Melanocortins as potential therapeutic agents in severe hypoxic conditions

Melanocortin peptides with the adrenocorticotropin/melanocyte-stimulating hormone (ACTH/MSH) sequences and synthetic analogs have protective and life-saving effects in experimental conditions of circulatory 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 models of cerebral ischemia. These beneficial effects of ACTH/MSH-like peptides are mostly mediated by brain melanocortin MC3/MC4 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 MC3 and MC4 receptors could provide the potential for development of a new class of drugs for a novel approach to management of severe ischemic diseases.

► Melanocortins protect against ischemia/reperfusion-induced organ damage. ► Melanocortins modulate local and systemic inflammatory response. ► Melanocortins stimulate neurogenesis. ► Melanocortins improve functional recovery. ► These effects are mostly mediated by brain melanocortin MC3/MC4 receptors.