Melanocortin Abstracts 1


The melanocortin system in control of inflammation

         (Catania, Lonati et al. 2010) Download

Melanocortin peptides, the collective term for alpha-, beta-, and gamma-melanocyte-stimulating hormone (alpha-, beta-, gamma-MSH) and adrenocorticotropic hormone (ACTH), are elements of an ancient modulatory system. Natural melanocortins derive from the common precursor pro-opiomelanocortin (POMC). Five receptor subtypes for melanocortins (MC1-MC5) are widely distributed in brain regions and in peripheral cells. Melanocortin receptor activation by natural or synthetic ligands exerts marked anti-inflammatory and immunomodulatory effects. The anticytokine action and the inhibitory influences on inflammatory cell migration make melanocortins potential new drugs for treatment of inflammatory disorders. Effectiveness in treatment of acute, chronic, and systemic inflammatory disorders is well documented in preclinical studies. Further, melanocortins are promising compounds in neuroprotection. This review examines the main signaling circuits in anti-inflammatory and immunomodulatory actions of melanocortins, and the potential therapeutic use of these molecules.

Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration

         (Ebanks, Wickett et al. 2009) Download

Skin pigmentary abnormalities are seen as aesthetically unfavorable and have led to the development of cosmetic and therapeutic treatment modalities of varying efficacy. Hence, several putative depigmenting agents aimed at modulating skin pigmentation are currently being researched or sold in commercially available products. In this review we will discuss the regulation of processes that control skin complexion coloration. This includes direct inhibition of tyrosinase and related melanogenic enzymes, regulation of melanocyte homeostasis, alteration of constitutive and facultative pigmentation and down-regulation of melanosome transfer to the keratinocytes. These various processes, in the complex mechanism of skin pigmentation, can be regulated individually or concomitantly to alter complexion coloration and thus ameliorate skin complexion diseases.

Neural control of erection

         (Giuliano and Rampin 2004) Download

Penile erection is a vascular event controlled by the autonomic nervous system. The spinal cord contains the autonomic preganglionic neurons that innervate the penile erectile tissue and the pudendal motoneurons that innervate the perineal striated muscles. Sympathetic pathways are anti-erectile, sacral parasympathetic pathways are pro-erectile, and contraction of the perineal striated muscles upon activity of the pudendal nerves improves penile rigidity. Spinal neurons controlling erection are activated by information from peripheral and supraspinal origin. Both peripheral and supraspinal information is capable of either eliciting erection or modulating or inhibiting an erection already present. Sensory information from the genitals is a potent activator of pro-erectile spinal neurons and elicits reflexive erections. Some pre-motor neurons of the medulla, pons and diencephalon project directly onto spinal sympathetic, parasympathetic and pudendal motoneurons. They receive in turn sensory information from the genitals. These spinal projecting pathways release a variety of neurotransmitters, including biogenic amines (serotonin, dopamine, noradrenaline, and adrenaline) and peptides that, through interactions with many receptor subtypes, exert complex effects on the spinal network that controls penile erection. Some supraspinal structures (e.g. the paraventricular nucleus and the medial preoptic area of the hypothalamus, the medial amygdala), whose roles in erection have been demonstrated in animal models, may not project directly onto spinal pro-erectile neurons. They are nevertheless prone to regulate penile erection in more integrated and coordinated responses of the body, as those occurring during sexual behavior. The application of basic and clinical research data to treatment options for erectile dysfunction has recently proved successful. Pro-erectile effects of phosphodiesterase type 5 inhibitors, acting in the penis, and of melanocortin agonists, acting in the brain, illustrate these recent developments.

Examining the impact of skin lighteners in vitro

         (Gruber and Holtz 2013) Download

Three cosmetically important skin lightening agents, hydroquinone (HQ), kojic acid (KA), and niacinamide (NA), consume the bulk of successful skin lightening ingredients in cosmetic applications. However, the mechanisms by which these ingredients work are still unclear. In this study, melanocytes and keratinocytes were treated with high, nontoxic doses of HQ, KA, and NA and the cells were examined by human microarrays and protein assays for several important targets including cytotoxicity, melanin expression, tyrosinase gene (TYR) and protein expression, melanocortin-1 receptor (MC1R) gene and protein expression, cytochrome c oxidase-1 (COX1) gene and protein expression, and ferritin (FTH1) gene and protein expression. It was found that all the skin lighteners examined showed marked increases in TYR, COX1, and FTH1 gene and protein expression, but not in MC1R expression in melanocytes. Upregulation of COX1 and FTH1 genes and proteins was common across both cell lines, melanocytes and keratinocytes. The results of the tyrosinase expression were somewhat unexpected. The role of iron in the expression of melanin is somewhat unexplored, but common and strong upregulation of ferritin protein in both types of cells due to the treatments suggests that iron plays a more pivotal role in melanin synthesis than previously anticipated.

