Melanotropic Peptides: more than Just 'Barbie Drugs' and 'Sun-tan Jabs'?

E.A. Langan; Z. Nie; L.E. Rhodes

Disclosures

The British Journal of Dermatology. 2010;163(3):451-455. 

In This Article

Mechanisms of Action

Ultraviolet radiation (UVR) induces DNA damage in epidermal cells, and evidence supports that a p53-mediated response to DNA damage is a key signalling event in UVR-induced tanning, triggering increased α-MSH synthesis by keratinocytes.[4–6] The secreted α-MSH binds to the melanocortin 1 receptor (MC1R) on nearby melanocytes, increasing cAMP and cAMP-dependent protein kinase production and ultimately the activity of the melanogenic enzymes, including tyrosinase (Fig. 1).[7] Increased cutaneous eumelanin production results in skin pigmentation, providing a partial barrier to penetration of UVR and visible light. In particular it forms a protective 'nuclear cap' of melanin over the nuclei of basal keratinocytes. Eumelanin also scavenges UVR-induced reactive oxygen species that can damage DNA, proteins and lipids.

Figure 1.

Melanogenesis. L-Phenylalanine is metabolized in the presence of three major enzymes, phenylalanine hydroxylase, tyrosine hydroxylase isoform I and tyrosinase, to eumelanin and phaeomelanin. Alpha MSH, α-melanocyte stimulating hormone; UV, ultraviolet.

First synthesized almost three decades ago, the α-MSH analogue [Nle4-D-Phe7]-α-MSH is a superpotent melanocortin.[8] Like α-MSH, this is a linear 13 amino acid peptide; here the fourth amino acid, methionine, is replaced by norleucine, and the seventh amino acid, L-phenyalanine, is replaced by its dextrorotary form,D-phenylalanine. Its potency is related to its resistance to enzymatic breakdown, which prolongs its duration of action at the MC1R compared with the endogenous α-MSH molecule. Stimulation of the MC1R promotes melanogenesis both by stimulating melanocyte proliferation and by upregulating tyrosinase activity.[9,10] This pharmacological intervention thus harnesses eumelanization at a point downstream of DNA damage.[6]

A shorter cyclic variant containing a lactam bridge, i.e. Ac-Nle-[Asp-His-D-Phe-Arg-Trp-Lys]-α-MSH-NH2, increases skin pigmentation at lower cumulative doses than [Nle4-D-Phe7]-α-MSH, but was also found in clinical trials to result in more side-effects, including nausea, somnolence and penile erections.[11] These side-effects were thought to result from its interaction with a wider range of melanocortin receptors, namely MC2R in the gut, causing nausea, and MC3R in the brain, resulting in penile erections via a neural mechanism. The combination of tanning, penile erections and decreased appetite led to the nickname 'Barbie drug'.[1]

Analogues of α-MSH may also potentially share further (nonpigmenting) properties that have been described for the natural α-MSH molecule. α-MSH has been shown to have anti-inflammatory and immunosuppressive effects in experimental models,[12,13] including a very recent study demonstrating the role of α-MSH, via the MC1R, in induction of cytotoxicity in human CD8+ T cells in vitro.[14] Furthermore, in mouse skin, α-MSH upregulates the oxidative stress response to UVB.[15,16] A functioning MCR1 appears important in many of these responses induced experimentally by α-MSH.

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