The effects of selective cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, on experimental colitis induced by acetic acid in rats

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Abstract

Several mediators may be involved in the pathogenesis of inflammatory bowel disease, as well as in experimental colitis. The present work was conducted to investigate the effects of the two selective cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, on experimentally induced colitis in rats. Rectal instillation of acetic acid was used to induce the colitis. Acetic acid treatment caused haemorrhagic diarrhoea and weight loss in rats. Celecoxib (5 mg/kg) or rofecoxib (2.5 mg/kg), when given twice daily by the oral route, reduced the degree of haemorrhagic diarrhoea and the weight loss produced. In addition, they produced a significant reduction in the degree of colonic injury, the rise in myeloperoxidase (MPO) levels, total nitric oxide synthetase (NOS) activity, platelet-activating factor (PAF), histamine levels and prostaglandin E2 levels. In contrast, there was a significant increase in the levels of reduced glutathione (GSH). Thus, the findings of the present study provide evidence that selective cyclooxygenase-2 inhibitors may be beneficial in patients with inflammatory bowel disease.

Introduction

The cyclooxygenase pathway leads to the production of prostaglandins, which possess both pro- and antiinflammatory properties. There are two known isoforms of cyclooxygenase, namely, cyclooxygenase-1, which is a constitutive enzyme. It is present in nearly all tissues and appears to be critical in maintaining mucosal defenses and plays a key role in mediating platelet aggregation (Carty et al., 2000, Gerd and Werner, 2001). On the other hand, cyclooxygenase-2 is the inducible form of the enzyme, which is expressed in response to the stimulation of inflammatory cells, such as synoviocytes, macrophages and endothelial cells. Stimulants of this isozyme include the proinflammatory cytokines, prostaglandins and tumor necrosis factor-α (Balfour, 1994, Newberry et al., 1999).

Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the generation of prostanoids, but their effects vary in different tissues and organs. The function of the two cyclooxygenase isoforms, cyclooxygenase-1 and cyclooxygenase-2, in maintaining mucosal homeostasis and modulating inflammation in the digestive tract remains uncertain. The generation of prostanoids in the colonic mucosa is increased in both experimentally induced colitis and in inflammatory bowel disease and correlates well with disease activity (Salvatore et al., 2001, Kruidenier and Verspaget, 2002).

Indomethacin, a conventional NSAID, inhibits both cyclooxygenase isoforms, which are induced by acute and chronic enterocolitis in genetically susceptible rats (Yamada et al., 1993). This effect is attributed to the inhibition of the synthesis of prostaglandins in the gastric mucosa. These prostaglandins are known to possess cytoprotective properties (Wallace et al., 1992). The relative contribution of cyclooxygenase-1 and cyclooxygenase-2 isoforms to the biological actions of prostaglandins in the gastrointestinal mucosa is less clear. Several investigators advocated the hypothesis that the inducible form of cyclooxygenase is the source for the proinflammatory prostaglandins released during mucosal injury. In contrast, cyclooxygenase-1 regulates gastrointestinal homeostasis through the synthesis of cytoprotective prostaglandins (Masferrer et al., 1996).

In mice, cyclooxygenase-1 has been reported to play a protective role against mucosal injury of the small intestine (Cohn et al., 1997) and the colon (Tessner et al., 1998). On the other hand, cyclooxygenase-2 expression is induced during inflammation (Singer et al., 1998), and its expression is inhibited by the release of endogenous glucocorticoids (O'Bannion et al., 1991, Karmeli et al., 2000). Based on these observations, some researchers have attributed the antiinflammatory action of NSAIDs to the inhibition of cyclooxygenase-2 and their harmful effects to the inhibition of cyclooxygenase-1 (Eliakim et al., 1992, Xie et al., 1992). This association between cyclooxygenase-2 and the inflammatory events led to the development of selective cyclooxygenase-2 inhibitors, which are expected to display systemic antiinflammatory properties without the anticipated gastrointestinal toxicity. Recently, clinical trials in patients with osteoarthritis documented the safety of the selective cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, on gastric mucosa as compared to the traditional NSAIDs (Goldstein et al., 2000, Martin et al., 2003).

The effect of NSAIDs in the possible modulation of colon inflammation is still controversial and remains uncertain. NSAIDs may be associated with exacerbation of ulcerative colitis and Crohn's disease (Fabia et al., 1993, Felder et al., 2000). Many patients with ulcerative colitis and Crohn's disease are advised to avoid the use of NSAIDs to prevent disease exacerbation (Bonner, 2001). However, the data in this regard have been inconsistent. There are some reports that showed no association between the use of NSAIDs and exacerbation of the underlying inflammatory bowel disease (Dominitz and Boyko, 2000, Mahadevan et al., 2001). This relative contraindication is a problem for those patients who suffer from irritable bowel disease-associated inflammatory arthropathies.

Animal models are used extensively to study the pathogenesis and pathophysiology of inflammatory bowel disease and to evaluate therapies (Morris et al., 1989, Elson et al., 1995, Wallace and Tigley, 1995). Acetic-acid-induced colitis in rats resembles human ulcerative colitis in histology, eicosanoid production and excessive oxygen-derived free radicals release by inflamed mucosa (Millar et al., 1996). Therefore, this study was undertaken to evaluate and compare the effects of two selective cyclooxygenase-2 inhibitors, namely, celecoxib and rofecoxib, on the extent and severity of colitis induced by acetic acid in rats, using macroscopic, microscopic and biochemical studies.

Section snippets

Materials

Celecoxib and rofecoxib were a generous gift from Searle, USA, and Merck, USA, respectively. 5,5-Dithiobis-2-nitrobenzoic acid (DTNB), reduced glutathione (GSH), adenosine diphosphate, platelet-activating factor (PAF) and agents for myeloperoxidase (MPO) assay were purchased from Sigma, St. Louis, MO, USA. Histamine diphosphate monohydrate was purchased from BDH, U.K. l-Arginine and l-citrulline were from Amersham, Bucks, UK. All other chemicals used were of analytical grade.

Animals

Forty male Wistar

Macroscopic

Twenty-four hours after the administration of 3% acetic acid into the colon, macroscopic inspection showed evidence of damage, namely, the presence of mucosal congestion, extensive disruption and linear and deep haemorrhagic ulceration (Fig. 1). In this experimental group, there was evidence of haemorrhagic diarrhoea and weight loss (Fig. 2).

Treatment of rats with either rofecoxib or celecoxib significantly attenuated the extent and severity of the colonic injury and reduced the score of the

Discussion

The present study showed that treatment with the cyclooxygenase-2 inhibitors rofecoxib and celecoxib reduced the inflammation and the damage to the colon, induced by acetic acid, as verified by our macroscopic, histological and biochemical findings.

The results of the present study clearly demonstrated that celecoxib and rofecoxib exert a significant attenuation of the extent and severity of the histological signs of cell damage. These results are in agreement with Martin et al. (2003), who

Acknowledgements

The authors wish to express their gratitude to Ms. Elsa Lina Aureus for her technical assistance and typing of the manuscript.

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