Construction of a Tandem Repeat Peptide Sequence with Pepsin Cutting Sites to Produce Recombinant α-Melanocyte-Stimulating Hormone.

The production of α-melanocyte-stimulating hormone (α-MSH), a peptide hormone composed of 13 amino acids, is attempted by recombinant expression using E. coli as the host. To achieve this aim, a synthetic gene containing eight tandem repeats of msh gene (8msh) was designed for ribosomal synthesis of 8 α-MSH. The merit of the strategy is to diminish the peptide toxicity against the host cell and to achieve a higher production yield. Pepsin cleavage sites are introduced between the peptides for enzymatic proteolysis to obtain the monomeric peptide of α-MSH. The constructed plasmid was transformed into different strains of E. coli hosts, and E. coli XL1-Blue with gene 8msh revealed the highest yield of 8 α-MSH. Although 8 α-MSH was fractionalized in the insoluble pellets after cell lysis, pepsin cleavage was able to produce soluble α-MSH peptide, as analyzed and confirmed by mass spectrometry and peptide activity assays. The production of α-MSH was quantified using HPLC with a yield of 42.9 mg/L of LB culture. This study demonstrates the feasibility of producing α-MSH using recombinant expression of tandem repeat gene. The production procedure involves minimal post-treatment and processing and can be scaled up for industrial application.

Intracerebroventricular administration of α-melanocyte-stimulating hormone (α-MSH) enhances thigmotaxis and induces anxiety-like behavior in the goldfish Carassius auratus.

α-Melanocyte-stimulating hormone (α-MSH) is a body pigmentation-regulating hormone secreted from the intermediate lobe of the pituitary in vertebrates. It is also produced in the brain, and acts as an anorexigenic neuropeptide involved in feeding regulation. In rodents, intracerebroventricular (ICV) administration of α-MSH has been shown to affect not only feeding behavior, but also psychomotor activity. However, there is still no information regarding the psychophysiological effects of α-MSH on behavior in fish. Therefore, we examined the effect of synthetic α-MSH on psychomotor activity in goldfish. Since this species prefers the edge to the central area of a tank, we used this as a preference test for assessing psychomotor activity. When α-MSH was administered ICV at 1 and 10 pmol g-1 body weight (BW), the time spent in the edge area of a tank was prolonged at 10 pmol g-1 BW. However, α-MSH at these doses did not affect locomotor activity. The action of α-MSH mimicked those of FG-7142 (a central-type benzodiazepine receptor (CBR) inverse agonist with an anxiogenic effect) at 10 pmol g-1 BW and melanotan II (a melanocortin 4 receptor (MC4R) agonist) at 50 pmol g-1 BW, whereas ICV administration of tofisopam (a CBR agonist with an anxiolytic effect) at 10 pmol g-1 BW prolonged the time spent in the central area. The anxiogenic-like effect of α-MSH was abolished by treatment with the MC4R antagonist HS024 at 50 pmol g-1 BW. These data indicate that α-MSH affects psychomotor activity in goldfish, and exerts an anxiogenic-like effect via the MC4R-signaling pathway.

α-MSH ameliorates corneal surface dysfunction in scopolamine-induced dry eye rats and human corneal epithelial cells via enhancing EGFR expression.

Dry eye (DE) is a chronic, multifactorial ocular surface disease associated with visual disturbance, tear film instability, hyperosmolarity, ocular surface inflammation and damage. Effective intervention is necessary to control this disease. In this study we topically applied α-melanocyte stimulating hormone (α-MSH) on the ocular surface of scopolamine-induced DE rats and found that it promoted tear secretion, reduced tear breakup time and fluorescein sodium staining and increased the number of conjunctival goblet cells. To investigate the mechanism, protein array was conducted, which showed that α-MSH exerted its effects via epithelial growth factor receptor (EGFR) in the JAK-STAT signaling pathway. Furthermore, in vitro experiments showed that α-MSH protected human corneal epithelial cells (hCECs) by maintaining their migration ability and viability and decreasing apoptosis. However, blockade of EGFR abolished these protective effects. Moreover, α-MSH decreased the level of autophagy in benzalkonium chloride (BAC)-stressed hCECs via EGFR. These results demonstrated that α-MSH ameliorated lesions and restored ocular surface functions by upregulating EGFR expression.

Afamelanotide: An Orphan Drug with Potential for Broad Dermatologic Applications.

