[Nle4,D-Phe7]-α-MSH

[Nle4, D-Phe7]-alpha-MSH Inhibits Toll-Like Receptor (TLR)2- and TLR4-Induced Microglial Activation and Promotes a M2-Like Phenotype.[Pubmed:27359332]

PLoS One. 2016 Jun 30;11(6):e0158564.

alpha-melanocyte stimulating hormone (alpha-MSH) is an anti-inflammatory peptide, proved to be beneficial in many neuroinflammatory disorders acting through melanocortin receptor 4 (MC4R). We previously determined that rat microglial cells express MC4R and that NDP-MSH, an analog of alpha-MSH, induces PPAR-gamma expression and IL-10 release in these cells. Given the great importance of modulation of glial activation in neuroinflammatory disorders, we tested the ability of NDP-MSH to shape microglial phenotype and to modulate Toll-like receptor (TLR)-mediated inflammatory responses. Primary rat cultured microglia were stimulated with NDP-MSH followed by the TLR2 agonist Pam3CSK4 or the TLR4 agonist LPS. NDP-MSH alone induced expression of the M2a/M2c marker Ag1 and reduced expression of the M2b marker Il-4ralpha and of the LPS receptor Tlr4. Nuclear translocation of NF-kappaB subunits p65 and c-Rel was induced by LPS and these effects were partially prevented by NDP-MSH. NDP-MSH reduced LPS- and Pam3CSK4-induced TNF-alpha release but did not affect TLR-induced IL-10 release. Also, NDP-MSH inhibited TLR2-induced HMGB1 translocation from nucleus to cytoplasm and TLR2-induced phagocytic activity. Our data show that NDP-MSH inhibits TLR2- and TLR4-mediated proinflammatory mechanisms and promotes microglial M2-like polarization, supporting melanocortins as useful tools for shaping microglial activation towards an alternative immunomodulatory phenotype.

Evaluation of the immunogenicity of the synthetic alpha-melanocyte-stimulating hormone (alpha-MSH) analogue afamelanotide ([Nle4-D-Phe7]-alpha-MSH, Scenesse(R)) in erythropoietic protoporphyria patients by ELISA detecting both anti-afamelanotide and anti-alpha-MSH antibodies.[Pubmed:25402764]

Skin Pharmacol Physiol. 2015;28(2):103-13.

UNLABELLED: Afamelanotide is an alpha-melanocyte-stimulating hormone (alpha-MSH) agonist with proven efficacy in photodermatoses such as erythropoietic protoporphyria (EPP). This peptide drug, repeatedly administered over prolonged time, may induce anti-drug antibodies (ADA). Here, we describe a new ELISA method developed to monitor the occurrence of ADA against afamelanotide as well as against alpha-MSH. Covalent binding instead of absorption of antigen onto the microtitre wells prevented antigen leakage and enabled extensive washings followed by lower background. The cut-off between antibody-negative and -positive sera was determined. Inhibition of the antigen-antibody reaction by excess soluble antigen tested for specificity. The sensitivity of the ELISA was 608 and 1,390 ng/ml of specific ADA against afamelanotide and alpha-MSH, respectively. This ELISA method enabled us to investigate the occurrence of ADA during long-term administration of afamelanotide. No immunoreactivity was found in 23 of the 26 EPP patients exposed to the drug for up to 6 years. Pre-existing immunoreactivity against afamelanotide as well as alpha-MSH was found in 3 patients, whose titres did not change during afamelanotide administration. CONCLUSION: The new ELISA is suitable to determine ADA against afamelanotide and alpha-MSH. Afamelanotide did not elicit ADA during long-term administration in patients with EPP.

Beneficial effects of the melanocortin analogue Nle4-D-Phe7-alpha-MSH in acne vulgaris.[Pubmed:22845050]

J Eur Acad Dermatol Venereol. 2014 Jan;28(1):108-11.

