Melanocyte Stimulating Hormone Analogue Research Articles

Into the Light: Afamelanotide and the Treatment of Erythropoietic Protoporphyria in the United States.

Erythropoietic protoporphyria (EPP) is a rare disease that causes disabling cutaneous photosensitivity with pain and burning sensations. In 2019, afamelanotide, an α-melanocyte-stimulating hormone analogue, was approved in the United States for treatment of EPP. In this study, patients receiving afamelanotide filled out questionnaires assessing the benefit of treatment. Outcomes measured included: return to normal activities, experience of phototoxic reactions, effect on patient confidence, and more. Patients ranked their experience on a descriptive scale ranging from "very much" to "never". Prior to treatment, 75% of patients indicated that EPP affected their lives "very much" or "a lot". This number fell to 11% after the 1st implant and to 0% after each subsequent implant. The number of patients that willingly ventured outside increased with each subsequent implant. The results of this study clearly show that afamelanotide treatment can dramatically and positively impact the lives of EPP patients.  Citation: Resnik SR, Targett D, Resnik BI. Into the light: afamelanotide and the treatment of erythropoietic protoporphyria in the United States. J Drugs Dermatol. 2023;22(9):941-949. doi:10.36849/JDD.7126R1.

Protective effects of β‐carotene and melanin against protoporphyrine IX‐induced phototoxicity in the photo hen's egg test

The aim of our study was to evaluate the photoprotective potential of melanin and β-carotene against protoporphyrine IX-induced phototoxicity via photo hen's egg test. In three independent test groups, the yolk sac blood vessel system of hen's eggs was exposed to protoporphyrine IX and irradiated with ultraviolet A (UVA). One of the test groups also received melanin to investigate its photoprotective capacity; another test group received β-carotene for the same purpose. Morphological changes and embryo lethality were recorded in these three test groups for a period of 24 h. The same parameters were obtained in five different control groups. The control groups exhibited only minimal morphological changes and no fatalities. In contrast, severe phototoxic damage and a high lethality rate (75%) were observed in the test group exposed to protoporphyrine IX and UVA. Lethality was somewhat lower in the β-carotene test group (58%) and was considerably lower in the melanin test group (17%). The photoprotective potential against protoporphyrine IX-induced phototoxic damage was moderate for β-carotene and was remarkable for melanin. Given that synthetic melanocyte stimulating hormone (MSH) analogues induce a de novo synthesis of melanin without any previous ultraviolet irradiation in human skin, the application of MSH analogues might be conceived of as 'light hardening' without light. Synthetic MSH analogues thus may represent a new promising therapeutic option for photodermatoses especially for erythropoietic protoporphyria.

Future research into the treatment of vitiligo: where should our priorities lie? Results of the vitiligo priority setting partnership.

BackgroundVitiligo is the most frequent depigmentation disorder of the skin and is cosmetically and psychologically devastating. A recently updated Cochrane systematic review ‘Interventions for vitiligo’ showed that the research evidence for treatment of vitiligo is poor, making it difficult to make firm recommendations for clinical practice.ObjectivesTo stimulate and steer future research in the field of vitiligo treatment, by identifying the 10 most important research areas for patients and clinicians.MethodsA vitiligo priority setting partnership was established including patients, healthcare professionals and researchers with an interest in vitiligo. Vitiligo treatment uncertainties were gathered from patients and clinicians, and then prioritized in a transparent process, using a methodology advocated by the James Lind Alliance.ResultsIn total, 660 treatment uncertainties were submitted by 461 participants. These were reduced to a list of the 23 most popular topics through an online/paper voting process. The 23 were then prioritized at a face-to-face workshop in London. The final list of the top 10 treatment uncertainties included interventions such as systemic immunosuppressants, topical treatments, light therapy, melanocyte-stimulating hormone analogues, gene therapy, and the impact of psychological interventions on the quality of life of patients with vitiligo.ConclusionsThe top 10 research areas for the treatment of vitiligo provide guidance for researchers and funding bodies, to ensure that future research answers questions that are important both to clinicians and to patients.

Altered glucose homeostasis in proopiomelanocortin-null mouse mutants lacking central and peripheral melanocortin.