Afamelanotide (SCENESSE®) is a synthetic analogue of α-melanocyte-stimulating hormone that is FDA-approved to increase pain-free sunlight exposure in adult patients with erythropoietic protoporphyria. Its dual photoprotective and anti-inflammatory effects also make it a promising therapy for other photosensitive dermatologic diseases that are resistant to treatment. The PubMed/MEDLINE and ClinicalTrials.gov databases were searched for literature and ongoing trials describing the use of afamelanotide in treating cutaneous diseases. There is randomized controlled trial (RCT) evidence for the successful use of afamelanotide in several conditions beyond erythropoietic protoporphyria, including polymorphic light eruption and vitiligo. Smaller studies have also demonstrated its efficacy in treating acne vulgaris, Hailey-Hailey disease, and solar urticaria. No serious adverse effects with afamelanotide use have been reported, though diffuse hyperpigmentation is experienced by almost all patients. Larger scale studies are needed to confirm the efficacy of afamelanotide in treating dermatologic conditions beyond erythropoietic protoporphyria, and further research should focus on determining the safety, efficacy, and optimal dosing of afamelanotide for pediatric patients.J Drugs Dermatol. 2021;20(3):290-294. doi:10.36849/JDD.5526.

Afamelanotide for prevention of phototoxicity in erythropoietic protoporphyria.

Introduction: In erythropoietic protoporphyria (EPP), an inherited disorder of heme biosynthesis, accumulation of protoporphyrin IX results in acute phototoxicity. EPP patients experience severe burning pain after light exposure, which results in a markedly reduced quality of life. Afamelanotide is the first effective approved medical treatment for EPP, acting on melanocortin-1 receptors. This article aims to review afamelanotide.Areas covered: This review summarizes the chemical properties, pharmacokinetics, safety, preclinical and clinical data on afamelanotide in EPP, and post-marketing surveillance. PubMed search, manufacturers' websites, and relevant articles used for approval by authorities were used for the literature search.Expert opinion: Afamelanotide is an α-melanocyte-stimulating hormone analog. It can activate eumelanogenesis without exposure to UV radiation. Clinical studies in EPP showed that afamelanotide treatment significantly increased exposure to sunlight and QoL. In our clinical experience afamelanotide treatment is much more effective in clinical practice than demonstrated in clinical trials and should be made available for all EPP patients meeting inclusion criteria. The 60-day interval period was not based on effectiveness studies, and therefore for some of the patients the maximum of four implants per year with the 60-day interval is insufficient. Afamelanotide is well tolerated; common adverse events were headache, fatigue, and nausea.

Neuroprotection of Intermedin Against Cerebral Ischemia/Reperfusion Injury Through Cerebral Microcirculation Improvement and Apoptosis Inhibition.

Ischemic stroke is the primary cause of disability and mortality worldwide. Ischemia/reperfusion (I/R)-induced microcirculatory dysfunction and organ injury generally occur after ischemic stroke. Several studies have shown that intermedin (IMD) has a regulating function on cerebral microcirculation and blood-brain barrier via relaxing cerebral vessels and improving the local blood supply after cerebral ischemia. However, a unified conclusion has not been reached, and the underlying mechanism remains unclear. To observe and analyze the changes of cerebral microcirculation perfusion of cerebral IRI by IMD post-treatment in the rats and further explore the mechanism underlying the beneficial effect of IMD on cerebral IRI. Thirty-nine rats were divided into three groups: sham, I/R, and I/R + IMD groups. After IMD ischemia post-treatment, the rat cerebral infarction rate and the degree of neurological deficit were evaluated by TTC staining and neurological function score; the changes in the amount of cerebral microcirculation implantation on the injured side of the rats were observed by laser Doppler; the pathological changes and cell ultrastructure of rat cortex and hippocampus were observed by HE staining and transmission electron microscopy; the neuron apoptosis in the rat cortex and hippocampus was detected by TUNEL staining and immunohistochemical staining. Impaired neurological function, abnormal cortical/hippocampal neuron morphology, and the proportion of cerebral infarction were significantly improved in the IMD group compared with the I/R group, which suggested a possible neuroprotective role of IMD. IMD treatment also increased the average perfusion of cerebral surface microcirculation in rats by astonished 42.7 times. Finally, IMD administration decreased the caspase-3- and Bax-positive cell numbers and apoptotic cell ratio. IMD has a significant protective effect on neuronal damage caused by cerebral I/R in rats by improving cerebral microcirculation and inhibiting apoptosis.

