Elsevier

Peptides

Volume 21, Issue 8, August 2000, Pages 1271-1277
Peptides

Regular paper
The effect of α-melanocyte stimulating hormone on colonic inflammation in the rat

https://doi.org/10.1016/S0196-9781(00)00269-2Get rights and content

Abstract

The effect of α-melanocyte stimulating hormone (α-MSH) on colonic inflammation in the rat. In this study, we investigated the effects of α-MSH administration on trinitrobenzene sulfonic acid-induced colitis and the role of nitric oxide and prostaglandins in this response. α-MSH treatment (25 μg/rat, intraperitoneally; twice daily for 3 days) reduced the colonic macroscopic lesions compared to untreated ones in both acute and chronic colitis groups. This effect was reversed by pretreatment with the nitric oxide donor, sodium NP (4 mg/kg, intravenously) or cyclooxygenase-1 selective antagonist indomethacin (5 mg/kg, subcutaneously) in the acute group and with the cyclooxygenase-2 selective antagonist nimesulide (3 mg/kg, subcutaneously) in the chronic group. α-MSH had no effect on colonic wet weight and myeloperoxidase acitivity compared to the untreated colitis group. However, protein oxidation was markedly elevated in the α-MSH-treated group compared to untreated ones. Nitroprusside and indomethacin reversed the effect of α-MSH on macroscopic lesions in the acute groups, whereas nimesulide showed a similar effect in the chronic group. In conclusion, the results of our study show a protective role of α-MSH on colonic lesions which partially involves nitric oxide and prostaglandins.

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.

Section snippets

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

References (31)

  • N.K. Boughton et al.

    The induction nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat

    Br J Parmacol

    (1993)
  • N.K. Boughton–Smith et al.

    Elevated nitric oxide synthase activity in inflamed colon from a rat model of colitis

    Gut

    (1992)
  • N.K. Boughton–Smith et al.

    Characterization of nitric oxide synthase activity in the rat colonic mucosa and muscle after endotoxin and in a rat model of colitis

    Agents Actions

    (1994)
  • J.G. Cannon et al.

    α-Melanocyte stimulating hormone inhibits immunostimulatory and inflammatory actions of interleukin 1

    J Immunol

    (1986)
  • A. Catania et al.

    Alpha-melanocyte stimulating hormone in the modulation of host reactions

    Endocr Rev

    (1993)
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