MSH or Melanocyte-Stimulating Hormone Basics

MSH is an explosively new hormone that is deficient in many people due to inflammation, infections and possible toxin exposures of various kinds. Some feel it can even be permanently destroyed, but this is unfortunately usually due to very narrow and limited treatment abilities — fetish medical interests. According to the brilliant leader in MSH research, who has the two major textbooks on the topic, Dr. Cone, MSH has vast roles in the body — perhaps one reason it is being made all over the world with eagerness for many years.

He includes in his The Melanocortin System, from a paper by Hruby, Cai, et. al. (2002) that MSH has some of these sample effects:

  • Heart Function Benefits
  • Stress Coping Help
  • Better Attention and Memory
  • Cancer and UV Protection, e.g., skin cancer
  • Addiction Treatment
  • Neuron Repair
  • Pain Control
  • Anti-inflammatory Effects
  • Weight Control or a Restoration of Normal Eating
  • Normal Urination
  • Fever Control
  • Erection Benefits

Amusingly, some authors act like they have discovered MSH, when everything they say about MSH is well-known throughout the pharmaceutical and research world community. One just needs to read the basics in basic books and articles. Some feel they have discovered a link between Leptin and obesity and MSH. And while these things are related, there is no simplistic path, since as the article by Shimizu and others below shows Leptin and MSH are independent in a great many ways.

* * * * *

Nat Neurosci. 2005 May;8(5):571-8.
Anatomy and regulation of the central melanocortin system.
Cone RD.

The central melanocortin system [which makes MSH] is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.

J Endocrinol. 2007 Apr;193(1):1-9.

The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure.
Shimizu H, Inoue K, Mori M.

The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived alpha-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.

1: Gastroenterology. 2008 Jan;134(1):166-78. Epub 2007 Oct 17.
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PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation.

Dalmasso G, Charrier-Hisamuddin L, Thu Nguyen HT, Yan Y, Sitaraman S, Merlin D.

Department of Medicine, Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.

BACKGROUND & AIMS: KPV is a tripeptide (Lys-Pro-Val), which possesses anti-inflammatory properties; however, its mechanisms of action still remain unknown. PepT1 is a di/tripeptide transporter normally expressed in the small intestine and induced in colon during inflammatory bowel disease (IBD). The aim of this study was to 1) investigate whether the KPV anti-inflammatory effect is PepT1-mediated in intestinal epithelian and immune cells, and 2) examine the anti-inflammatory effects in two models of mice colitis. METHODS: Human intestinal epithelial cells Caco2-BBE, HT29-Cl.19A, and human T cells (Jurkat) were stimulated with pro-inflammatory cytokines in the present or absence of KPV. KPV anti-inflammatory effect was assessed using a NF-kappaB luciferase gene reporter, Western blot, real-time RT-PCR and ELISA. Uptake experiments were performed using cold KPV as a competitor for PepT1 radiolabelled substrate or using [(3)H]KPV to determine kinetic characteristics of KPV uptake. Anti-inflammatory effect of KPV was also investigated in DSS- and TNBS-induced colitis in mice. KPV was added to drinking water and inflammation was assessed at the histologic level and by proinflammatory cytokine mRNA expression. RESULTS: Nanomolar concentrations of KPV inhibit the activation of NF-kappaB and MAP kinase inflammatory signaling pathways, and reduce pro-inflammatory cytokine secretion. We found that KPV acts via PepT1 expressed in immune and intestinal epithelial cells. Furthermore, oral administration of KPV reduces the incidence of DSS- and TNBS-induced colitis indicated by a decrease in pro-inflammatory cytokine expression. CONCLUSIONS: This study indicates tht KPV is transported into cells by PepT1 and might be a new therapeutic agent for IBD.

Publication Types:

  • Research Support, N.I.H., Extramural

PMID: 18061177 [PubMed - indexed for MEDLINE]


2:  Basic Clin Pharmacol Toxicol. 2007 Dec;101(6):416-20.
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Functional evaluation of THIQ, a melanocortin 4 receptor agonist, in models of food intake and inflammation.

Muceniece R, Zvejniece L, Vilskersts R, Liepinsh E, Baumane L, Kalvinsh I, Wikberg JE, Dambrova M.

Faculty of Medicine, University of Latvia, Riga, Latvia.

The central melanocortinergic system plays an important role in regulating different aspects of energy homeostasis and the immunomodulatory response. In the present study, we evaluated the in vivo activities of food intake suppression and anti-inflammatory activity of THIQ, which has been proposed to possess high and selective melanocortin-4 receptor agonistic activity in vitro. The results showed that THIQ (0.1, 0.3 and 1 nmol/rat, intracerebroventricularly) is less effective in reducing food intake and body weights of rats than the non-selective melanocortin receptor agonist melanotan II. Electron paramagnetic resonance measurements in mice brain tissue showed that THIQ at doses of 0.001 and 0.01 nmol/mouse (intracisternally) increased the concentration of nitric oxide, which is not typical for melanocortin receptor agonists. In an experimental brain inflammation model, THIQ only weakly antagonized lipopolysaccharide-induced nitric oxide overproduction in brain tissue at a dose of 0.01 nmol/mouse. Our findings provide new insight into the in vivo pharmacological profile of the in vitro selective melanocortin-4 receptor agonist THIQ and give grounds for caution when interpreting and predicting melanocortin receptor selective agonist activity in vivo.

Publication Types:

  • Comparative Study
  • Research Support, Non-U.S. Gov't

PMID: 18028105 [PubMed - indexed for MEDLINE]


3:  J Sex Med. 2007 Nov;4 Suppl 4:269-79.
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Bremelanotide: an overview of preclinical CNS effects on female sexual function.

Pfaus J, Giuliano F, Gelez H.

Concordia University-Psychology, Montreal, Canada. [email protected]

INTRODUCTION: Bremelanotide is an analogue of the naturally occurring peptide alpha-melanocyte-stimulating hormone (alpha-MSH). It stimulates erection in men and male rats, and is currently in clinical trials for the treatment of erectile dysfunction. AIM: To review the effects of bremelanotide, an analogue of the naturally occurring peptide alpha-MSH, on the preclinical indices of sexual desire in female rats, and where in the brain these actions may occur. MAIN OUTCOME MEASURES: Appetitive sexual behaviors, such as solicitations, hops and darts, and pacing, were assessed along with consummatory behaviors such as lordosis. The involvement of brain regions was assessed following direct administration to the region, by the stimulation of molecular markers of neural activation, and using microdialysis to examine extracellular fluid for different neurotransmitters. METHODS: Using a model that allows ovariectomized, hormone-primed female rats to control the timing of sexual encounters with males, we tested the ability of bremelanotide to increase appetitive (proceptive) and/or consummatory sexual behaviors. RESULTS: Bremelanotide dramatically and selectively increased measures of solicitation in female rats, without altering pacing or lordosis, following both peripheral (subcutaneous) administration or infusions directly into the lateral ventricles or medial preoptic area (mPOA), but not the ventromedial hypothalamus. The mPOA is critical for the display of appetitive sexual behaviors in females and males of a variety of species. Peripheral administration of bremelanotide activates the mPOA and other hypothalamic and limbic regions of the brain involved in sexual behavior, and may work by activating dopamine terminals in the mPOA. CONCLUSIONS: To the extent that solicitations indicate the desire of female rats to engage in sexual activity, bremelanotide appears to possess the behavioral, pharmacological, and neuroanatomical specificity required of a drug in the treatment of hypoactive sexual desire disorders.

PMID: 17958619 [PubMed - indexed for MEDLINE]


4:  Ann Rheum Di 2007 Nov;66 Suppl 3:iii52-5.
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alpha-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs.

Luger TA, Brzoska T.

Department of Dermatology, University Clinics M�nster, Von-Esmarch-Str. 58, D-48149 M�nster, Germany. [email protected]

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a tridecapeptide derived from the proopiomelanocortin by post-translational processing. In addition to its effects on melanocytes, alpha-MSH has potent anti-inflammatory effects when administered systemically or locally. The anti-inflammatory effects of alpha-MSH are mediated by direct effects on cells of the immune system as well as indirectly by affecting the function of resident non-immune cells. alpha-MSH affects several pathways implicated in regulation of inflammatory responses such as NF-kappa B activation, expression of adhesion molecules and chemokine receptors, production of pro-inflammatory cytokines and other mediators. Thus alpha-MSH may modulate inflammatory cell proliferation, activity and migration. The anti-inflammatory effects of alpha-MSH have been confirmed by means of animal models of inflammation such as irritant and allergic contact dermatitis, cutaneous vasculitis, asthma, inflammatory bowel disease, rheumatoid arthritis, ocular and brain inflammation. Most of the anti-inflammatory activities of alpha-MSH can be attributed to its C-terminal tripeptide KPV. K(D)PT, a derivative of KPV corresponding to the amino acid 193-195 of IL-1beta, is currently emerging as another tripeptide with potent anti-inflammatory effects. The anti-inflammatory potential together with the favorable physiochemical properties most likely will allow these agents to be developed for the treatment of inflammatory skin, eye and bowel diseases, allergic asthma and arthritis.

