fr-167653 and Colitis

To investigate the effects of FR167653 on the development of dextran sulfate sodium (DSS)-induced colitis in mice.. BALB/c mice were fed rodent chow containing 3.5% (wt/wt) DSS. The recipient mice underwent intra-peritoneal injection of vehicles or FR167653 (30 mg/kg per day). The mice were sacrificed on day 14, and the degree of colitis was assessed. Immunohistochemical analyses for CD4(+) T cell and F4/80(+) macrophage infiltration were also performed. Mucosal cytokine expression was analyzed by RT-PCR.. The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. The colon length was shorter in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. Disease activity index and histological colitis score were significantly higher in FR167653- than in vehicle-treated DSS animals. Microscopically, mucosal edema, cellular infiltration (CD4 T cells and F4/80 macrophages), and the disruption of the epithelium were much more severe in FR167653-treated mice than in controls. Mucosal mRNA expression for interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were found to be markedly reduced in FR167653-treated DSS mice.. Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1beta and TNF-alpha expression, suggesting a role of p38 mitogen-activated protein kinase (MAPK)-mediated proinflammatory cytokine induction in host defense mechanisms.

Topics: Animals; Antigens, Differentiation; Body Weight; CD4-Positive T-Lymphocytes; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Interleukin-1beta; Intestinal Mucosa; Macrophages; Male; Mice; Mice, Inbred BALB C; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyrazoles; Pyridines; RNA, Messenger; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha

Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are believed to play a significant role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin-1 and TNF-alpha possess overlapping and synergetic activities inducing the production in cascade of other cytokines, adhesion molecules, arachidonic acid metabolites, as well as activating immune and non-immune cells. FR167653 (C24H18FN5O2-H2SO4-H2O) is a newly synthesized organic compound with a potent inhibitory effect on IL-1beta and TNF-alpha production. We hypothesized that the suppression of IL-1 and TNF-alpha induced by FR167653 could effectively attenuate experimentally induced colonic damage.. Colonic lesions were induced in male Sprague-Dawley rats (250-300 g) by intrarectal instillation of 4% acetic acid. The effect of FR167653 administration at 1.0, 1.5, 2.5 mg/kg per 6 h subcutaneously on acetic acid-induced colonic damage was assessed. The lesion area, microscopic findings, colonic and serum levels of TNF-alpha and IL-1beta were also evaluated.. Treatment with FR167653 at 1.5 and 2.5 mg/kg per 6 h was able to ameliorate the gross macroscopic appearance of colonic lesions significantly, as well as ameliorate the lesion area induced by acetic acid. Colonic mucosal TNF-alpha and IL-1beta levels of rats treated with FR167653 showed significant decrease in a dose-dependent fashion compared with the control group. In the same manner, serum TNF-alpha of rats treated with FR167653 was significantly lower than that of respective controls.. Subcutaneous administration of FR167653 was able to ameliorate the acute changes induced by acetic acid instillation in a dose-dependent manner. This is the first report to evaluate the dual inhibition of the production of IL-1 and TNF-alpha, offered by FR167653, in acute experimental colitis. Further studies are necessary to evaluate FR167653's efficacy and safety on long-term conditions.

Topics: Acetic Acid; Acute Disease; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Disease Models, Animal; Interleukin-1; Male; Molecular Structure; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha