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: 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.
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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)
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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
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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)
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