title: Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia.
abstract: 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] alpha-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 gamma2-MSH had no protective effects. Pharmacological blockade of MC4 receptors prevented the neuroprotective effects of [Nle4, D-Phe7] alpha-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.
authors.affiliation: Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100 Modena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Chiara
authors.initials: C
authors.lastname: Mioni
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Sheila
authors.initials: S
authors.lastname: Leone
authors.forename: Carla
authors.initials: C
authors.lastname: Bazzani
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Maria-Michela
authors.initials: MM
authors.lastname: Cainazzo
authors.forename: Herbert
authors.initials: H
authors.lastname: Marini
authors.forename: Davide
authors.initials: D
authors.lastname: Zaffe
authors.forename: Annibale R
authors.initials: AR
authors.lastname: Botticelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Pizzala
authors.forename: Monica
authors.initials: M
authors.lastname: Savio
authors.forename: Daniela
authors.initials: D
authors.lastname: Necchi
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: Alfio
authors.initials: A
authors.lastname: Bertolini
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology* / Q000628:therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002490:Central Nervous System; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism; D000860:Hypoxia / Q000628:therapy; D007249:Inflammation; D007511:Ischemia / Q000378:metabolism; D007858:Learning; D020935:MAP Kinase Signaling System; D008297:Male; D018782:Maze Learning; D008568:Memory; D015233:Models, Statistical; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism / Q000627:therapeutic use*; D020521:Stroke / Q000628:therapy; D013997:Time Factors; D016896:Treatment Outcome; D000521:alpha-MSH / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D016207:Cytokines; C470072:MC4R protein, human; D018696:Neuroprotective Agents; D044105:Receptor, Melanocortin, Type 4; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000521:alpha-MSH; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases