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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 [Nle? D-Phe?]?-MSH (NDP-?-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-?-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? receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-?-MSH. KEY RESULTS: At day 7, in the liver and lung NDP-?-MSH, significantly reduced mRNA expression of tumour necrosis factor-? (TNF-?), increased mRNA expression of interleukin-10 and improved the histological picture, as well as reduced TNF-? plasma levels; furthermore, NDP-?-MSH dose-dependently increased survival rate, as assessed throughout the 16 day observation period. HS024 and chlorisondamine prevented all the beneficial effects of NDP-?-MSH in MODS mice. CONCLUSIONS AND IMPLICATIONS: These data indicate that NDP-?-MSH protects against experimental MODS by counteracting the systemic inflammatory response, probably through brain MC? 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.

SUBMITTER: Bitto A

PROVIDER: S-EPMC3042202 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Melanocortins protect against multiple organ dysfunction syndrome in mice.

Bitto Alessandra A Polito Francesca F Altavilla Domenica D Irrera Natasha N Giuliani Daniela D Ottani Alessandra A Minutoli Letteria L Spaccapelo Luca L Galantucci Maria M Lodi Renzo R Guzzo Giuseppe G Guarini Salvatore S Squadrito Francesco F

British journal of pharmacology 20110201 4

<h4>Background and purpose</h4>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 mo ...[more]

PMID: 21039420

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Project description:BackgroundSevere stroke patients have poor clinical outcome which may be associated with development of multiple organ dysfunction syndrome (MODS). Therefore, the aim of our study was to investigate independent risk factors for development of MODS in severe stroke patients.MethodsNinety seven severe stroke patients were prospective recruited from Jan 2011 to Jun 2015. The development of MODS was identified by Sequential Organ Failure Assessment (SOFA) score (score ? 3, at least two organs), which was assessed on day 1, 4, 7, 10 and 14 after admission. Baseline characteristics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Glasgow coma score (GCS) and cerebral imaging parameters were collected at admission. Cox regression was performed to determine predictors for the development of MODS. Medical complications after admission and in-hospital mortality were also investigated.Results33 (34%) patients were in MODS group and 64 (66%) were in non-MODS group within 14 days after admission. Patients in MODS group had more smoker (51.5% vs 28.1%, p = 0.023), higher NIHSS score (23.48 ± 6.12 vs 19.81 ± 4.83, p = 0.004), higher APACHE II score (18.70 ± 5.18 vs 15.64 ± 4.36, p = 0.003) and lower GCS score (6.33 ± 2.48 vs 8.14 ± 2.73, p = 0.002). They also had higher rate of infarction in multi vascular territories (36.4% vs 10.9%, p = 0.003). The most common complication in all patients was pulmonary infection, while complication scores were comparable between two groups. Patients with MODS had higher in-hospital mortality (69.7% vs 9.4%, p = 0.000). In Cox regression, NIHSS score (RR = 1.084, 95% CI 1.019-1.153) and infarction in multi vascular territories (RR = 2.345 95% CI 1.105-4.978) were independent risk factors for development of MODS.ConclusionsIn acute phase of stroke, NIHSS score and infarction in multi vascular territories predicted MODS in severe stroke patients. Moreover, patients with MODS had higher in-hospital mortality, suggesting that early identification of MODS is critical important.

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Melanocortins protect against multiple organ dysfunction syndrome in mice.

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Melanocortins protect against multiple organ dysfunction syndrome in mice.

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