Neuroprotective actions of melanocortins: a therapeutic opportunity

doi:10.1016/j.tins.2008.04.002

Trends in Neurosciences

Volume 31, Issue 7, July 2008, Pages 353-360

https://doi.org/10.1016/j.tins.2008.04.002 Get rights and content

α-Melanocyte stimulating hormone (α-MSH) and other melanocortins make up a family of endogenous peptides derived from pro-opiomelanocortin. Through binding to five melanocortin receptors (MCR), these peptides exert multiple influences on the host, including anti-inflammatory and immunomodulatory effects. The wide distribution of at least three melanocortin receptor subtypes (MC1R, MC3R and MC4R) in neural, glial and endothelial cells suggests that these receptors could be pharmacological targets for neuroprotective therapies. As a consequence of modulation of NF-κB-mediated transcription, melanocortins reduce production of pro-inflammatory agents in brain cells after injury. During brain ischemia, α-MSH and other melanocortins exert protective influences with a broad time window. Further, melanocortins rescue neurons subjected to excitotoxic insults, accelerate neurophysiological recovery after spinal cord injury and increase regenerative capacity of peripheral nerves in postlesion repair. Based on their established actions, melanocortins could form a novel class of therapeutic agents for acute and chronic disorders of the nervous system.

Introduction

Adrenocorticotropic hormone (ACTH) and α-, β- and γ-melanocyte stimulating hormone (α-, β-, γ-MSH) make up a family of endogenous peptides derived from pro-opiomelanocortin (POMC) [1]. Recognition and cloning of melanocortin receptors (MCR) have greatly improved understanding of peptide–target cell interactions [2]. The five MCRs cloned so far (MC1R–MC5R) belong to class A guanine nucleotide-binding protein (G-protein)-coupled, seven-transmembrane-spanning receptors; all are functionally coupled to adenylyl cyclase and mediate their effects primarily by activating a cyclic 3′,5′-adenosine monophosphate (cAMP)-dependent signaling pathway.

Melanocortins compose an ancient regulatory system (Box 1) that exerts multiple influences on the host, including anti-inflammatory, immunomodulatory and antimicrobial effects 1, 3. Synthetic melanocortins could soon form the basis for new classes of therapeutic molecules. This article reviews the neuroprotective actions of melanocortins and examines their potential therapeutic value in treatment of brain inflammation, stroke, spinal cord injury and nerve regeneration.

Section snippets

Brain cells are a source of and a target for melanocortins

Melanocortinergic terminals are found in various hypothalamic regions such as the paraventricular and dorsomedial hypothalamic nuclei, the arcuate nucleus and lateral hypothalamic regions [4]; they send projections to the hypothalamus, thalamus, midbrain, amygdala and brain stem. POMC mRNA is also detectable in the spinal cord and dorsal root ganglion 5, 6.

Binding sites for α-MSH in the brain were recognized long before melanocortin receptors were cloned [7]. A neuroanatomic map of potential

Melanocortins inhibit NF-κB-mediated transcription in brain cells

During damage caused by vascular, inflammatory or traumatic brain injury there is production of similar effector molecules including cytokines, adhesion molecules and nitric oxide. A common feature among these detrimental mediators is that their production is under control of the transcription factor nuclear factor κB (NF-κB) [21] (Figure 1). As a consequence of trauma, ischemia, glutamate excitotoxicity and hypoxia there is degradation of the protective protein IκB, and free NF-κB is

Melanocortins reduce inflammatory mediator production in brain cells

As a consequence of modulation of NF-κB-mediated transcription, melanocortins reduce production of pro-inflammatory agents by leukocytes and other cell types [1]. Consistently, inhibition of cytokines and other mediators was observed in models of neural damage in vitro and in vivo. This is a critical effect because damage to oligodendrocytes and Schwann cells is primarily caused by pro-inflammatory cytokines and free radicals produced by activated microglia, macrophages and astrocytes [28].

