α-MSH

α-Melanocyte-Stimulating Hormone (MSH), amide stimulates melanocortin 1 receptor that results in the activation of adenylyl cyclase. Sequence: Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2.

In Vitro:α-Melanocyte-Stimulating Hormone (MSH), amide is an ancient tridecapeptide with potent inhibitory activity in all major forms of inflammation. α-Melanocyte-stimulating hormone (α-MSH) acts as an anti-inflammatory agent via down regulating the production and activity of the pro-inflammatory cytokines interleukin-1 (IL-1), tumor necrosis factor (TNF)-α and IL-6 expressed in various cells of the immune system. It also controls the nitric oxide production associated with inflammation. α−MSH inhibits nuclear factor-κB (NF-κB)-dependent gene transcription and NF-κB pathway induced by TNF and other inflammatory agents. This activity of α-MSH is mediated through the production of cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA) enzyme. α–MSH functions as a potent therapeutics for various conditions resulted through NF-κB activation including, inflammatory diseases, human immunodeficiency virus (HIV) replication in AIDS (acquired immunodeficiency syndrome), and septic shock[2].

In Vivo:α-Melanocyte-Stimulating Hormone (MSH), amide (α-MSH) has an essential role to play in melanin production in animals. α-MSH regulates development of several skin diseases, including cutaneous inflammation and hyper-proliferative skin diseases[2].

References:
[1]. Jo H, et al. Synthesis and biological evaluation of caffeic acid derivatives as potent inhibitors of α-MSH-stimulated melanogenesis. Bioorg Med Chem Lett. 2017 Aug 1;27(15):3374-3377. [2]. Lu XY, et al. Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses. J Neurosci. 2003 Aug 27;23(21):7863-72.

Plumbagin Suppresses alpha-MSH-Induced Melanogenesis in B16F10 Mouse Melanoma Cells by Inhibiting Tyrosinase Activity.[Pubmed:28165370]

Int J Mol Sci. 2017 Feb 3;18(2). pii: ijms18020320.

Recent studies have shown that plumbagin has anti-inflammatory, anti-allergic, antibacterial, and anti-cancer activities; however, it has not yet been shown whether plumbagin suppresses alpha-melanocyte stimulating hormone (alpha-MSH)-induced melanin synthesis to prevent hyperpigmentation. In this study, we demonstrated that plumbagin significantly suppresses alpha-MSH-stimulated melanin synthesis in B16F10 mouse melanoma cells. To understand the inhibitory mechanism of plumbagin on melanin synthesis, we performed cellular or cell-free tyrosinase activity assays and analyzed melanogenesis-related gene expression. We demonstrated that plumbagin directly suppresses tyrosinase activity independent of the transcriptional machinery associated with melanogenesis, which includes micropthalmia-associated transcription factor (MITF), tyrosinase (TYR), and tyrosinase-related protein 1 (TYRP1). We also investigated whether plumbagin was toxic to normal human keratinocytes (HaCaT) and lens epithelial cells (B3) that may be injured by using skin-care cosmetics. Surprisingly, lower plumbagin concentrations (0.5-1 muM) effectively inhibited melanin synthesis and tyrosinase activity but do not cause toxicity in keratinocytes, lens epithelial cells, and B16F10 mouse melanoma cells, suggesting that plumbagin is safe for dermal application. Taken together, these results suggest that the inhibitory effect of plumbagin to pigmentation may make it an acceptable and safe component for use in skin-care cosmetic formulations used for skin whitening.

Alpha-Melanocyte-stimulating Hormone Induces Vasodilation and Exerts Cardioprotection Through the Heme-Oxygenase Pathway in Rat Hearts.[Pubmed:28195947]

J Cardiovasc Pharmacol. 2017 May;69(5):286-297.

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a protein with known capacity for protection against cardiovascular ischemia-reperfusion (I/R) injury. This investigation evaluates the capacity of alpha-MSH to mitigate I/R effects in an isolated working rat heart model and determine the dependency of these alterations on the activity of heme oxygenase-1 (HO-1, hsp-32), a heat shock protein that functions as a major antioxidant defense molecule. Healthy male Sprague Dawley rats were used for all experiments. After treatment with selected doses of alpha-MSH, echocardiographic examinations were performed on live, anesthetized animals. Hearts were harvested from anesthetized rats pretreated with alpha-MSH and/or the HO-1 inhibitor SnPP, followed by cardiac function assessment on isolated working hearts, which were prepared using the Langendorff protocol. Induction of global ischemia was performed, followed by during reperfusion assessment of cardiac functions. Determination of incidence of cardiac arrhythmias was made by electrocardiogram. Major outcomes include echocardiographic data, suggesting that alpha-MSH has mild effects on systolic parameters, along with potent antiarrhythmic effects. Of particular significance was the specificity of dilatative effects on coronary vasculature, and similar outcomes of aortic ring experiments, which potentially allow different doses of the compound to be used to selectively target various portions of the vasculature for dilation.

alpha-MSH and melanocortin receptors at early ontogeny in European sea bass (Dicentrarchus labrax, L.).[Pubmed:28378841]

Sci Rep. 2017 Apr 5;7:46075.

