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Both Early and Delayed Treatment with Melanocortin 4 Receptor-Stimulating Melanocortins Produces Neuroprotection in Cerebral Ischemia

Department of Biomedical Sciences (D.G., C.M., S.L., C.B., S.G.), Section of Pharmacology, Department of Diagnostic Services (M.-M.C., A. Bertolini), Section of Clinical Pharmacology, and Department of Anatomy and Histology (D.Z.), University of Modena and Reggio Emilia, 41100 Modena, Italy; Department of Clinical and Experimental Medicine and Pharmacology (D.A., L.M., A. Bitto, H.M., F.S.), Section of Pharmacology, University of Messina, 98100 Messina, Italy; Departments of Human Pathology (A.R.B.) and Experimental Medicine (R.P., M.S., D.N.), University of Pavia, 27100 Pavia, Italy; and Department of Neuroscience (H.B.S.), University of Uppsala, 75124 Uppsala, Sweden

Address all correspondence and requests for reprints to: Salvatore Guarini, Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100 Modena, Italy. E-mail: guarini.salvatore{at}unimore.it.

Ischemic stroke is one of the main causes of death and disability. We investigated whether melanocortin peptides, which have protective effects in severe hypoxic conditions, also produce neuroprotection in a gerbil model of ischemic stroke. A 10-min period of global cerebral ischemia, induced by occluding both common carotid arteries, caused impairment in spatial learning and memory that was associated with activation of inflammatory and apoptotic pathways, including severe DNA damage and delayed neuronal death, in the hippocampus. Treatment with nanomolar doses of the melanocortin analog [Nle⁴, D-Phe⁷] -MSH [which activates the melanocortin receptor subtypes (MC) mainly expressed in central nervous system, namely MC₃ and MC₄] modulated the inflammatory and apoptotic cascades and reduced hippocampus injuries even when delayed up to 9 h after ischemia, with consequent dose-dependent improvement in subsequent functional recovery. The selective MC₃ receptor agonist ₂-MSH had no protective effects. Pharmacological blockade of MC₄ receptors prevented the neuroprotective effects of [Nle⁴, D-Phe⁷] -MSH and worsened some ischemia outcomes. Together, our findings suggest that MC₄ receptor-stimulating melanocortins might provide potential to develop a class of drugs with a broad treatment window for a novel approach to neuroprotection in ischemic stroke.

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