Melanocortins exert protective effects in ischemic brain injury

Blood flow interruption causes depletion of energy substrates, impairment of transmembrane ionic gradients and excessive release of excitatory neurotransmitters including glutamate [35]. These events promote an early wave of excitotoxicity and cell damage associated with entry of Ca²⁺ and other ions, cell swelling, activation of intracellular kinases and proteases, and excessive production of reactive oxygen and nitrogen species [35]. Activation of transcription factors, including NF-κB,

Melanocortins exert neurotrophic effects in spinal cord injury and promote peripheral nerve regeneration

The objective in treatment of neurotrauma is to improve regeneration of damaged axons. However, axonal regrowth in the central nervous system is very poor or absent [46]. Therefore, traumatic spinal cord injury often results in a permanent loss of motor and sensory functions. Pathophysiology of traumatic spinal cord injury is characterized by two distinct phases: initially, damage arises directly from physical injury to the nervous tissue; subsequently, there is substantial destruction of the

Reduction of detrimental consequences of brain injury on peripheral cells: a further therapeutic opportunity for melanocortins

Neuroimmunomodulation studies indicate that the central nervous system and peripheral organs communicate via neuronal pathways and soluble mediators [65]. Indeed, although the traditional focus in inflammation and immunity research has been on events and mediators in the periphery, it is clear that the brain has the capacity to reduce or augment several host responses via pathways independent from the hypothalamic-pituitary-adrenal axis [66]. Seminal investigations indicated that IL-1β infused

Conclusions

The severe physical and cognitive disability caused by brain injury has very high costs in terms of decrease in quality of life and ability to work. These conditions also entail a heavy economic cost for both the patients and society. It is clear, therefore, that effective treatments would be a beneficial response to significant needs. No consistently efficacious therapies have yet been identified and implemented in clinical practice. The need is imperative. Melanocortins have a remarkable

Acknowledgements

The author is grateful to S. Gatti and J.M. Lipton for helpful comments. Work in the author's laboratory is supported by research funds of Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena and Progetto Fondazione Fiera Milano.

Glossary

Melanocortin peptides: The term melanocortin peptides or melanocortins denotes the pro-opiomelanocortin derivatives melanotropins and corticotropins. This distinction, based on the originally discovered effects, is only partly biologically adequate. Indeed, although recognition of the melanocortin 2 receptor (MC2R) in the adrenal glands is distinctive for the corticotropin ACTH, this peptide also binds the other melanocortin receptor subtypes. Consequently, in addition to unique corticosteroid

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Trends in Neurosciences

ReviewNeuroprotective actions of melanocortins: a therapeutic opportunity

Introduction

Section snippets

Brain cells are a source of and a target for melanocortins

Melanocortins inhibit NF-κB-mediated transcription in brain cells

Melanocortins reduce inflammatory mediator production in brain cells

Melanocortins exert protective effects in ischemic brain injury

Melanocortins exert neurotrophic effects in spinal cord injury and promote peripheral nerve regeneration

Reduction of detrimental consequences of brain injury on peripheral cells: a further therapeutic opportunity for melanocortins

Conclusions

Acknowledgements

Glossary

Brain Res. Mol. Brain Res.

Brain Res. Mol. Brain Res.

Brain Res.

Microvasc. Res.

J. Biol. Chem.

Biochem. Pharmacol.

Exp. Neurol.

Brain Res.

J. Neuroimmunol.

Peptides

Biochem. Biophys. Res. Commun.

Neurosci. Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuroscience

Exp. Neurol.

Peptides

Peptides

Prog. Brain Res.

Prog. Brain Res.

Exp. Neurol.

Peptides

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Behav. Immun.

J. Surg. Res.

J. Surg. Res.

Exp. Neurol.

J. Neuroimmunol.

Gen. Comp. Endocrinol.

Gen. Comp. Endocrinol.

Peptides

J. Control. Release

Peptides

Brain Res.

The melanocortin system in leukocyte biology

J. Leukoc. Biol.

The melanocortin system

Am. J. Physiol. Endocrinol. Metab.

Targeting melanocortin receptors as a novel strategy to control inflammation

Pharmacol. Rev.

Anatomy and regulation of the central melanocortin system

Nat. Neurosci.

Specific receptors for α-melanocyte-stimulating hormone are widely distributed in tissues of rodents

Endocrinology

Expression of melanocortin 1 receptor in periaqueductal gray matter

Neuroreport

A potential mechanism of local anti-inflammatory action of α-melanocyte-stimulating hormone within the brain: modulation of tumor necrosis factor-α production by human astrocytic cells

Neuroimmunomodulation

Identification of a receptor for γ melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system

Proc. Natl. Acad. Sci. U. S. A.

Activation and endocytic internalization of melanocortin 3 receptor in neuronal cells

Ann. N. Y. Acad. Sci.

Review
Neuroprotective actions of melanocortins: a therapeutic opportunity