Metal ion-mediated agonism and agonist enhancement in melanocortin MC1 and MC4 receptors

         (Holst, Elling et al. 2002) Download

An endogenous metal-ion site in the melanocortin MC1 and MC4 receptors was characterized mainly in transiently transfected COS-7 cells. ZnCl(2) alone stimulated signaling through the Gs pathway with a potency of 11 and 13 microm and an efficacy of 50 and 20% of that of alpha-melanocortin stimulating hormone (alpha-MSH) in the MC1 and MC4 receptors, respectively. In the presence of peptide agonist, Zn(II) acted as an enhancer on both receptors, because it shifted the dose-response curves to the left: most pronounced was a 6-fold increase in alpha-MSH potency on the MC1 receptor. The effect of the metal ion appeared to be additive, because the maximal cAMP response for alpha-MSH in the presence of Zn(II) was 60% above the maximal response for the peptide alone. The affinity of Zn(II) could be increased through binding of the metal ion in complex with small hydrophobic chelators. The binding affinities and profiles were similar for a number of the 2,2'-bipyridine and 1,10-phenanthroline analogs in complex with Zn(II) in the MC1 and MC4 receptors. However, the potencies and efficacies of the metal-ion complexes were very different in the two receptors, and close to full agonism was obtained in the MC1 receptor. Metal ion-chelator complexes having antagonistic properties were also found. An initial attempt to map the metal-ion binding site in the MC1 receptor indicated that Cys(271) in extracellular loop 3 and possibly Asp(119) at the extracellular end of TM-III, which are both conserved among all MC receptors, are parts of the site. It is concluded that the function of the MC1 and MC4 receptors can be positively modulated by metal ions acting both as partial agonists and as potentiators for other agonists, including the endogenous peptide ligand alpha-MSH at Zn(II) concentrations that could be physiological. Furthermore, the metal ion-chelator complexes may serve as leads in the development of novel melanocortin receptor modulators.

Melanocortin receptors, melanotropic peptides and penile erection

         (King, Mayorov et al. 2007) Download

Penile erection is a complex physiologic event resulting from the interactions of the nervous system on a highly specialized vascular organ. Activation of central nervous system melanocortinergic (MC) receptors with either endogenous or synthetic melanotropic ligands may initiate and/or facilitate spontaneous penile erection. While the CNS contains principally the MC3 and MC4 receptor subtypes, there is conflicting data as to which receptor mediates erection. Although the MC4R is emerging as the principle effector of MC induced erection, the role of the MC3R is poorly understood. Manipulation of each receptor subtype with newly synthesized receptor specific agonists and antagonists, as well as knockout mice, has elucidated their individual contributions. Novel data from our laboratories suggests that antagonism of forebrain MC3R may enhance melanocortin-induced erections. Furthermore, melanocortin agents may interact with better-studied systems such as oxytocinergic pathways at the hypothalamic, brainstem or spinal level. Current therapies for erectile dysfunction target end organ vascular tissue. Manipulation of MC receptors may provide an alternative, centrally mediated therapeutic approach for erectile and other sexual dysfunctions. The non-specific "superpotent" MC agonist, PT-141, which is the carboxylate derivative of MT-II, has reached phase II human trials. Through their centrally mediated activity, melanocortin agonists have potential to treat erectile dysfunction as well as possible applications to the unmet medical needs of decreased sexual motivation and loss of libido.

Melanocortin receptors and erectile function

         (Martin and MacIntyre 2004) Download

OBJECTIVE: Review the historical and current evidence that suggests that activation of melanocortin receptors modulates erectile activity. METHODS: The available literature was reviewed. RESULTS: Melanocortin peptides derived from the pro-opiomelanocortin (POMC) precursor protein exert a host of diverse physiological effects in the periphery and in the CNS through interactions with one or more of the five cloned melanocortin receptors. Natural and synthetic melanocortin peptide agonists influence erectile and sexual function in a range of preclinical species. Emerging clinical evidence now suggests that the proerectile effects observed in preclinical species are evident in man as well. CONCLUSIONS: Preclinical and clinical results support the involvement of melanocortins in the modulation of erectile and sexual function. Current evidence indicates that the melanocortin 4 receptor subtype contributes to the proerectile effects observed with pan-receptor agonists. However, the putative receptor subtypes, pathways and mechanisms implicated in mediating the proerectile effects of melanocortins remain to be fully elucidated.