Vitiligo: an update on systemic treatments.

Vitiligo is an autoimmune skin condition characterized by depigmented macules and patches, and has a huge psychosocial impact on patients. Treatment of vitiligo aims to prevent the spread of disease and facilitate repigmentation of affected lesions. The mainstay of treatment for unstable vitiligo has been topical agents (corticosteroids, calcineurin inhibitors) and phototherapy. However, systemic treatments are increasingly being shown to have a significant impact on the course of the disease as monotherapy or adjunctive therapy. Of note, oral mini-pulsed corticosteroid therapy, methotrexate, minocycline, ciclosporin, Janus kinase inhibitors and certain supplements have been used in the systemic treatment of vitiligo. We review the underlying evidence supporting the use of each of these systemic treatments.

Biodistribution and Multicompartment Pharmacokinetic Analysis of a Targeted α Particle Therapy.

Targeted α particle therapy (TAT) is ideal for treating disease while minimizing damage to surrounding nontargeted tissues due to short path length and high linear energy transfer (LET). We developed a TAT for metastatic uveal melanoma, targeting the melanocortin-1 receptor (MC1R), which is expressed in 94% of uveal melanomas. Two versions of the therapy are being investigated: 225Ac-DOTA-Ahx-MC1RL (225Ac-Ahx) and 225Ac-DOTA-di-d-Glu-MC1RL (225Ac-di-d-Glu). The biodistribution (BD) from each was studied and a multicompartment pharmacokinetic (PK) model was developed to describe drug distribution rates. Two groups of 16 severe combined immunodeficient (SCID) mice bearing high MC1R expressing tumors were intravenously injected with 225Ac-Ahx or 225Ac-di-d-Glu. After injection, four groups (n = 4) were euthanized at 24, 96, 144, and 288 h time points for each cohort. Tumors and 13 other organs were harvested at each time point. Isomeric γ spectra were measured in tissue samples using a scintillation γ detector and converted to α activity using factors for γ ray abundance per α decay. Time activity curves were calculated for each organ. A five-compartment PK model was built with the following compartments: blood, tumor, normal tissue, kidney, and liver. This model is characterized by a system of five ordinary differential equations using mass action kinetics, which describe uptake, intercompartmental transitions, and clearance rates. The ordinary differential equations were simultaneously solved and fit to experimental data using a genetic algorithm for optimization. The BD data show that both compounds have minimal distribution to organs at risk other than the kidney and liver. The PK parameter estimates had less than 5% error. From these data, 225Ac-Ahx showed larger and faster uptake in the liver. Both compounds had comparable uptake and clearance rates for other compartments. The BD and PK behavior for two targeted radiopharmaceuticals were investigated. The PK model fit the experimental data and provided insight into the kinetics of the compounds systematically.

Association of Afamelanotide With Improved Outcomes in Patients With Erythropoietic Protoporphyria in Clinical Practice.

Importance: The effectiveness of afamelanotide treatment in patients with erythropoietic protoporphyria (EPP) in clinical practice who experience pain after light exposure that substantially impairs quality of life is unknown. Objective: To evaluate the association of afamelanotide treatment with outcomes in patients with EPP in regular practice during longer-term follow-up. Design, Setting, and Participants: This single-center, prospective postauthorization safety and efficacy cohort study was directed and approved by the European Medicines Agency. Data were collected from patients with EPP treated with afamelanotide at Erasmus MC between June 2016 and September 2018. Analysis began October 2018. Main Outcomes and Measures: Time spent outside during treatment, number of phototoxic reactions, disease-specific quality of life, usage of protective clothing, and adverse events. Results: A total of 117 patients with EPP (59 women [50.4%]; mean [SD] age, 43.0 [15.5] years) were treated with afamelanotide. Nearly all patients continued treatment (115 [98%]) with a median (interquartile range) follow-up of 2.0 (1.3-2.1) years. Compared with baseline, mean time spent outside during treatment increased significantly by an added 6.1 hours per week (95% CI, 3.62-8.67; P < .001). Mean quality of life score improved significantly by 14.01% (95% CI, 4.53%-23.50%; P < .001). Phototoxic reactions were less painful (ß, -0.85; 95% CI, -1.43 to -0.26; P < .001), but there was no significant difference in number or duration of reactions. Minor self-limiting adverse events occurred, such as nausea, fatigue, and headache. Conclusions and Relevance: This cohort study found that afamelanotide treatment was associated with improved clinical outcomes and a good safety profile for patients with EPP. The treatment has clinically significant, sustained positive associations with quality of life, is associated with increased duration of sun exposure, and is associated with less severe phototoxic reactions.

Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder.

Objective: To review data regarding bremelanotide, a recently approved therapy for hypoactive sexual desire disorder (HSDD). Data Sources: Literature search of Medline, SCOPUS, and EMBASE was performed using the search terms bremelanotide, bremelanotide injection, Vyleesi, and melanocortin 4 receptor agonist between January 1, 1996, and December 15, 2019. Reference lists from included articles were also reviewed for pertinent citations. Study Selection/Data Extraction: We included phase 2 and 3 trials of bremelanotide. There were 2 reports of phase 3 trials and 2 reports of phase 2 trials. Additional information from supplementary analyses was also referenced. Data Synthesis: Bremelanotide demonstrates significant improvement in desire and a significant decrease in distress related to lack of desire. The most common adverse effects include nausea (39.9%), facial flushing (20.4%), and headache (11%). Relevance to Patient Care and Clinical Practice: Bremelanotide is the second Food and Drug Administration-approved medication for the treatment of HSDD. Bremelanotide's place in therapy is unknown, as the HSDD guidelines were last updated in 2017. Although the trials met statistical significance for change in sexual desire elements and distress related to sexual desire, the clinical benefit may only be modest. Conclusion: Bremelanotide is a subcutaneous injection that can be administered as needed approximately 45 minutes prior to sexual activity. Bremelanotide is safe and has limited drug-drug interactions, including no clinically significant interactions with ethanol. Prescribing guidelines recommend no more than 1 dose in 24 hours and no more than 8 doses per month. Individuals should discontinue use after 8 weeks without benefit.

Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition.

Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MTII using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MTII potently inhibited the migration, invasion, and colony-forming capability of melanoma cells. Moreover, topical MTII application significantly attenuated the tumor progression in mice bearing established melanoma. Histological analysis revealed that MTII therapy induced apoptosis while inhibiting the proliferation and neovaluarization in melanoma tissues. By immunoblot and immunohistochemical analysis, it was found that MTII dose-dependently increased the phosphatase and tensin homolog (PTEN) protein level while reducing PTEN phosphorylation, which resulted in the inhibition of AKT/nuclear factor kappa B (NFκB) signaling. Consistently, MTII treatment inhibited cyclooxygenase II (COX-2) expression and prostaglandin E2 (PGE2) production in melanoma cells. Finally, studies of antibody neutralization suggest that the melanocortin 1 receptor (MC1R) plays a critical role in MTII-induced PTEN upregulation and melanoma suppression. Together, these results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling. Hence, topical MTII therapy may facilitate a novel therapeutic strategy against melanoma.

Case report on premature hair graying treated with Melitane 5% and oral hair supplements.

With chronological aging, hair turns gray. Untimely premature hair graying (PHG) may tremendously influence on cosmesis, self-credibility, and social life of the affected individuals. Consequently, early treatment is required to improve cosmetic appearance. To the best of our knowledge, until today, only one case of PHG is reported in the literature, and it occurred due to iron deficiency and successfully treated with ferrous sulfate. Herein, we delineate a case of PHG in a 14-year-old female treated with the topical formulation of Melitane 5% and oral hair supplements which resulted in boosting improvement in hair color.

Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials.

OBJECTIVE: To evaluate the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder. METHODS: Two identical phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trials (RECONNECT) evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in premenopausal women with hypoactive sexual desire disorder. Patients were randomized 1:1 to 24 weeks of treatment with bremelanotide or placebo. Sample size was estimated based on simulations from key endpoints in patients with hypoactive sexual desire disorder from a prior trial. Coprimary efficacy endpoints were change from baseline to end-of-study in the Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13. RESULTS: Study 301 began on January 7, 2015, and concluded on July 26, 2016. Study 302 began on January 28, 2015, and concluded on August 4, 2016. Of the 1,267 women randomized, 1,247 and 1,202 were in the safety and efficacy (modified intent-to-treat) populations, respectively. Most participants were white (85.6%), from U.S. sites (96.6%), and had a mean age of 39 years. From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, P<.001; study 302: 0.42, P<.001; integrated studies 0.35, P<.001) and statistically significant reductions in distress related to low sexual desire (study 301: -0.37, P<.001; study 302: -0.29, P=.005; integrated studies -0.33, P<.001) compared with placebo. Patients taking bremelanotide experienced more nausea, flushing, and headache (10% or more in both studies) compared with placebo. CONCLUSIONS: Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder. The safety profile was favorable. Most treatment-emergent adverse events were related to tolerability and the majority were mild or moderate in intensity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302). FUNDING SOURCE: Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder.