Temporal patterns of whole-body alpha-MSH concentrations and of transcripts of melanocortin receptors during early development as well as the endocrine response (alpha-MSH, cortisol, MCR mRNAs) to stress at the end of the larval period were characterized in Dicentrarchus labrax. Immunohistochemistry showed alpha-MSH positive cells in the pituitary pars intermedia in all stages examined. As development proceeds, alpha-MSH content gradually increases; mRNA levels of mc2r and mc4r remain low until first feeding where peak values are observed. Mc1r expression was constant during development, pomc mRNA levels remain low until the stage of flexion after which a significant increase is observed. At the stage of the formation of all fins, whole-body cortisol and alpha-MSH concentrations responded with peak values at 2 h post stress. Additionally, the stress challenge resulted in elevated transcript levels of pomc, mc2r and mc4r but not in mc1r, with a pattern characterized by peak values at 1 h post stress and a strong correlation with whole body alpha-MSH concentrations was found. Our data provide for the first time a view on the importance of the alpha-MSH stress response in early development of European sea bass, an additional and relatively poorly understood signal involved in the stress response in teleosts.

Decreased Synovial Fluid alpha-Melanocyte-Stimulating-Hormone (alpha-MSH) Levels Reflect Disease Severity in Patients with Posttraumatic Ankle Osteoarthritis.[Pubmed:28164623]

Clin Lab. 2016 Aug 1;62(8):1491-1500.

BACKGROUND: alpha-Melanocyte-stimulating hormone (alpha-MSH), an endogenous melanocortin peptide, has been demonstrated to have anti-inflammation effects and protect against cartilage damage. Objective In this study, we aimed to investigate whether alpha-MSH in ankle joint synovial fluid is associated with the disease severity of posttraumatic ankle osteoarthritis (PTAOA). METHODS: 66 PTAOA patients undergoing ankle arthroscopical debridement or ankle joint replacement were enrolled in the study. Synovial fluid alpha-MSH concentrations were explored by a special radioimmunoassay method. Cartilage degradation biomarkers such as collagen type II (CTX-II), aggrecan-1 (AGG-1), as well as inflammatory markers, interleukin-6 (IL-6) and matrix metalloproteinases-3 (MMP-3) in the synovial fluid were determined by enzyme-linked immunosorbent assay (ELISA). The symptomatic and functional severity was evaluated using Teeny-Wiss scoring and AOFAS ankle-hindfoot rating scale. The radiographic progression of PTAOA was identified according to the modified ankle osteoarthritis Kellgren-Lawrence (KL) grading system. The modified Mankin score was used for assessing the histopathological severity for cartilage lesions. Receiver operating characteristic (ROC) curve was conducted and the area under curve (AUC) was used to the evaluate the diagnostic value of alpha-MSH levels for the prediction of the modified K-L grading by comparing with other biomarkers examined. RESULTS: alpha-MSH levels in synovial fluid showed a negative correlation with, modified ankle K-L grading, Mankin scores, and degradation biomarkers CTX-II and AGG-1, as well as inflammation markers IL-6 and MMP-3. In addition, alpha-MSH levels were also positively associated with Teeny-Wiss scoring and AOFAS ankle-hindfoot scores. The AUC area of alpha-MSH was similar to CTX-II, AGG-1, IL-6, and MMP-3. CONCLUSIONS: Synovial fluid alpha-MSH levels showed an independent and negative correlation with disease severity in patients with PTAOA. Application of alpha-MSH locally may serve as a potential adjuvant therapy for delaying the process of PTAOA.

Central neurotranspeptide, alpha-melanocyte-stimulating hormone (alpha-MSH) is upregulated in patients with congestive heart failure.[Pubmed:16679696]

Intern Med. 2006;45(7):429-34. Epub 2006 May 1.