Melanocortins in brain inflammation: the role of melanocortin receptor subtypes

         (Muceniece and Dambrova 2010) Download

The melanocortins (MC) are released from neurons and paracrine cells in the CNS where they are involved in important physiological functions, including regulation of body temperature and immune responses. MC bind to melanocortin receptors, a class of cell surface G-protein-coupled receptors. Of the five subtypes of MC receptors that have been cloned in mammals, the MC1, MC3, MC4 and MC5 receptors are expressed in brain tissues. Expression of MC receptors in both brain cells and cells of the immune system suggests direct involvement of MC in regulation of inflammatory processes in the brain. The binding of MC to MC receptors induces activation of adenylate cyclase, increase in intracellular cAMP level and, consequently, inhibition of the nuclear transcription factor kappaB (NF-kappaB) signalling. Inflammatory processes contribute to development of severe CNS diseases, both in acute and chronic conditions. Thus far, the anti-inflammatory effects of MC in the CNS have been mainly studied using peptides that are relatively unselective for individual MC receptor subtypes. Consequently, these studies do not allow identification of specific MC receptor(s) involved in the regulation of inflammatory processes. However, recently synthesized ligands selective for individual MC receptors indicated that both MC4 and MC3 agonists are promising anti-inflammatory agents in treatment of brain inflammation.

Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: a double-blind placebo-controlled, fixed dose, randomized study

         (Safarinejad 2008) Download

INTRODUCTION: Sexual arousal disorder affects about 30% of women worldwide and there are no effective drug treatments for the disorder. AIM: To evaluate the efficacy and safety of bremelanotide in menstruating women with female sexual arousal disorder (FSAD) as a sole entity. METHODS: A total of 80 married women (mean age 31 years) with FSAD were randomly assigned to receive 20-mg bremelanotide as an intranasal spray (group 1, N = 40) on "as required" basis 45-60 minutes before attempting sexual intercourse, or a similar regimen of placebo (group 2, N = 40). The patients were asked to use at least 20 attempts at home. They underwent preliminary assessment, including medical and sexual history, blood chemistry, measurement of serum levels of sex hormones and prolactin, and self-administered Female Sexual Function Index (FSFI). MAIN OUTCOME MEASURES: Primary efficacy end points were FSFI questions 3-6 and 14-16. Secondary efficacy end points included the remaining items from this questionnaire. The efficacy of the two treatments was assessed every four attempts during treatment and at the end of study, using responses to FSFI and evaluation of total number of sexual events, total number of orgasm, personal distress, and adverse drug effects. Results. Mean pretreatment arousal score of 2.7 and 2.8 in groups 1 and 2 increased to 4.1 and 3.0, respectively, at the end of the trial (P = 0.001). The bremelanotide group reported significantly greater intercourse satisfaction than those in the placebo group (P = 0.001). More drug-related adverse effects occurred in the bremelanotide group and two (5%) had to discontinue treatment (P = 0.01). CONCLUSIONS: Bremelanotide was effective and well tolerated in menstruating women with FSAD as a sole entity. Further studies are required to draw final conclusions on the efficacy and safety of this drug in FSAD.

