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-MSH
J. M. Lipton was previously in the Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas 75235-9040 and is now Chief Scientific Officer of ZENGEN, Inc., Woodland, California; A. Catania is in the Neuroimmunomodulation Laboratory, IRCCS Ospedale Maggiore, Milan, Italy 20122; and T. Ichiyama is at the Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505, Japan.
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Abstract |
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-MSH. Because activation of glial and peripheral cell receptors modulates inflammatory activity, -MSH peptides may aid treatment of a variety of CNS and peripheral inflammatory disorders. Activation of melanocortin receptors should thus promote control of inflammatory diseases. |
Introduction |
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 Top Introduction Potential therapeutic strategy...Summary of the...References |
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With recognition of the influence of inflammation and inflammatory cytokines in central nervous system (CNS) disorders such as Alzheimer's disease, stroke, multiple sclerosis, and traumatic head injury, the "incidence" figures for inflammation have risen. One of the more costly CNS diseases is Alzheimer's Disease (AD), the most common cause of dementia in the elderly, which is marked by senile plaques, neurofibrillary tangles, and loss of cholinergic neurons. In 1994, AD costs in the US were approximately $174,000 per patient lifetime (5). Clearly, delaying onset or reducing pathology in AD would have major economic, social, and psychological benefits. Inflammatory processes contribute to AD pathology; treatment with glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with inhibition of onset or progression of AD in 14 of 15 studies (1). The local inflammatory cytokine tumor necrosis factor- (TNF-) occurs in AD plaques (9) and in other CNS disorders (8). Neuroimmunomodulators such as -melanocyte-stimulating hormone (-MSH), which inhibits this cytokine within the brain, may limit neurodegeneration and other CNS disorders that have an inflammatory component.
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Potential therapeutic strategy based on the peptide -MSH
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TopIntroductionPotential therapeutic strategy...Summary of the...References |
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-MSH, a peptide known to reduce inflammation. There are five known melanocortin receptor subtypes. One of them, MC-2R, appears to be the adrenocorticotropic hormone (ACTH) receptor. Four of the subtypes (MC-1R, -3R, -4R, -5R) have been identified in brain (10), one or more of which could mediate the anti-inflammatory activity of centrally administered melanocortin peptides.
Centrally administered -MSH peptides inhibit peripheral and systemic inflammation.
-MSH peptides injected into the cerebral ventricles markedly inhibit inflammation in peripheral tissues. Three approaches have been taken to explore this effect. In the first, severing the spinal cord prevented the anti-inflammatory effect of centrally administered -MSH, indicating that a descending neural anti-inflammatory pathway is required. In the second approach, systemic (but not central) injections of butoxamine, a specific ß2-antagonist, or of the less specific ß-adrenergic antagonist propranolol inhibited the anti-inflammatory effect of centrally administered -MSH. Thus the descending anti-inflammatory effect depends on peripheral ß2-adrenergic receptors. The combined results indicate the existence of a descending anti-inflammatory pathway that includes peripheral ß2-adrenergic receptors in mediation of the anti-inflammatory activity of centrally administered -MSH. In the third approach, small amounts of -MSH injected into the cerebral ventricles of mice given a systemic injection of lipopolysaccharide (LPS) modulated the resulting elevations in circulating TNF- and inflammatory nitric oxide (NO) and inhibited TNF- production, NO synthase, and myeloperoxidase activity (an estimate of neutrophil migration) in lung and liver tissue. Furthermore, these markers of inflammation were increased in the circulation, lungs, and liver by central administration of -MSH antibodies. The latter results suggest that increased release of central -MSH normally contributes to control of systemic inflammation. The pathways through which these effects occur in peripheral tissue are unknown, but they are likely to include inhibition of release of neurogenic inflammatory agents, such as substance P and calcitonin gene-related peptide, from free nerve endings surrounding blood vessels and in tissues.
Central -MSH in lethal sepsis.
The most difficult of the inflammatory disorders to understand and treat is sepsis. Despite the recent great increase in information about inflammatory mediators in sepsis and many promising therapeutic leads (e.g., anti-TNF antibodies, interleukin (IL)-1 receptor antagonist), there has been little or no increase in survival during the last 30 years, and there is no agreed-upon medical therapy for sepsis (6). In recent research, mice given a large systemic injection of LPS and central injection of saline died within 48 h, whereas ~45% of animals given a single central injection of -MSH survived and were still alive three months later (Fig. 1
). These results suggest that a key to the control of sepsis lies first in the prevention or reversal of disturbances within the brain, changes perhaps marked by increases in local production of TNF- and related proinflammatory agents. Such CNS "chaos" could cause dysregulation or even counterregulatory events in the periphery in systemic inflammation, such as failure to react to glucocorticoids. These results and observations that glial cells bear -MSH receptors indicate that targeting of CNS melanocortin receptors may lead to successful treatment of sepsis. This novel idea is particularly appealing given the low toxicity of -MSH peptides and the limited therapeutic alternatives for treatment of an often lethal disorder.
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-MSH peptides modulate inflammation directly within the brain. induces or contributes to CNS inflammation. This cytokine has been linked to pathology in AD, multiple sclerosis, meningitis, ischemia/reperfusion injury, and head trauma. -MSH injected centrally and/or peripherally in mice given LPS centrally markedly reduced brain TNF- concentration (10). The powerful inhibitory effect of -MSH on central TNF- in vivo does not depend on factors outside the brain because similar results were obtained when experiments were performed on excised brain tissue. Glial cells are likely responsible for the elevation of brain TNF-; human glial cells bear -MSH receptors, and activation of these receptors inhibits production of TNF-. -MSH likewise reduces production of inflammatory TNF-, IL-6, and NO by activated microglia (4).
-MSH modulates effects of brain stem ischemia/reperfusion.
Stroke, marked by local ischemia and reperfusion of brain tissue, can be conceptualized as a relatively sterile CNS inflammatory reaction. Proinflammatory cytokines are increased in brain ischemia/reperfusion, and it is clear that -MSH generally modulates their production and activity (8). To determine if -MSH can improve function in ischemia/reperfusion injury, auditory evoked potentials were recorded in animals with temporary occlusion of vertebral arteries. The peptide had no marked actions on physiological changes caused by this manipulation (temperature, cerebral blood flow, and so forth), but it did protect the function of the brain stem, as estimated from preservation of auditory evoked potentials, when given during ischemia but more so when given during ischemia and reperfusion. Because of the great safety of the peptide, it might be useful in the treatment of stroke and perhaps as a preemptive therapy to inhibit the inflammation and swelling that often accompany neurosurgical operations and cerebral vasospasm.
-MSH: the neuroimmunomodulator in peripheral host cells.
-MSH is a true neuroimmunomodulatory peptide; it acts on receptors on cells in the periphery as well as within the brain. In the periphery, -MSH reduces production of inflammatory NO and neopterin by monocytes/macrophages. This influence appears to be based on endogenous autocrine regulatory circuits in these cells. Furthermore, the neuropeptide inhibits neutrophil chemotaxis in vitro (8); prevention of neutrophil migration results in modulation of inflammation. Both neutrophils and monocytes express melanocortin receptors, and it is clear that -MSH has direct effects on these inflammatory cells. -MSH inhibits production of all proinflammatory cytokines and mediators against which it has been tested, but its primary influence appears to be on transcription of their genes. Nuclear factor-
B (NF-B) is a ubiquitous and pivotal transcription factor for genes that encode proinflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-. Activation of NF-B requires degradation of the cytoplasmic inhibitor IB protein. -MSH inhibits nuclear translocation of NF-B by slowing degradation of IB induced by LPS in astrocytoma cells (7). Similar effects were observed in brain tissue when the peptide was injected centrally after intracerebroventricular administration of LPS. Chloramphenicol acetyltransferase assays indicated that -MSH suppresses NF-B-dependent reporter gene expression induced by LPS in glioma cells. These findings suggest that the anti-inflammatory action of -MSH occurs via inhibition of production of inflammatory agents by modulation of NF-B activation in both peripheral and central inflammation.