PMID: 17934097 [PubMed - indexed for MEDLINE]


5: Invest Ophthalmol Vis Sci. 2007 Nov;48(11):5112-7.
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In vitro generated autoimmune regulatory T cells enhance intravitreous allogeneic retinal graft survival.

Ng TF, Kitaichi N, Taylor AW.

Schepens Eye Research Institute, Boston, MA 02114, USA.

PURPOSE: The authors demonstrated that in vitro-generated alpha-melanocyte stimulated hormone (MSH)-induced Treg cells specific to ocular autoantigen suppress ocular autoimmune disease in vivo when adoptively transferred. They examined the possibility of using these ocular autoantigen-specific Treg cells to promote the survival of a retinal allograft placed in the mouse vitreous. METHODS: Enhanced green fluorescent protein (eGFP)-C57BL/6 neonatal retinal microaggregates were injected into the vitreous of B10-RIII mice before the adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP; an ocular antigen) or ovalbumin (OVA)-specific alpha-MSH-induced Treg cells. GFP transplants were imaged in vivo on days 7 and 12. In addition, on day 12, the eyes were cryosectioned and immunostained with a panel of neuronal and immune cell markers. RESULTS: GFP allografts underwent no detectable changes in size on days 7 and 12 in the B10-RIII mice injected with IRBP-specific Treg cells; however, mice that received OVA-specific Treg cells or no Treg cells experienced remarkable reductions in graft size on day 12. Only one quarter of the original size was seen. Using neuronal-specific markers, immunohistochemistry showed that the architecture of the retinal allografts in the IRBP Treg cell-injected group had intact rosettes and neuronal cells on the outermost layer, whereas the allografts in the OVA Treg cell-injected mice were disorganized. Immune cell-specific markers demonstrated that Treg cells and activated microglial cells were found in the retinal allografts of the mice injected with IRBP Treg cells, but not in the retinal allografts of the OVA Treg-injected mice. CONCLUSIONS: These results demonstrate that adoptive transfer of alpha-MSH-generated IRBP-specific Treg cells promotes retinal allograft survival and development.

PMID: 17962463 [PubMed - indexed for MEDLINE]


6: Peptides. 2007 Oct;28(10):2009-15. Epub 2007 Aug 1.
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MIF-1 and its peptidomimetic analogs attenuate haloperidol-induced vacuous chewing movements and modulate apomorphine-induced rotational behavior in 6-hydroxydopamine-lesioned rats.

Castellano JM, Batrynchuk J, Dolbeare K, Verma V, Mann A, Skoblenick KJ, Johnson RL, Mishra RK.

Department of Psychiatry and Behavioral Neurosciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.

Two melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) also known as L-prolyl-L-leucyl-glycinamide (PLG) peptidomimetic analogs, 3(R)-[[[2(S)-pyrrolidinyl]carbonyl]-amino]-3-(butyl)-2-oxo-1-pyrrolidineacetamide trifluoroacetate (A) and 3(R)-[[[2(S)-pyrrolidinyl]carbonyl]amino]-3-(benzyl)-2-oxo-1-pyrrolidineacetamide trifluoroacetate (B), were evaluated for their ability to modulate dopaminergic activity by measuring apomorphine-induced rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats, and haloperidol (HP)-induced vacuous chewing movements (VCMs) in rats; animal models of Parkinson's disease (PD) and human tardive dyskinesia (TD), respectively. In the 6-OHDA model, both analogs were found to potentiate the contralateral rotational behavior induced by apomorphine dose-dependently and with approximately the same potency. Furthermore, each analog was able to significantly attenuate HP-induced VCMs with almost equal efficacy. The potency and efficacy of these analogs were significantly greater than their parent compound, PLG. These results suggest that both analogs can modulate dopaminergic activity in vivo, likely by the same mechanisms recruited by PLG previously reported.