Prolonged obesity frequently leads to insulin resistance and, eventually, to diabetes. This relationship reflects the integration of fat stores and carbohydrate metabolism and the coordination of central nervous system functions, e.g. appetite, and peripheral metabolism. Recent work suggests that the melanocortin system is involved in this integration; specifically, central administration of melanocyte-stimulating hormone (MSH) decreases, whereas lack of central MSH signaling increases, peripheral insulin resistance. Here we asked whether MSH acting in the periphery has a complementary role in insulin resistance. We tested this in a mouse model where the proopiomelanocortin (POMC) gene encoding all of the melanocortins has been genetically deleted. The homozygous POMC-null mouse lacks central as well as peripheral MSH signaling; in addition, it lacks adrenal glands and thus is devoid of corticosterone and epinephrine. Here we report that homozygous POMC mutants have normal serum levels of insulin, normal fasting levels of glucose, and normal clearance of glucose in glucose tolerance tests. Thus, insulin production and sensitivity and glucose uptake in peripheral tissues are functioning normally. However, we found a striking inability of the homozygous POMC mutants to recover from insulin-induced hypoglycemia. This defect was in the glucagon-mediated counterregulatory response. Both peripheral administration of an MSH analog and supplementation with corticosterone alleviated the hypoglycemia after insulin challenge, but did not make the obese POMC mutant mice diabetic. We conclude that, similar to the regulation of body weight homeostasis, the regulation of glucose homeostasis requires the integration of both central and peripheral melanocortin signaling systems.

Skin pigmentation enhancers

The highest incidences of cancer are found in the skin, but endogenous pigmentation is associated with markedly reduced risk. Agents that enhance skin pigmentation have the potential to reduce both photodamage and skin cancer incidence. The purpose of this review is to evaluate agents that have the potential to increase skin pigmentation. These include topically applied substances that simulate natural pigmentation: dihydroxyacetone and melanins; and substances that stimulate the natural pigmentation process: psoralens with UVA (PUVA), dimethylsulfoxide (DMSO), l-tyrosine, l-Dopa, lysosomotropic agents, diacylglycerols, thymidine dinucleotides, DNA fragments, melanocyte stimulating hormone (MSH) analogs, 3-isobutyl-1-methylxanthine (IBMX), nitric oxide donors, and bicyclic monoterpene (BMT) diols. These agents are compared with regards to efficacy when administered to melanoma cells, normal human epidermal melanocytes, animal skin, and human skin. In addition, mechanisms of action are reviewed since these may reveal issues related to both efficacy and safety. Both dihydroxyacetone and topically applied melanins are presently available to the consumer, and both of these have been shown to provide some photoprotection. Of the pigmentation stimulators, only PUVA and MSH analogs have been tested extensively on humans, but there are concerns about the safety and side effects of both. At least some of the remaining pigmentation stimulators under development have the potential to safely induce a photoprotective tan.

Discovery of novel melanocortin4 receptor selective MSH analogues.

1. We synthesized a novel series of cyclic melanocyte stimulating hormone (MSH) analogues and tested their binding properties on cells transiently expressing the human melanocortin1 (MC1), MC3, MC4 and MC5 receptors. 2. We discovered that compounds with 26 membered rings of [Cys4,D-Nal7,Cys11]alpha-MSH(4-11) displayed specific MC4 receptor selectivity. The preference order of the different MC receptor subtypes for the novel [Cys4D-Nal7Cys11]alpha-MSH(4-11) analogues are distinct from all other known MSH analogues, particularly as they bind the MC4 receptor with high and the MC1 receptor with low relative affinities. 3. HS964 and HS014 have 12 and 17 fold MC4/MC3 receptor selectivity, respectively, which is much higher than for the previously described cyclic lactam and [Cys4,Cys10]alpha-MSH analogues SHU9119 and HS9510. 4. HS964 is the first substance showing higher affinity for the MC5 receptor than the MC1 receptor. 5. HS014, which was the most potent and selective MC4 receptor ligand (Ki 3.2 nM, which is approximately 300 fold higher affinity than for alpha-MSH), was also demonstrated to antagonize alpha-MSH stimulation of cyclic AMP in MC4 receptor transfected cells. 6. We found that a compound with a 29 membered ring of [Cys3,Nle10,D-Nal7,Cys11]alpha-MSH(3-11) (HS010) had the highest affinity for the MC3 receptor. 7. This is the first study to describe ligands that are truly MC4 selective and a ligand having a high affinity for the MC3 receptor. The novel compounds may be of use in clarifying the physiological roles of the MC3, MC4 and MC5 receptors.

Melanotropic peptide-conjugated beads for microscopic visualization and characterization of melanoma melanotropin receptors.

We developed two solid-phase reagent systems for microscopic visualization and characterization of melanocyte-stimulating hormone (MSH) receptors of melanoma cells. Multiple copies of [Nle-4,D-Phe-7]-alpha-MSH, a potent analog of alpha-MSH, were conjugated to microspheres (latex beads) or macrospheres (polyamide beads) through a thioether or disulfide bond. Binding between the beads and mouse and human melanoma cells was examined by scanning electron microscopy and by light microscopy. Each mouse and human melanoma cell (of all cell lines) evinced binding to the beads. Binding of the melanotropin conjugates was not restricted to any one phase of the cell cycle. Specificity of binding was demonstrated by several studies. Negative controls included cell types of nonmelanocyte origin (e.g., mammary cancer cells) and beads that lacked the melanotropic ligand or had other attached ligands. Beads with a disulfide-linked melanotropin analog served as a direct control. Treatment of these beads with DTT during or before incubation of the beads with melanoma cells (resulting in release of the MSH analog from the beads) eliminated binding of the beads to melanoma cells. Binding interactions between melanoma cells and melanotropin-bound beads also could be abolished by prior incubation with unconjugated MSH analog. During these experiments, certain membrane receptor-hormone associated phenomena, such as capping (aggregation) of the receptor-ligand complex, also were observed. These results provide visual evidence that MSH receptors are a property common to melanoma cells. Normal human epidermal melanocytes and keratinocytes were also shown to express melanotropin receptors by the same criteria established for melanoma cells.

