Regular paperThe effect of α-melanocyte stimulating hormone on colonic inflammation in the rat
Introduction
α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide with broad anti-inflammatory properties that inhibits tissue injury in a wide array of experimental models of inflammation [7]. α-MSH prevents local inflammation in a rat model of arthritis [9] and a mouse model of hepatic injury from septic shock [11] It increases survival in the experimental model of endotoxemia/peritonitis [17]. It has been reported that α-MSH inhibits the synthesis and actions of various cytokines and chemokines [7], [17] and inhibits neutrophil functions directly [8]. In addition, it is a potent inhibitor of the induction of the inducible nitric oxide synthase (iNOS) in cultured macrophages and of nitric oxide (NO) production in a sepsis model [11], [28].
The inflammatory bowel diseases (IBD) are clinical conditions of unknown etiology. Many factors have been implicated in the pathogenesis of these diseases, such as neutrophil infiltration and overproduction of proinflammatory mediators (i.e., cytokines and arachidonate metabolites). Recently, attention has been focused on the overproduction of NO in the pathogenesis of IBD. Increased colonic NO generation and NOS activity have been reported in several models of experimental colitis [3], [5], [20] and IBD patients [2], [19], [22], [27]. In addition, it is believed that prostaglandins are capable of reducing the production of reactive oxygen metabolites [25] and various inflammatory mediators that are suggested to contribute to the pathogenesis of experimental colitis and human IBD (i.e., leukotriene B4 and tumor necrosis factor [TNF]-α) [13], [14]. It has been suggested that constitutive cyclooxygenase (COX-1) is responsible for producing prostaglandins under normal physiological conditions, whereas inducible COX-2 elaborates prostaglandins involved in inflammation. Thus, iNOS and COX-2, which are both induced by cytokines (i.e., interleukin-1 [IL-1], TNF-α, and interferon-γ), are important regulators of mucosal inflammation. Increased iNOS and COX-2 expression and activity occur in the inflamed mucosa of patients with inflammatory bowel disease [2] and of animals with experimental colitis and ileitis [10], [20].
Based on these findings, this study was designed to investigate [1] the effects of α-MSH administration on trinitrobenzene sulfonic acid (TNBS)-induced colitis and, [2] the role of NO and prostaglandins in this response.
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Animals
Sprague–Dawley rats of either sex (200–250 g) were kept in a room at a constant temperature of 22 ± 1°C with 12 h light/dark cycles and fed standard pellet chow and water ad libitum. The study was approved by Marmara University, School of Medicine, Animal Care and Use Commitee.
Induction of colitis
After an overnight fasting, inflammation was induced in the colon, under light ether anesthesia by intrarectal administration of 1 ml of a 30 mg/ml TNBS solution dissolved in 50% ethanol in saline with an 8-cm long
Macroscopic lesion score
In acute groups, the macroscopic lesion score of the colitis group (5.15 ± 0.85) which was higher than that of the control and the vehicle-treated groups (P < 0.001 and P < 0.01, respectively) was reduced by α-MSH treatment (1.62 ± 0.65; P < 0.01). Pretreatment with NP or Indo abolished this effect (P < 0.01 and P < 0.05, respectively; Fig. 1). However, no protection was observed when NP or Indo were administered alone (data not shown).
Similarly, the macroscopic lesion score of the chronic
Discussion
The results of the present study indicate that twice-daily treatment of α-MSH markedly improves macroscopic colonic lesions of TNBS-induced colitis rats. According to various studies, the proopiomelanocortin-derived peptide α-MSH has potent anti-inflammatory effects in a wide array of inflammation models [7]. Understanding of the mechanism by which this occurs is incomplete, although there is recent evidence for α-MSH receptors in murine and human macrophages and for modulation of production of
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