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Submitted on June 9, 2005
Accepted on October 20, 2005
Departments of Biomedical Sciences, Section of Pharmacology (D.G., C.M., S.L., C.B., S.G.), Diagnostic Services, Section of Clinical Pharmacology (M.M.C., A. Bertolini.), Anatomy and Histology (D.Z.), University of Modena and Reggio Emilia, Modena, Italy, Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology (D.A., L.M., A.Bitto, H.M., F.S.), University of Messina, Messina, Italy, Departments of Human Pathology (A.R.B.), and Experimental Medicine (R.P., M.S., D.N.), University of Pavia, Pavia, Italy, Department of Neuroscience (H.B.S.), University of Uppsala, Uppsala, Sweden
* To whom correspondence should be addressed. E-mail: guarini.salvatore.
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, produce also 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, 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 [Nle (4), D-Phe7] 
-melanocyte-stimulating hormone (NDP-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 if 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 NDP-MSH, and worsened some ischemia outcomes. Together, our findings suggest that MC4 receptor-stimulating melanocortins might provide potential to develope a class of drugs with a broad treatment window for a novel approach to neuroprotection in ischemic stroke.
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