That such peptide influences occur in nature is supported by the observation of changes in plasma -MSH concentration in human disease. Increased concentrations have been observed in the plasma of patients with infectious or inflammatory disorders and in sites of inflammation. -MSH concentration increases in the circulation of patients with acute myocardial infarction who receive thrombolytic therapy, perhaps as an endogenous anti-inflammatory response. -MSH is found in the synovial fluid of arthritis patients, and its concentration is greater in arthropathy marked by greater inflammation; in contrast, there were no significant changes in plasma -MSH in any arthropathy (2). There is an increase in plasma -MSH in normal human subjects given endotoxin; however, during naturally-occurring septic illness ("whole body inflammation"), concentrations of the peptide are below normal control values. Circulating -MSH is low during the critical phase of septic illness and returns to control level after recovery (2). This suggests that low release of the peptide, or insufficient release during sepsis, is linked to poor prognosis. In brief, the effects of melanocortin peptides on inflammatory processes in host cells, and observations on circulating and local -MSH in humans, indicate that the peptide generally becomes available to influence peripheral host cells and CNS receptors during challenge. These observations support the idea that the peptide is part of an endogenous neuroimmunomodulatory response to inflammation. The low concentration in sepsis likely indicates failure of secretion of counteracting -MSH.
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Summary of the neuroimmunomodulatory influences of -MSH
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TopIntroductionPotential therapeutic strategy...Summary of the...References |
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-MSH peptides can now be divided into three categories: direct actions on melanocortin receptors on peripheral host cells (monocyte/macrophages and neutrophils), actions on glial cells, and descending anti-inflammatory influences stemming from melanocortin receptors on neurons (Fig. 2). The actions of the peptide on circulating and tissue host cells directly modulate production of soluble mediators of inflammation, likely via inhibition of gene transcription. Host cells in the CNS, the microglia, and astrocytes, share with peripheral host cells this inhibitory response to -MSH. The descending neurogenic anti-inflammatory response to central -MSH peptides is more complex and involves neuronal pathways not yet fully known. The consistency of these anti-inflammatory influences of melanocortins in peripheral host cells, glia, and in descending anti-inflammatory neural circuits suggests a strong and lengthy evolutionary pressure to preserve these modulatory influences. It should be possible to take advantage of these powerful neuroimmunomodulatory anti-inflammatory influences to control resistant inflammation.
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References |
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TopIntroductionPotential therapeutic strategy...Summary of the...References |
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-MSH in AIDS and other conditions in humans. Ann NY Acad Sci 840: 848–856. 1998.[Medline]
-Melanocyte-stimulating hormone inhibits NF-B degradation in human astrocytes and in experimental brain inflammation. Exp Neurol 157: 359–365, 1999.[ISI][Medline]
-MSH. Immunol Today 18: 140–145, 1997.[ISI][Medline]
-MSH modulates local and circulating TNF- in experimental brain inflammation. J Neurosci 17: 2181–2186, 1997.This article has been cited by other articles:
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  L. Kang, K. W. McIntyre, K. M. Gillooly, Y. Yang, J. Haycock, S. Roberts, A. Khanna, T. F. Herpin, G. Yu, X. Wu, et al. A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice J. Leukoc. Biol., October 1, 2006; 80(4): 897 - 904. [Abstract] [Full Text] [PDF]
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 C. W. Lam, S. J. Getting, and M. Perretti In Vitro and In Vivo Induction of Heme Oxygenase 1 in Mouse Macrophages following Melanocortin Receptor Activation J. Immunol., February 15, 2005; 174(4): 2297 - 2304. [Abstract] [Full Text] [PDF]
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 A. Catania, S. Gatti, G. Colombo, and J. M. Lipton Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation Pharmacol. Rev., March 1, 2004; 56(1): 1 - 29. [Abstract] [Full Text] [PDF]
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