Title

 

Authors

M. Galantucci¹, A. Bitto², F. Polito³, D. Altavilla², N. Irrera², D. Giuliani¹, A. Ottani¹, L. Minutoli², L. Spaccapelo¹, G. Guzzo², S. Guarini¹ and F. Squadrito^2
 
1Dept. of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Italy
²Dept. of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Italy
³Dept. of Biochemical, Physiological and Nutritional Sciences, Section of Physiology and Human Nutrition, University of Messina, Italy 

 

Abstract

Multiple organ dysfunction syndrome (MODS) is the leading cause of morbidity and mortality in the intensive care unit. MODS may occur after several pathologic conditions, including circulatory shock by various causes, injury by accident or surgery, hypermetabolism, pancreatitis, and there is the need of novel therapeutically effective approaches. Melanocortins are endogenous peptides of the adrenocorticotropin/melanocyte-stimulating hormone (ACTH/MSH) group. Melanocortins reverse circulatory shock and improve survival by counteracting the systemic inflammatory response, and through the activation of the vagus nerve-mediated “cholinergic anti-inflammatory pathway”, these effects being mediated by acetylcholine – the major vagus nerve neurotransmitter – which interacts with nicotinic receptors located on inflammatory cells (Guarini et al., 2003, 2004; Giuliani et al., 2010). To gain insight into the potential therapeutic value of melanocortins against multiple organ damage following systemic inflammatory response, here we investigated the effects of the melanocortin analog [Nle⁴, D-Phe⁷]α-MSH (NDP-α-MSH) in a widely used murine model of multiple organ dysfunction. MODS was induced in mice by a single intraperitoneal injection of lipopolysaccharide followed, 6 days later (= day 0), by zymosan. After MODS or sham MODS induction, animals were randomized to receive intraperitoneally NDP-α-MSH(340 μg/kg/day) or saline for up to 16 days. Additional groups of MODS mice were concomitantly treated with the melanocortin MC₄receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-α-MSH. At day 7, in the liver and lung NDP-α-MSH significantly reduced mRNA expression of tumour necrosis factor-α (TNF-α), increased mRNA expression of interleukin-10 and improved the histologic picture, as well as reduced TNF-α plasma levels. Furthermore, NDP-α-MSH dose-dependently increased survival rate, as assessed throughout the 16-day observation period. HS024 and chlorisondamine abrogated all beneficial effects of NDP-α-MSH in MODS mice. These data indicate that NDP-α-MSH protects against experimental MODS by counteracting the systemic inflammatory response, likely through brain MC₄ receptor-triggered activation of the vagus nerve-mediated cholinergic anti-inflammatory pathway. These findings disclose previously undescribed effects of melanocortins, and provide further insights into the potential therapeutic value of these endogenous peptides and synthetic analogs.
 
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Giuliani et al. (2010). Adv Exp Med Biol.681:71-87.