Melanocortins protect against multiple organ dysfunction syndrome in mice

作者：Bitto Alessandra; Polito Francesca; Altavilla Domenica; Irrera Natasha; Giuliani Daniela; Ottani Alessandra; Minutoli Letteria; Spaccapelo Luca; Galantucci Maria; Lodi Renzo; Guzzo Giuseppe; Guarini Salvatore^*; Squadrito Francesco

来源：British Journal of Pharmacology, 2011, 162(4): 917-928.

DOI：10.1111/j.1476-5381.2010.01098.x

• multiple organ dysfunction syndrome
• melanocortin peptides
• cholinergic anti-inflammatory pathway
• melanocortin MC4 receptors
• nicotinic acetylcholine receptors
• mouse

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.

• 出版日期2011-2