Desensitization of melanotropin receptors in COS-7 cells

Non-transfected COS-7 cells have been found to possess functional melanotropin receptors on their cell surface. These receptors, and the properties of the melanocyte stimulating hormone (MSH) peptides can be characterized by measuring melanotropin stimulation of cAMP accumulation in the cells. In these cells we studied the ultra-long lasting super agonist [Nle 4-D-Phe 7]-α-MSH (NDP-α-MSH), and compared it with the endogenous MSH peptides with respect to potency, maximal activity, duration of action, and rate of desensitization. Surprisingly, NDP- α-MSH did not act as a full agonist in COS-7 cells. In multiple experiments, it could stimulate cAMP accumulation to approximately 50% of the level of α-MSH, β-MSH and adrenocorticotropic hormone (ACTH). The MSH receptor mediating this activity is unknown. The time course of cAMP accumulation, and the duration of receptor activation was also investigated. In contrast to other systems, NDP-α-MSH did not induce prolonged activity, with respect to cAMP accumulation, in COS-7 cells. The MSH receptors present in COS-7 were found to desensitize rapidly subsequent to pretreatment by any of the MSH peptides. As expected for a partial agonist, the activity of NDP-α-MSH desensitized more rapidly than any of the full agonists. Surprisingly, desensitization induced by pretreatment with NDP-α-MSH also occurred more rapidly than desensitization induced by the other MSH analogs.

Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA

Melanocytes and melanoma cells are known to possess receptors for melanocyte stimulating hormone (MSH). A cDNA clone, designated IID, has been isolated from human melanoma cells and encodes a MSH receptor. The cloned cDNA encodes a 317 amino acid protein with transmembrane topography characteristics of a G-protein-coupled receptor, but it does not show striking similarity to already published sequences of other G-protein-coupled receptors. When IID cDNA is expressed in COS-7 cells, it binds an 125I-labelled MSH analogue (NDP-MSH) in a specific manner. The bound ligand could be displaced by melanotropic peptides, α-MSH, β-MSH, γ-MSH and ACTH (adrenocorticotropic hormone), but not by the non-melanotropic peptide, β-endorphine. This is the first report of the cloning of a receptor gene of the melanotropin receptor family.

Down-regulation of tyrosinase mRNA levels in melanoma cells by tumor promoters and by insulin

Mouse melanoma cells in culture respond to melanocyte-stimulating hormone (MSH) or to cyclic AMP analogues by demonstrating an increase in tyrosinase activity. In this study the effect of the tumor promoter, 12- O-tetradecanoylphorbol 13- acetate (TPA), on the hormonal induction of tyrosinase was examined. TPA was found to lower basal levels of tyrosinase activity in melanoma cells and to reduce tyrosinase levels in cells treated with either MSH (10 −7 M), dibutyryl cAMP (10 −4 M), isobutylmethylxanthine (IBMX, 10 −4 M), or with the potent MSH analogue, [Nle 4, d-phe 7]-α-MSH. The phorbol ester, phorbol 12,13-dibutyrate was also effective in lowering tyrosinase activity levels, while 4α-phorbol 12,13-didecanoate, which does not bind protein kinase C, was ineffective. In order to determine how TPA may reduce tyrosinase activity in melanoma cells, the levels of tyrosinase mRNA in untreated or TPA-treated cells were determined by Northern blot analysis. A marked down-regulation of constitutive levels of tyrosinase mRNA was observed in cells treated with the tumor promoter. Tyrosinase mRNA levels in cultures exposed to TPA for 48 h were only 7% of control levels. Tyrosinase mRNA levels in cells treated with both MSH and TPA were also lower than in cells treated with MSH alone. Previous studies from this laboratory have shown that insulin both lowers basal tyrosinase activity in melanoma cells and antagonizes the MSH stimulation of the enzyme. We have now determined that this inhibition is also due to reduced levels of tyrosinase mRNA. These results implicate a role for protein kinase C in the phorbol ester and insulin-mediated down-regulation of tyrosinase gene activity in melanoma cells and suggest the possible presence of both inhibitory and stimulatory DNA control elements in the tyrosinase gene which may control transcriptional rates.