Review Melanocortins as potential therapeutic agents in severe hypoxic conditions Daniela Giuliani a , Letteria Minutoli b , Alessandra Ottani a , Luca Spaccapelo a , Alessandra Bitto b , Maria Galantucci a , Domenica Altavilla b , Francesco Squadrito b , Salvatore Guarini a,⇑ a Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, 41125 Modena, Italy b Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, 98125 Messina, Italy article info Article history: Available online 17 April 2012 Keywords: Ischemic diseases Melanocortins Resuscitation Protective effects Vagus nerve Neurogenesis Functional recovery abstract Melanocortin peptides with the adrenocorticotropin/melanocyte-stimulating hormone (ACTH/MSH) sequences and synthetic analogs have protective and life-saving effects in experimental conditions of cir- culatory shock, myocardial ischemia, ischemic stroke, traumatic brain injury, respiratory arrest, renal ischemia, intestinal ischemia and testicular ischemia, as well as in experimental heart transplantation. Moreover, melanocortins improve functional recovery and stimulate neurogenesis in experimental mod- els of cerebral ischemia. These beneficial effects of ACTH/MSH-like peptides are mostly mediated by brain melanocortin MC 3 /MC 4 receptors, whose activation triggers protective pathways that counteract the main ischemia/reperfusion-related mechanisms of damage. Induction of signaling pathways and other molecular regulators of neural stem/progenitor cell proliferation, differentiation and integration seems to be the key mechanism of neurogenesis stimulation. Synthesis of stable and highly selective agonists at MC 3 and MC 4 receptors could provide the potential for development of a new class of drugs for a novel approach to management of severe ischemic diseases. Ó 2012 Elsevier Inc. All rights reserved. 1. Introduction Adrenocorticotropic hormone (ACTH), and a-, b- and c-melano- cyte-stimulating hormones (a-, b- and c-MSH) are endogenous peptide products of the pro-opiomelanocortin gene, collectively called melanocortins. Studies by Professor William Ferrari and co- workers were the first to show, since 1955, some extra-hormonal effects of melanocortins, and over the ensuing decades several other independent investigators reported many extra-hormonal ef- fects of these neuropeptides [19,20,23,30,41,49,53–55,64,151,192]. Melanocortins are found in a variety of peripheral tissues and within the central nervous system (CNS) [30,32,117,143,168,197], and the general idea is that the melanocortin system contributes to protect the host from damage caused by excessive reactions. a-MSH is the natural melanocortin peptide able to induce all ex- tra-hormonal effects of melanocortins. It affects many central and peripheral body functions, including food intake, sexual behavior, pain sensitivity, fever control, pigmentation, learning and memory [19,20,27,32,40,41,49,55,64,151,168,196], and plays a protective role in hypoxic conditions [30,32,40,64,70,96,192]. Several a-MSH fragments, including synthetic analogs and the C-terminal tripep- tide, have been also tested [27,32,192,196,197]. For further and invaluable information about the here not dis- cussed areas where melanocortins are involved we refer readers to some of the excellent reviews and papers referred to above. This paper, in fact, is aimed to review the protective actions of melano- cortins – and to discuss their potential therapeutic value – in severe ischemia/reperfusion conditions causing organ damage. 2. Melanocortin receptors Melanocortins act via five different melanocortin G protein- linked, seven transmembrane receptors (MC 1 –MC 5 ), all positively coupled to adenylate cyclase. The transmembrane signaling pri- marily involves activation of a cAMP-dependent pathway, but sim- ilarly to other G-protein-linked receptors melanocortin signaling is conveyed through additional, cAMP-independent pathways [27,29,30,32,64,117,143,144,168,169,182,183,185,197]. MC recep- tors are largely distributed in various brain areas and peripheral tissues (Table 1). MC 1 is expressed in melanocytes, melanoma cells, skin glands, hair follicles, testis and cells involved in the immune/ inflammatory response; MC 2 , the ACTH receptor, is mainly ex- pressed in the adrenal glands but also in white adipose tissue and in the skin; MC 3 is expressed in the brain, placenta, gut, heart and testis; MC 4 occurs in various brain areas, but it has been re- cently recognized also in the periphery; the MC 5 receptor, initially recognized in the brain, was subsequently found to be ubiquitous, but mainly in peripheral organs. MC 3 and MC 4 are the predominant subtypes expressed in the CNS, the expression of MC 4 being broad- er than that of MC 3 receptors. It is well-known that melanocortins and synthetic analogs reach the CNS in pharmacologically-relevant 0091-3022/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yfrne.2012.04.001 ⇑ Corresponding author. Fax: +39 59 2055376. E-mail address: salvatore.guarini@unimore.it (S. Guarini). Frontiers in Neuroendocrinology 33 (2012) 179–193 Contents lists available at SciVerse ScienceDirect Frontiers in Neuroendocrinology journal homepage: www.elsevier.com/locate/yfrne