The effect of -melanocyte stimulating hormone on colonic inflammation in the rat Berna K. Oktar, a Ferı ˙ha Ercan, b Berrak C ¸ . Yeg ˘en, a I ˙ ncı ˙ Alı ˙can a, * a Departments of Physiology, Marmara University School of Medicine 81326 Haydarpasa, Istanbul, Turkey b Histology and Embryology, Marmara University School of Medicine 81326 Haydarpasa, Istanbul, Turkey Received 2 December 1999; accepted 21 April 2000 Abstract The effect of -melanocyte stimulating hormone (-MSH) on colonic inflammation in the rat. In this study, we investigated the effects of -MSH administration on trinitrobenzene sulfonic acid-induced colitis and the role of nitric oxide and prostaglandins in this response. -MSH treatment (25 g/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. -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 -MSH-treated group compared to untreated ones. Nitroprusside and indomethacin reversed the effect of -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 -MSH on colonic lesions which partially involves nitric oxide and prostaglandins. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Colitis; -Melanocyte stimulating hormone; Nitric oxide; Prostaglandins; Neutrophils 1. Introduction -Melanocyte-stimulating hormone (-MSH) is a neu- ropeptide with broad anti-inflammatory properties that in- hibits tissue injury in a wide array of experimental models of inflammation [7]. -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 -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 syn- thase (iNOS) in cultured macrophages and of nitric oxide (NO) production in a sepsis model [11,28]. The inflammatory bowel diseases (IBD) are clinical con- ditions of unknown etiology. Many factors have been im- plicated in the pathogenesis of these diseases, such as neu- trophil 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 experi- mental colitis and human IBD (i.e., leukotriene B4 and tumor necrosis factor [TNF]-) [13,14]. It has been sug- gested that constitutive cyclooxygenase (COX-1) is respon- sible for producing prostaglandins under normal physiolog- ical conditions, whereas inducible COX-2 elaborates prostaglandins involved in inflammation. Thus, iNOS and COX-2, which are both induced by cytokines (i.e., interleu- kin-1 [IL-1], TNF-, and interferon-), are important reg- ulators of mucosal inflammation. Increased iNOS and COX-2 expression and activity occur in the inflamed mu- * Corresponding author. Tel.: +90-216-414-4736; fax: +90-216-414- 4731. Peptides 21 (2000) 1271–1277 0196-9781/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0196-9781(00)00269-2