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.

• Authors: Alessandra Bitto, Francesca Polito, Domenica Altavilla, Natasha Irrera, Daniela Giuliani, Alessandra Ottani, Letteria Minutoli, Luca Spaccapelo, Maria Galantucci, Renzo Lodi, Giuseppe Guzzo, Salvatore Guarini, Francesco Squadrito
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 162 Issue 4 Pg. 917-28 (Feb 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21039420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• IL10 protein, mouse
• Inflammation Mediators
• Melanocortins
• Nicotinic Antagonists
• Protective Agents
• RNA, Messenger
• Receptor, Melanocortin, Type 4
• Tumor Necrosis Factor-alpha
• alpha-MSH, DTPA-Nle(4)-Phe(7)-
• Interleukin-10
• Pentetic Acid
• Melanocyte-Stimulating Hormones

Topics

• Animals
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Inflammation Mediators (blood, metabolism)
• Interleukin-10 (genetics, metabolism)
• Liver (drug effects, metabolism, pathology)
• Lung (drug effects, metabolism, pathology)
• Male
• Melanocortins (metabolism)
• Melanocyte-Stimulating Hormones (administration & dosage, antagonists & inhibitors, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Multiple Organ Failure (blood, drug therapy, metabolism, pathology)
• Nicotinic Antagonists (pharmacology)
• Pentetic Acid (administration & dosage, analogs & derivatives, antagonists & inhibitors, therapeutic use)
• Protective Agents (administration & dosage, therapeutic use)
• RNA, Messenger (metabolism)
• Random Allocation
• Receptor, Melanocortin, Type 4 (antagonists & inhibitors)
• Survival Analysis
• Tumor Necrosis Factor-alpha (blood, genetics, metabolism)