title: Melanocortin MC₄ receptor agonists counteract late inflammatory and apoptotic responses and improve neuronal functionality after cerebral ischemia.
abstract: Indirect evidence indicates that, in cerebral ischemia, melanocortins have neuroprotective effects likely mediated by MC₄ receptors. To gain direct insight into the role of melanocortin MC₄ receptors in ischemic stroke, we investigated the effects of a highly selective MC₄ receptor agonist. Gerbils were subjected to transient global cerebral ischemia by occluding both common carotid arteries for 10 min. In saline-treated stroke animals, an impairment in learning and memory occurred that, at day 11 after stroke, was associated with hippocampus up-regulation of tumor necrosis factor-α (TNF-α), BAX, activated extracellular signal-regulated kinases (ERK1/2), c-jun N-terminal kinases (JNK1/2) and caspase-3, down-regulation of Bcl-2, and neuronal loss. Treatment for 11days with the selective melanocortin MC₄ receptor agonist RO27-3225, as well as with the well known non-selective [Nle⁴,D-Phe⁷]α-melanocyte-stimulating hormone (NDP-α-MSH) as a reference non-selective melanocortin, counteracted the inflammatory and apoptotic responses, as indicated by the changes in TNF-α, BAX, ERK1/2, JNK1/2, caspase-3 and Bcl-2 protein expression. Furthermore, melanocortin treatment reduced neuronal loss and dose-dependently improved learning and memory. These positive effects were associated with overexpression of Zif268, an immediate early gene involved in injury repair, synaptic plasticity and memory formation. Pharmacological blockade of MC₄ receptors with the selective MC₄ receptor antagonist HS024 prevented all effects of RO27-3225 and NDP-α-MSH. These data give direct evidence that stimulation of MC₄ receptors affords neuroprotection and promotes functional recovery from stroke, by counteracting prolonged and/or recurrent inflammatory and apoptotic responses, and likely by triggering brain repair pathways.
authors.affiliation: Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Spaccapelo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Maria
authors.initials: M
authors.lastname: Galantucci
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Davide
authors.initials: D
authors.lastname: Zaffe
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D002452:Cell Count; D005849:Gerbillinae; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008568:Memory / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology
chemical_list: D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; C560214:butir-His-Phe-Arg-Trp-Sar-NH2