Publication Types:

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

PMID: 17766011 [PubMed - indexed for MEDLINE]


7: Am J Hypertens. 2007 Aug;20(8):862-5.
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Prevention of salt-induced hypertension by an analog of gamma-melanocyte-stimulating hormone in the rat.

Ni XP, Humphreys MH.

Division of Nephrology, San Francisco General Hospital, and Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA.

BACKGROUND: Rats with suppression of pituitary intermediate lobe (IL) function by treatment with the dopaminergic agonist bromocriptine develop salt-sensitive hypertension accompanied by a deficiency of gamma-melanocyte-stimulating hormone (gamma-MSH). METHODS: To study the time course, and establish the causal role, of gamma-MSH deficiency in the development of salt-sensitive hypertension, we instrumented 12 male Sprague-Dawley rats with radiotelemetry transmitters to record intraaortic mean arterial pressure (MAP). One week later, they were placed on a high-sodium diet (8% NaCl, HSD) and received daily intraperitoneal injections of bromocriptine (5 mg/kg). The rats were also implanted with micro-osmotic pumps to deliver either a stable analog of gamma-MSH ([Nle3, D-Phe6]-gamma-MSH, NDP-gamma-MSH) at 12 pmol/h or normal saline vehicle. RESULTS: In vehicle-treated rats on the HSD and receiving bromocriptine injections, MAP rose so that it was significantly greater than that in NDP-gamma-MSH-treated animals by Day 4, and reached a stable plateau of approximately 135 mm Hg between Days 7 and 14. After Day 14, bromocriptine injections were stopped, and MAP in vehicle-infused rats fell progressively despite continued ingestion of the HSD, so that by Day 18, MAP was no longer different from NDP-gamma-MSH-infused animals. The MAP in the latter group did not vary significantly from the control level of 101+/-4 mm Hg throughout the 21 days of the experiment. CONCLUSIONS: These results indicate that gamma-MSH deficiency is a consequence of the bromocriptine treatment responsible for the salt-sensitive hypertension, and these results also identify the time course during which this hypertension develops.

Publication Types:

  • Research Support, N.I.H., Extramural

PMID: 17679034 [PubMed - indexed for MEDLINE]


8: Cancer Biother Radiopharm. 2007 Jun;22(3):333-41.
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Therapeutic efficacy of a 177Lu-labeled DOTA conjugated alpha-melanocyte-stimulating hormone peptide in a murine melanoma-bearing mouse model.

Miao Y, Shelton T, Quinn TP.

College of Pharmacy, University of New Mexico, Albuquerque, NM, USA.

The aim of this study was to examine the therapeutic efficacy of (177)Lu-DOTA-Re(Arg(11))CCMSH in the B16/F1 murine melanoma-bearing mouse model. METHODS: (177)Lu-DOTA-Re(Arg(11))CCMSH was prepared in 0.5 M NH(4)OAc at a pH of 5.4. Two (2) treatment groups of 10 melanoma-bearing C57 mice were administrated with 2 x 18.5 MBq and 1 x 37.0 MBq of (177)Lu-DOTA-Re(Arg(11))CCMSH through the tail vein, respectively. One (1) group of 10 melanoma-bearing C57 mice was injected with saline placebos as untreated melanoma-bearing controls. RESULTS: In contrast to the untreated melanoma-bearing control group, (177)Lu-DOTA-Re(Arg(11))CCMSH administration yielded rapid and lasting therapeutic effects in the treatment groups. (177)Lu-DOTA-Re(Arg(11))CCMSH treatment decreased the tumor growth rate and significantly (p > 0.05) prolonged the survival time of melanoma-bearing C57 mice. Treatment with 2 x 18.5 MBq or 1 x 37.0 MBq of (177)Lu-DOTA-Re(Arg(11))CCMSH significantly extended the mean survival of tumor-bearing mice from 13.3 to 15.1 and 16.2 days, respectively. (177)Lu-DOTA-Re(Arg(11))CCMSH treatment produced no observed acute renal toxicity. CONCLUSIONS: The therapy study results revealed that (177)Lu-DOTA-Re(Arg(11))CCMSH yielded quantitative therapeutic effects in B16/F1 melanoma-bearing mice and appeared to be a promising radiolabeled peptide for the targeted radionuclide therapy of melanoma.

Publication Types:

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

PMID: 17651039 [PubMed - indexed for MEDLINE]

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