OBJECTIVE: To evaluate the long-term safety and efficacy of bremelanotide as treatment for hypoactive sexual desire disorder in premenopausal women. METHODS: Women who completed the 24-week double-blind core phase of RECONNECT, composed of two parallel phase 3 trials (301 and 302) examining the safety and efficacy of bremelanotide compared with placebo in premenopausal women with hypoactive sexual desire disorder, could enroll in the 52-week open-label extension, provided they had not experienced serious adverse events during the core phase. Efficacy was assessed using the coprimary endpoints from the core phase, and all adverse events were collected during the open-label extension. All statistical analyses were descriptive. RESULTS: The study 301 open-label extension began on July 17, 2015, and concluded on July 13, 2017; the study 302 open-label extension began on October 5, 2015, and concluded on June 29, 2017. Of the 856 eligible patients who completed the core phase, 684 elected to participate in the open-label extension, and 272 completed it. The most common treatment-emergent adverse events considered related to study drug were nausea (40.4%), flushing (20.6%), and headache (12.0%), and the only severe treatment-emergent adverse event experienced by more than one participant in both studies was nausea during the open-label extension. The change in Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13 from baseline to end of the open-label extension ranged from 1.25 to 1.30 and -1.4 to -1.7, respectively, for patients who received bremelanotide during the core phase, and 0.70-0.77 and -0.9, respectively, for patients who received placebo during the core phase. CONCLUSION: During the 52-week open-label extension of RECONNECT, no new safety signals were observed, and premenopausal women treated with bremelanotide exhibited sustained improvements in hypoactive sexual desire disorder symptoms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302). FUNDING SOURCE: Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide.

BACKGROUND: Responder analyses are used to determine whether changes that occur during a clinical trial are clinically meaningful; for subjective endpoints such as those based on patient-reported outcomes (PROs), responder analyses are particularly useful. AIM: To identify the minimal clinically important difference (MCID) for selected scores on questionnaires assessing female sexual functioning and to use these differences to analyze the response in a large, controlled, phase 2b, dose-finding study of bremelanotide in premenopausal women with hypoactive sexual desire disorder (HSDD) and mixed HSDD/female sexual arousal disorder (FSAD). METHODS: The responder analyses were performed for the change from baseline to end of study for a total of 7 endpoints. Each PRO endpoint was assessed using at least 1 of 4 types of responder analyses: a planned analysis anchored to MCIDs based on expert estimates (historical anchors); post hoc analyses based on self-reported global benefit; receiver operating characteristic (ROC) curves; and cumulative distribution function. The prespecified analysis groups were all female sexual dysfunction (FSD)-based diagnoses (all study participants), those with HSDD alone, and a combined group of those with FSAD alone plus those with mixed HSDD/FSAD. Post hoc analyses were also performed for subjects with mixed HSDD/FSAD with a primary diagnosis of HSDD. OUTCOMES: MCIDs based on the ROC curves for changes in Female Sexual Function Index-desire domain, Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) total score, FSDS-DAO item 13 and 14 scores, and number of satisfying sexual events. RESULTS: Outcomes matched those based on input from clinical experts. For all 7 endpoints, responder rates at the 1.75 mg dose in the overall modified intention-to-treat population achieved statistical significance compared with placebo (P ≤ .03). CLINICAL IMPLICATIONS: These responder definitions were subsequently used in the bremelanotide phase 3 registration studies (RECONNECT) that evaluated the safety and efficacy of the bremelanotide 1.75 mg subcutaneous dose in premenopausal women with HSDD. STRENGTHS & LIMITATIONS: MCIDs for this study were based on changes from a single-blind phase to account for changes due to the placebo effect. These analyses were restricted to a study population composed only of premenopausal women with a clinical diagnosis of HSDD and/or FSAD and were based on data from the same clinical trial. CONCLUSION: Bremelanotide was safe and well tolerated and demonstrated significant improvement in efficacy vs placebo in the phase 2b trial. The multiple responder analyses offer a valuable approach for determining clinically important effects of bremelanotide for HSDD and FSAD. Althof S, Derogatis LR, Greenberg S, et al. Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide. J Sex Med 2019;16:1226-1235.

