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 [Nle(4) , D-Phe(7) ]α-MSH (NDP-α-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-α-MSH (340 µg kg(-1) day) or saline for up to 16 days. Additional groups of MODS mice were concomitantly treated with the melanocortin MC(4) receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-a-MSH. Key results: 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 histological 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 prevented all the beneficial effects of NDP-a-MSH in MODS mice. Conclusions and Implications: These data indicate that NDP-a-MSH protects against experimental MODS by counteracting the systemic inflammatory response, probably through brain MC(4) 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.