Melanotan II

Social deficits are debilitating features of many psychiatric disorders, including autism. While time-intensive behavioral therapy is moderately effective, there are no pharmacological interventions for social deficits in autism. Many studies have attempted to treat social deficits using the neuropeptide oxytocin for its powerful neuromodulatory abilities and influence on social behaviors and cognition. However, clinical trials utilizing supplementation paradigms in which exogenous oxytocin is chronically administered independent of context have failed. An alternative treatment paradigm suggests pharmacologically activating the endogenous oxytocin system during behavioral therapy to enhance the efficacy of therapy by facilitating social learning. To this end, melanocortin receptor agonists like Melanotan II (MTII), which induces central oxytocin release and accelerates formation of partner preference, a form of social learning, in prairie voles, are promising pharmacological tools. To model pharmacological activation of the endogenous oxytocin system during behavioral therapy, we administered MTII prior to social interactions between male and female voles. We assessed its effect on oxytocin-dependent activity in brain regions subserving social learning using Fos expression as a proxy for neuronal activation. In non-social contexts, MTII only activated hypothalamic paraventricular nucleus, a primary site of oxytocin synthesis. However, during social interactions, MTII selectively increased oxytocin-dependent activation of nucleus accumbens, a site critical for social learning. These results suggest a mechanism for the MTII-induced acceleration of partner preference formation observed in previous studies. Moreover, they are consistent with the hypothesis that pharmacologically activating the endogenous oxytocin system with a melanocortin agonist during behavioral therapy has potential to facilitate social learning.

Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4-10) fragment, ACTH(4-7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4-10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4-10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4-10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.

BACKGROUND: Melanotan II (MT II) is a synthetic analogue of α-melanocyte-stimulating hormone that, via interaction with the melanocortin 1 receptor, induces skin hyperpigmentation. The unregulated acquisition of MT II injections via the internet and other outlets has become popular over the last decades in order to exploit its properties for use as a tanning agent. Due to the covert nature of MT II use, it is difficult to assess the extent of its use among the general population and to characterise any associated side effects. OBJECTIVES: The aim of this study was to qualitatively examine MT II use, as portrayed on online forums, and to explore the motivations for its use and side effect profile. METHODS: Data were extracted retrospectively from UK and Ireland online chatrooms and forums from January 2016 to October 2017. Inclusion criteria were active MT II chatrooms and forums considered to be within the public domain. An inductive thematic analysis identified themes within discussion threads. RESULTS: A total of 623 discussion entries were extracted; 205 participants contributed to these entries. Emergent themes included motivation for MT II use, misinformation in the context of using an unregulated product, product preparation and administration, dosing regimens, sunbed use, side effects and concerning practices associated with MT II use. CONCLUSION: Motivations for MT II use included the pursuit of a tanned appearance, often in anticipation of sun holidays and fitness/body building competitions. Clinicians should be aware not only of the potential risks in relation to pigmented skin lesions, but also remain cognisant of the other medical hazards associated with the use of this substance, namely transmission of infectious diseases, use of potentially contaminated products, polypharmacy, and sunbed exposure.

The functions of anorexigenic neurons secreting proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) of the melanocortin system in the hypothalamus in vertebrates are energy homeostasis, food intake, and body weight regulation. However, the mechanisms remain elusive. This article reports on zebrafish that have been genetically engineered to produce α-MSH mutants, α-MSH-7aa and α-MSH-8aa, selectively lacking 7 and 8 amino acids within the α-MSH region, but retaining most of the other normal melanocortin-signaling (Pomc-derived) peptides. The α-MSH mutants exhibited hyperphagic phenotypes leading to body weight gain, as observed in human patients and mammalian models. The actions of several genes regulating appetite in zebrafish are similar to those in mammals when analyzed using gene expression analysis. These include four selected orexigenic genes: Promelanin-concentrating hormone (pmch), agouti-related protein 2 (agrp2), neuropeptide Y (npy), and hypothalamic hypocretin/orexin (hcrt). We also study five selected anorexigenic genes: Brain-derived neurotrophic factor (bdnf), single-minded homolog 1-a (sim1a), corticotropin-releasing hormone b (crhb), thyrotropin-releasing hormone (trh), and prohormone convertase 2 (pcsk2). The orexigenic actions of α-MSH mutants are rescued completely after hindbrain ventricle injection with a synthetic analog of α-MSH and a melanocortin receptor agonist, Melanotan II. We evaluate the adverse effects of MSH depletion on energy balance using the Alamar Blue metabolic rate assay. Our results show that α-MSH is a key regulator of POMC signaling in appetite regulation and energy expenditure, suggesting that it might be a potential therapeutic target for treating human obesity.

We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED). Melanotan II was administered to 20 men with psychogenic and organic ED using a double-blind placebo-controlled crossover design. Penile rigidity was monitored for 6 h using RigiScan. Level of sexual desire and side effects were reported with a questionnaire. In the absence of sexual stimulation, Melanotan II led to penile erection in 17 of 20 men. Subjects experienced a mean of 41 min Rigiscan tip rigidity>80%. Increased sexual desire was reported after 13/19 (68%) doses of Melanotan II vs 4/21 (19%) of placebo (P<0.01). Nausea and yawning were frequently reported side effects due to Melanotan II; at a dose of 0.025 mg/kg, 12.9% of subjects had severe nausea. We conclude that Melanotan II is a potent initiator of penile erection in men with erectile dysfunction. Our findings warrant further investigation of melanocortin agonists and antagonists on penile erection. International Journal of Impotence Research (2000) 12, Suppl 4, S74-S79.

The melanocortins (MCs) are a family of multifunctional peptidergic hormones. Several superpotent, prolonged acting, enzymatically resistant, MC analogs have been designed and synthesized to help clarify the nature and role of MCs and their receptors (MCRs) in physiological functions. Two of these analogs, a linear peptide, melanotan I, and a cyclic truncated peptide, melanotan II (MTI and MTII, respectively) have been patented and tested clinically for studies on tanning of the skin (MTI) and for diagnosis and treatment of male erectile dysfunction (MTII). A new MTII analog, PT-141 (Palatin Technologies) has initial phase I/II trials and is scheduled to enter pivotal stage III clinical trials leading to commercialization. MTI may provide a therapeutic tan with the potential to lower the risk of skin cancer. PT-141 may improve sexual functionality in both males and females.