BACKGROUND: Alpha-melanocyte-stimulating hormone (alpha-MSH), a pro-opiomelanocortin (POMC) derivative, is a neuropeptide with potent anti-inflammatory properties that inhibits tissue injury in a wide array of inflammation models. OBJECTIVE: To determine if alpha-MSH is involved in the development of congestive heart failure (CHF) with the specific aim of examining its peripheral source and one of the mechanisms. METHODS: The circulating levels of alpha-MSH were measured in 115 patients with CHF using a double-antibody radioimmunoassay. To determine one of the sources of circulating alpha-MSH, human peripheral blood mononuclear cells (PBMC) were stimulated with lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-alpha. Furthermore, to clarify one of the functions of alpha-MSH, PBMC were cultured in the presence or absence of alpha-MSH. RESULTS: Plasma levels of alpha-MSH were significantly higher in NYHA class II patients with CHF than in control subjects (p<0.0001). A significant correlation was found between the levels of alpha-MSH and high-sensitive testing for C-reactive protein in patients with CHF (r=0.41, p<0.0005). PBMC stimulated with LPS or TNF-alpha released alpha-MSH in a concentration-dependent manner. alpha-MSH inhibited LPS-induced TNF-alpha production, and alpha-MSH simultaneously augmented production of interleukin (IL)-10 by PBMC. CONCLUSIONS: Circulating alpha-MSH was increased in patients with CHF. Inflammatory response induced alpha-MSH production in cultured human PBMC. Treatment of alpha-MSH could modify the immunobalance between inflammatory and anti-inflammatory responses in cultured PBMC. These findings suggest that alpha-MSH may play an important role in the pathophysiology of CHF.

alpha-Melanocyte stimulating hormone and oxytocin induced penile erections, and intracavernous pressure increases in the rat.[Pubmed:11792967]

J Urol. 2002 Feb;167(2 Pt 1):757-60.

PURPOSE: alpha-Melanocyte stimulating hormone (alpha-MSH; Fluka Chemie AG, Geneva, Switzerland) and oxytocin induce erection in rats after intracerebroventricular administration. We studied possible interactions of alpha-melanocyte stimulating hormone with mechanisms pertaining to oxytocin or nitric oxide. MATERIALS AND METHODS: We used 78 anesthetized male Sprague-Dawley rats. Catheters were implanted in the lateral cerebral ventricle or into the subarachnoid space at L6 to S1. Intracavernous pressure was documented and arterial blood pressure was directly measured. RESULTS: Intracerebroventricular alpha-MSH (3 microg.) produced a mean of 2.6 +/- 0.6 erectile responses (p <0.05) with a mean duration of 3.4 +/- 1.1 minutes (p <0.05). Mean peak intracavernous pressure was 114 +/- 8 cm. water. An intracerebroventricular dose of 100 microg. N-nitro-L-arginine-methyl ester HCl (Sigma Chemical Co., St. Louis, Missouri) given in intracerebroventricular fashion abolished alpha-MSH induced erectile responses, whereas intracerebroventricular administration of 500 ng. of the oxytocin receptor antagonist l-deamino, 2-D-Tyr(Oet), 4-Thr, 8-Orn-OT (Ferring AB, Malmo, Sweden) had no effect. Intracerebroventricular oxytocin (30 ng.) induced a mean of 3.2 +/- 0.9 erectile responses (p <0.05) with a mean peak intracavernous pressure of 81 +/- 8 cm. water and a mean duration of 3.3 +/- 1.1 minutes. Intrathecal alpha-MSH (3 microg.) did not produce any erectile responses, whereas a mean of 5.7 +/- 0.9 responses (p <0.001) with a mean peak intracavernous pressure of 142 +/- 8 cm. water and mean duration of 5.0 +/- 1.3 minutes was obtained with 30 ng. oxytocin intrathecally. Responses induced by intrathecal oxytocin were abolished by 100 microg. N-nitro-L-arginine-methyl ester HCl intrathecally. CONCLUSIONS: We confirmed by monitoring intracavernous pressure and blood pressure that supraspinal erectile responses induced by alpha-melanocyte stimulating hormone involve effects mediated by nitric oxide but are independent of oxytocinergic mechanisms. At the spinal level oxytocin produces erectile responses involving nitric oxide. alpha-Melanocyte stimulating hormone does not seem to have a spinal site of action.

Melanocortin receptors: perspectives for novel drugs.[Pubmed:10443584]

Eur J Pharmacol. 1999 Jun 30;375(1-3):295-310.

The cloning of five different subtypes of melanocortin receptor subtypes have recently opened up new possibilities for the development of drugs. The physiological roles of the five melanocortin receptors have started to become understood, and compounds with selective actions on some of the five subtypes have become available. Presently, most clinically promising application for drugs active on melanocortin receptors are for control of feeding homeostasis and body weight and for treatment of inflammatory diseases. I review here the cloning, localisation, function and structure of the melanocortin receptors, in relation to the possibilities to develop selective drugs for these receptors.

α-Melanocyte-Stimulating Hormone (MSH), amide stimulates melanocortin 1 receptor that results in the activation of adenylyl cyclase.

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