BACKGROUND: alpha-Melanocyte-stimulating hormone (alpha-MSH) is a melanocortin peptide that increases skin pigmentation during ultraviolet light-mediated tanning. As alpha-MSH has been shown to possess anti-inflammatory effects, we assessed the clinical potential of a superpotent alpha-MSH analogue, afamelanotide (Nle(4)-D-Phe(7)-alpha-MSH), in patients with acne vulgaris, the most common inflammatory skin disorder. METHODS: Afamelanotide (16 mg) was given in a phase II open-label pilot study subcutaneously as a sustained-release resorbable implant formulation to 3 patients with mild-to-moderate facial acne vulgaris. Evaluation included lesion count, adverse effects and patient-reported outcome. Monitoring of laboratory parameters included differential blood counts, electrolytes, urine analysis, and liver and kidney function tests. Skin melanin density was measured by reflectance spectrophotometry. RESULTS: The total number as well as the number of inflammatory acne lesions declined in all patients 56 days after the first injection of afamelanotide. Life quality as measured by Dermatology Life Quality Index likewise improved in all 3 patients 56 days after the first injection of afamelanotide. There were no adverse effects except mild and short-term fatigue in one patient. All patients experienced increased pigmentation especially on the face. Clinically relevant changes in laboratory parameters were not detected. CONCLUSIONS: Afamelanotide appears to have anti-inflammatory effects in patients with mild-to-moderate acne vulgaris. Future trials are needed to confirm the anti-inflammatory action of this melanocortin analogue in patients with acne vulgaris.

Systemic photoprotection in solar urticaria with alpha-melanocyte-stimulating hormone analogue [Nle4-D-Phe7]-alpha-MSH.[Pubmed:20969564]

Br J Dermatol. 2011 Feb;164(2):407-14.

BACKGROUND: Solar urticaria is a rare photosensitivity disorder demonstrating a range of action spectra, which can inflict a very large impact on life quality despite available treatments. Melanin broadly reduces skin penetration by ultraviolet-visible wavelengths, thus increased melanization may protect in solar urticaria. OBJECTIVES: To examine quantitatively for impact of the potent alpha-melanocyte stimulating hormone analogue afamelanotide ([Nle(4)-D-Phe(7)]-alpha-MSH, Scenesse((R)); Clinuvel Pharmaceuticals Ltd, Melbourne, Vic., Australia) on the solar urticaria response and skin melanization. METHODS: Five patients with solar urticaria received a single dose of 16 mg subcutaneous afamelanotide implant in winter time. Melanin density was assessed spectrophotometrically from day 0 to day 60. Detailed monochromated light testing to geometric dose series (increment ) of wavelengths 300-600 nm was performed at 0, 30 and 60 days, with assessment of weal and flare area and minimum urticarial dose (MUD). Data were analysed by repeated-measures anova. RESULTS: Mean melanin density increased by day 7, peaked at day 15 and remained elevated at day 60 (P=0.03, 0.01, 0.02 vs. baseline, respectively). Baseline phototesting revealed action spectra of 320-400 (n=1), 320-500 (n=2), 300-600 (n=1) and 370-500 nm (n=1), and on afamelanotide mean rises in MUD of 1-12 and 1-3 dose increments were seen at the individual wavelengths tested, at 30 and 60 days, respectively. A significant fall in weal area occurred across responding wavelengths from 300 to 600 nm at 60 days postimplant (P=0.049 vs. baseline), accompanied by greater than twofold overall increase in MUD (P=0.058 vs. baseline). CONCLUSIONS: Melanization following afamelanotide is accompanied by reduction in solar urticaria response across a broad spectrum of wavelengths. Further study is warranted to assess clinical benefit under ambient conditions in summer.

Melanocortin receptors: perspectives for novel drugs.[Pubmed:10443584]

Eur J Pharmacol. 1999 Jun 30;375(1-3):295-310.

The cloning of five different subtypes of melanocortin receptor subtypes have recently opened up new possibilities for the development of drugs. The physiological roles of the five melanocortin receptors have started to become understood, and compounds with selective actions on some of the five subtypes have become available. Presently, most clinically promising application for drugs active on melanocortin receptors are for control of feeding homeostasis and body weight and for treatment of inflammatory diseases. I review here the cloning, localisation, function and structure of the melanocortin receptors, in relation to the possibilities to develop selective drugs for these receptors.