Alcohol Withdrawal and Proopiomelanocortin Neuropeptides in an Animal Model of Alcohol Dependence.

BACKGROUND: Alcohol is one of the leading threats to health worldwide. Craving for alcohol makes abstinence a difficult challenge by maintaining alcohol dependence. Many studies suppose the hypothalamic-pituitary-adrenal axis, especially the proopiomelanocortin (POMC)-derived neuropeptides, to mediate craving during withdrawal in alcohol dependence. Evidence is available that the two POMC proteins, α-melanocyte-stimulating hormone (α-MSH) and ß-endorphin (ß-END) are altered by alcohol consumption and influence alcohol consumption, respectively. OBJECTIVES: We investigated the dynamics of α-MSH and ß-END during alcohol withdrawal and the influence of intraperitoneal administration of either α-MSH or ß-END in an established rodent model (Wistar rats) for alcohol dependence. RESULTS: After long-term alcohol self-administration over 12 months and repeated deprivation periods for 3 days, we found a significant decrease in α-MSH levels during withdrawal in rodents (p = 0.006) compared to controls, while ß-END levels remained unchanged. Treatment with intraperitoneally administered α-MSH and ß-END did not affect alcohol drinking behavior after deprivation. CONCLUSION: We demonstrate the effects of alcohol deprivation on α-MSH in alcohol-dependent rodents, which appear to mimic α-MSH alteration found after fasting periods during appetite regulation. Therefore, low α-MSH levels are a possible indicator for craving in alcohol-dependent individuals and hence would be a potential target for anti-craving treatment.

Sleep deprivation exacerbates concussive head injury induced brain pathology: Neuroprotective effects of nanowired delivery of cerebrolysin with α-melanocyte-stimulating hormone.

Sleep deprivation (SD) is very common in military personnel resulting in mental anomalies and interfering with decision-making capabilities. Moreover during combat operation, these sleep-deprived soldiers often receive blunt head trauma casing concussive head injury (CHI). Recent observations clearly suggest that SD alone induces brain pathology and additional CHI further exacerbates brain damage. Thus, the need of the hour is to explore possible effective therapeutic measures to induce neuroprotection to enhance quality of life of these military personnel. This review deals with novel aspects of treatment using nanotechnology to induce superior neuroprotection following CHI in SD based on our own investigation in the light of recent literature in the field.

NDP-MSH reduces oxidative damage induced by palmitic acid in primary astrocytes.

Recent findings relate obesity to inflammation in key hypothalamic areas for body weight control. Hypothalamic inflammation has also been related to oxidative stress. Palmitic acid (PA) is the most abundant free fatty acid found in food, and in vitro studies indicate that it triggers a pro-inflammatory response in the brain. Melanocortins are neuropeptides with proven anti-inflammatory and neuroprotective action mediated by melanocortin receptor 4 (MC4R), but little is known about the effect of melanocortins on oxidative stress. The aim of this study was to investigate whether melanocortins could alleviate oxidative stress induced by a high fat diet (HFD) model. We found that NDP-MSH treatment decreased PA-induced reactive oxygen species production in astrocytes, an effect blocked by the MC4R inhibitor JKC363. NDP-MSH abolished nuclear translocation of Nrf2 induced by PA and blocked the inhibitory effect of PA on superoxide dismutase (SOD) activity and glutathione levels while it also per se increased activity of SOD and γ-glutamate cysteine ligase (γ-GCL) antioxidant enzymes. However, HFD reduced hypothalamic MC4R and brain derived neurotrophic factor mRNA levels, thereby preventing the neuroprotective mechanism induced by melanocortins.

A glimpse into the underground market of melanotan.

Melanotan-I and melanotan-II are alpha-melanocyte stimulating hormone (a-MSH) analogues that can be purchased illicitly online with relative ease and are injected subcutaneously to stimulate a tan. Little is known about the use of these unregulated substances. An observational survey was posted to an online forum in which participants share their experiences using melanotan-I or melanotan-II. Users were asked to complete this voluntary, anonymous survey, which had questions focusing on motivation and hesitation for and against using melanotan, difficulty in acquiring it, and plans for continuing to use melanotan in the future.