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Melanocortins protect against multiple organ dysfunction syndrome in mice.

Abstract：

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]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 MC₄ receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-α-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-α-MSH in MODS mice. CONCLUSIONS AND IMPLICATIONS:These data indicate that NDP-α-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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Bitto A,Polito F,Altavilla D,Irrera N,Giuliani D,Ottani A,Minutoli L,Spaccapelo L,Galantucci M,Lodi R,Guzzo G,Guarini S,Squadrito F

doi

10.1111/j.1476-5381.2010.01098.x

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

917-28

issue

eissn

0007-1188

issn

1476-5381

journal_volume

162

pub_type

杂志文章

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Melanocortins protect against multiple organ dysfunction syndrome in mice.