator of neurogenic inflammation in the small intestine, little information is available regarding the role of SP in the pathogenesis of chronic ulcerative colitis. In this study, our aim was to investigate whether the intraperitoneal administration of a nonpeptide neurokinin-1 (NK-1) antagonist, CP-96345, which antagonizes 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-isoprostanes were measured. Animals receiving DSS exhibited marked physical signs of colitis by day 5 compared with controls. Chronic administration of the NK-1 antagonist significantly reduced the disease activity index, mucosal myeloperoxidase activity, colonic tissue damage score, and mucosal and urinary levels of 8-isoprostanes compared with inactive enantiomer- or vehicle-injected (saline) animals receiving DSS alone. These data indicate that the administration of an NK-1 antagonist can attenuate colonic inflammation and oxidative stress and suggest a novel therapeutic approach in the treatment of chronic ulcerative colitis.

On the dynamics of nitrite, nitrate and other biomarkers of nitric oxide production in inflammatory bowel disease

“…In agreement with published data [39][40][41][42][43][44] , the DAI increased gradually over the time of DSS administration, reaching a maximum of 3.11 ± 0.05 on the last day of DSS administration (day 7), and subsequently decreased to 1.55 ± 0.17 at the 4 th day after DSS cessation. The full DAI time course is shown in Fig.1.…”

In vivo quercitrin anti‐inflammatory effect involves release of quercetin, which inhibits inflammation through down‐regulation of the NF‐κB pathway

“…The results obtained in the present study show that exposure to DSS in the drinking water induced a colonic inflammatory status with similar features to those described previously [28,29], and it was evidenced by the time course increase in the disease activity index (DAI) values in comparison with non-colitic rats (Fig. 5).…”

Metalloproteinases and Transforming Growth Factor-α Mediate Substance P-induced Mitogen-activated Protein Kinase Activation and Proliferation in Human Colonocytes

“…Thus, SP and NK-1R expression is increased in the colon of patients with inflammatory bowel disease (8), in Clostridium difficile-associated colitis (9), and in the ileum of rats injected with C. difficile toxin A (10,11). Pharmacologic antagonism of NK-1R (6,12,13) or genetic deletion of this receptor (14) results in reduced intestinal inflammation, whereas deletion of neutral endopeptidases, which degrade SP, enhances acute gut inflammation (15). Along these lines SP acts as a proinflammatory peptide in vitro and induces secretion of interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor-␣ (TNF␣) (10, 16 -20) via activation of the transcription factor NF-B in target cells (21,22).…”