Melanocortins protect against multiple organ dysfunction syndrome in mice

BACKGROUND AND PURPOSE 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. 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 analogue [Nle4, D-Phe7]alpha-MSH (NDP-alpha-MSH) in a widely used murine model of multiple organ dysfunction syndrome (MODS). EXPERIMENTAL APPROACH 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-alpha-MSH (340 mu g center dot kg-1 day) or saline for up to 16 days. Additional groups of MODS mice were concomitantly treated with the melanocortin MC4 receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-alpha-MSH. KEY RESULTS At day 7, in the liver and lung NDP-alpha-MSH, significantly reduced mRNA expression of tumour necrosis factor-alpha (TNF-alpha), increased mRNA expression of interleukin-10 and improved the histological picture, as well as reduced TNF-alpha plasma levels; furthermore, NDP-alpha-MSH dose-dependently increased survival rate, as assessed throughout the 16 day observation period. HS024 and chlorisondamine prevented all the beneficial effects of NDP-alpha-MSH in MODS mice. CONCLUSIONS AND IMPLICATIONS These data indicate that NDP-alpha-MSH protects against experimental MODS by counteracting the systemic inflammatory response, probably through brain MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway. These findings reveal previously undescribed effects of melanocortins and could have clinical relevance in the MODS setting.