Roquinimex inhibits dextran sodium sulfate-induced murine colitis

The majority of inflammatory bowel disease (IBD) consists of two related but clinically and histologically distinct conditions, ulcerative colitis and Crohn’s disease. Both conditions are characterized by chronically relapsing inflammation of the bowel of unknown etiology. Patients with IBD are frequently resistant to conventional therapy (5-aminosalicylic and glucocorticoids) and require immunosuppression or colectomy. Due to side-effects and risks associated with immunosuppressive treatment and surgical intervention, substantial effort has been devoted to studies in experimental animal models in order to improve the current medical treatment of IBD. One of these models is based on oral administration of dextran sodium sulfate (DSS) in the drinking water of mice, which results in an acute colitis with several morphological and pathophysiological features in common with human ulcerative colitis, including superficial ulceration, mucosal damage and leukocyte infiltration.

Roquinimex, a quinoline 3-carboxamide, is an immunomodulatory drug, which has been shown to prevent the induction of inflammatory and autoimmune diseases, such as septic death, systemic lupus erythematosus, arthritis, encephalomyelitis, and diabetes mellitus. However, it is unknown if roquinimex exerts a protective effect in experimental colitis. Interestingly, it has been documented that roquinimex suppresses upregulation of TNF-a and interferon-g (IFN-g), and concomitantly increases expression of anti-inflammatory cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), both locally and in peripheral leukocytes. Considering the potential key role of TNF-αin the pathogenesis of IBD and the successful treatment with anti-TNF-α antibodies in patients with IBD, it may be hypothesized that roquinimex may exert a beneficial effect on colitis.

Induction of colitis

The groups of experimental animals consisted of a normal control group, DSS control group, and a group receiving roquinimex and DSS with five animals in each group. Linomide<sup>TM</sup> is the registered trademark for roquinimex. All mice were non-fasting. Normal control mice received regular drinking water throughout the experiment. In all other groups were colonic inflammation induced by administration of 5% of DSS in the drinking water, which results in a reproducible colitis characterized by reduced body weight, rectal bleeding, mucosal ulceration, crypt destruction and infiltration of leukocytes. When the prophylactic effect of roquinimex was examined, the duration of DSS exposure was five days and when the therapeutic effect of roquinimex was evaluated this period was six days. An initial dose-finding study revealed that 30 mg kg<sup>–1</sup> day<sup>–1</sup> of roquinimex was ineffective against DSS-induced colitis. Thus, the prophylactic effect of roquinimex (300 mg kg<sup>–1</sup> day<sup>–1</sup>) was studied by s.c. administration of roquinimex three days prior to and in parallel with the five-day challenge with DSS. The therapeutic effect of roquinimex was investigated by s.c. administration of roquinimex subsequent to induction of colitis, i.e. injection of roquinimex was started three days after DSS challenge and continued in parallel to DSS for another three days. Both normal and DSS controls were injected with vehicle (PBS) alone. The volume of drinking water consumed was monitored to ensure that roquinimex treatment did not reduce the consumption of the DSS solution. At the end of the experiments, the colon tissues were harvested under anesthesia. The colon was flushed with saline and divided into sections; one section was fixed in formalin for histological evaluation and the second one was frozen at –20°C for later measurement of MPO activity.

 

Reference:

Q. Liu, Y. Wang, M. X .Wan, X. W. Zhang, G. Andersson,G. Hedlund and H.Thorlacius. Inflamm. res. 52 (2003) 64–68

 

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