Matrine improves 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice
Introduction
Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis, are idiopathic chronic inflammation in gut and its causes remain unknown [1], [2]. The current working hypothesis suggests that damage of the intestinal mucosa is related to dysfunction of mucosal T cells, abnormal cytokine production, and cellular inflammation [3]. In CD patients, the T-cell response exhibits a dominant T-helper 1 cell (Th1) phenotype with production of large amounts of TNF-α and interferon-γ, and interleukin-12 [4]. Support for this view has come from animal models of colitis, including the murine model of colonic inflammation induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS), which resembles many of the clinical, histopathologic, and immune characteristics of CD in human [5], [6]. This model consistently exhibits an imbalance of regulatory cytokines, most notably an excessive production of Th1 cytokines, such as interferon-γ, TNF-α, interleukin-12, interleukin-6, etc., and has been extensively used for the evaluation of a wide range of therapeutic approaches and potential anticolitic agents [7].
Most current therapies for IBD include glucocorticosteroids, sulfasalazine, 5-aminosalicylate, immunosuppressive agents and anti-TNF-α monoclonal antibody. There are some patients with IBD, however, who are refractory even to the combined use of these agents [8], [9], [10]. In many cases, the failure of these treatments results in the need for surgical resection of the colon and ileostomy [11]. Therefore, there is a great need for the development of new and specific therapies for IBD.
Matrine, an alkaloid found in kinds of Sophora plants mainly including Sophora flavescens, Sophora alopecuroides and Sophora subprotrata, has a wide range of pharmacological actions, including anti-inflammatory [12], [13], [14], analgesic [15], antiarrhythmic [16], [17], antitumour [18], [19], antifibrotic [20], anti-diarrhea [21] and immunosuppressive effects [22]. In recent years, matrine has been used in the treatment of chronic liver disease and has a significant effect on the inhibition of liver fibrosis [20].
Given that the anti-inflammatory and immunosuppressive effects of matrine, we hypothesize that matrine improves colonic inflammation and is preventive from IBD. Moreover, the effect of matrine on murine colitis has not been elucidated yet. The aim of this study, therefore, is to evaluate the effect of matrine on TNBS-induced colitis in mice and its possible mechanism.
Section snippets
Animals
Specific pathogen free 8-week-old female Balb/c mice were obtained from Experimental Animal Center of Wuhan University. They were housed under controlled temperature (22 °C) and 12-h light–12-h dark cycle, and were given free access to regular laboratory chow diet and water. They were allowed to acclimate to these conditions for 5 days before inclusion in an experiment. The study protocols were approved by the Animal Study Committee of Wuhan University according to governmental guidelines for
Effects of matrine on body weight change and gross appearance of TNBS-induced colitis
Mice treated with TNBS in 50% ethanol developed severe diarrhea and rectal prolapse accompanied by extensive wasting diseases. Matrine was administered by gastric gavage 2 h after TNBS instillation and daily thereafter for 7 days. Mice treated with matrine showed marked improvements of the wasting disease compared with mice treated with TNBS alone, as assessed by body weight change and gross appearance of mice.
First, the daily body weight changes in mice were observed. As shown in Fig. 1,
Discussion
In the present study, we demonstrated for the first time that early administration of matrine effectively attenuates colonic inflammation induced by TNBS in mice, an experimental model that mimics human Crohn's disease. After 1 week of treatment, body weight loss, colonic MPO activity, macroscopic and histological score was significantly reduced in mice treated with matrine at the dose of 10 or 20 mg kg−1 day−1. Further, we also showed that matrine was able to reduce the up-regulated mRNA and
Acknowledgements
This study was supported by a grant (2003AA301C08) from Hubei Provincial Science & Technology Foundation in China. The authors thank Ningxia Yanchi Pharmaceuticals Limited Co. for the generous gift of matrine.
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