Melanocortins in the treatment of male and female sexual dysfunction

         (Shadiack, Sharma et al. 2007) Download

Melanocortinergic agents are currently being investigated for a possible therapeutic role in male and female sexual dysfunction. These investigations were sparked by findings that systemic administration of a synthetic analog of alpha-MSH, MT-II, causes penile erections in a variety of species, including humans. Several other melanocortinergic agents including HP-228, THIQ, and bremelanotide (PT-141) have since been shown to have erectogenic properties thought to be due to binding to melanocortin receptors in the central nervous system, particularly the hypothalamus. Bremelanotide, a nasally administered synthetic peptide, is the only melanocortinergic agent that has been clinically studied in both males and females. Data from Phase II clinical trials of bremelanotide support the use of melanocortin-based therapy for erectile dysfunction. Studies using animal models have demonstrated that pre-copulatory behaviors in female rats analogous to sexual arousal are evoked, and preliminary clinical data also suggest a role in promoting sexual desire and arousal in women. Based on bremelanotide clinical experience, administration of a melanocortin agonist is well tolerated and not associated the hypotension observed with phosphodiesterase-5 inhibitors currently used to treat erectile dysfunction. This review discusses investigations of melanocortin agonists for the treatment of sexual dysfunction with emphasis on proposed sites and mechanisms of action in the central nervous system that appear to be involved in melanocortinergic modulation of sexual function. Current research validates use of melanocortinergic agents for the treatment of both male and female sexual dysfunction.

MT-II induces penile erection via brain and spinal mechanisms

         (Wessells, Hruby et al. 2003) Download

alpha-Melanocyte-stimulating hormone induces penile erection via melanocortin (MC) receptors in areas surrounding the third ventricle, but spinal and peripheral mechanisms have not been demonstrated. We used pharmacological strategies to localize the site of the proerectile action of the melanocortin receptor agonist MT-II. We administered MT-II intracerebroventribularly (i.c.v.), intrathecally (, and intravenously (i.v.) and scored penile erection and yawning for 90 min in awake male rats. In some animals i.c.v. or SHU-9119 was injected 10 minutes before i.c.v. and MT-II to confirm the MC receptor action of the agonist and to distinguish spinal from supraspinal effects. To exclude a site of action in the penis, we recorded intracorporal pressure responses to intracavernosal injection of MT-II in the anesthetized rat. MT-II induced penile erections in a dose-dependent fashion, with optimal response at 1 microg for both i.c.v. and routes. Supraspinal MT-II-induced erections were completely suppressed by 1 microg SHU-9119 i.c.v. Yawning was observed with i.c.v. and i.v. MT-II, whereas spinal injection did not produce this behavior. SHU-9119 blocked the erectile responses to MT-II when injected but not i.c.v. Intracavernosal MT-II neither increased intracorporal pressure nor augmented neurostimulated erectile responses. The lumbosacral spinal cord contains MC receptors that can initiate penile erection independent of higher centers. We confirmed the supraspinal proerectile action of MT-II. These results provide insight into the central melanocortinergic pathways that mediate penile erection and may allow for more efficacious melanotropin-based therapy for erectile dysfunction.


Catania, A., C. Lonati, et al. (2010). "The melanocortin system in control of inflammation." ScientificWorldJournal 10: 1840-53. [PMID: 20852827]

Ebanks, J. P., R. R. Wickett, et al. (2009). "Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration." Int J Mol Sci 10(9): 4066-87. [PMID: 19865532]

Giuliano, F. and O. Rampin (2004). "Neural control of erection." Physiol Behav 83(2): 189-201. [PMID: 15488539]

Gruber, J. V. and R. Holtz (2013). "Examining the impact of skin lighteners in vitro." Oxid Med Cell Longev 2013: 702120. [PMID: 23738040]

Holst, B., C. E. Elling, et al. (2002). "Metal ion-mediated agonism and agonist enhancement in melanocortin MC1 and MC4 receptors." J Biol Chem 277(49): 47662-70. [PMID: 12244039]

King, S. H., A. V. Mayorov, et al. (2007). "Melanocortin receptors, melanotropic peptides and penile erection." Curr Top Med Chem 7(11): 1098-1106. [PMID: 17584130]

Martin, W. J. and D. E. MacIntyre (2004). "Melanocortin receptors and erectile function." Eur Urol 45(6): 706-13. [PMID: 15149741]

Muceniece, R. and M. Dambrova (2010). "Melanocortins in brain inflammation: the role of melanocortin receptor subtypes." Adv Exp Med Biol 681: 61-70. [PMID: 21222260]

Safarinejad, M. R. (2008). "Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: a double-blind placebo-controlled, fixed dose, randomized study." J Sex Med 5(4): 887-97. [PMID: 18179455]

Shadiack, A. M., S. D. Sharma, et al. (2007). "Melanocortins in the treatment of male and female sexual dysfunction." Curr Top Med Chem 7(11): 1137-44. [PMID: 17584134]

Wessells, H., V. J. Hruby, et al. (2003). "MT-II induces penile erection via brain and spinal mechanisms." Ann N Y Acad Sci 994: 90-5. [PMID: 12851302]