title: Up-regulation of the canonical Wnt-3A and Sonic hedgehog signaling underlies melanocortin-induced neurogenesis after cerebral ischemia.
abstract: In experimental cerebral ischemia, melanocortin MC4 receptor agonists induce neuroprotection and neurogenesis with subsequent long-lasting functional recovery. Here we investigated the molecular mechanisms underlying melanocortin-induced neurogenesis. Gerbils were subjected to transient global cerebral ischemia, then they were treated every 12 h, and until sacrifice, with 5-bromo-2'-deoxyuridine (BrdU; to label proliferating cells), and the melanocortin analog [Nle(4),d-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) or saline. NDP-α-MSH increased hippocampus dentate gyrus (DG) expression of Wnt-3A, β-catenin, Sonic hedgehog (Shh), Zif268, interleukin-10 (IL-10) and doublecortin (DCX), as detected at days 3, 6 and 10 after the ischemic insult. Further, an elevated number of BrdU immunoreactive cells was found at days 3 and 10, and an improved histological picture with reduced neuronal loss at day 10, associated with learning and memory recovery. Pharmacological blockade of the Wnt-3A/β-catenin and Shh pathways, as well as of melanocortin MC4 receptors, prevented all effects of NDP-α-MSH. These data indicate that, in experimental brain ischemia, treatment with melanocortins acting at MC4 receptors induces neural stem/progenitor cell proliferation in the DG by promptly and effectively triggering the canonical Wnt-3A/β-catenin and Shh signaling pathways. Activation of these pathways is associated with up-regulation of the repair factor Zif268 and the neurogenesis facilitating factor IL-10, and it seems to address mainly toward a neuronal fate, as indicated by the increase in DCX positive cells.
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Spaccapelo
authors.forename: Maria
authors.initials: M
authors.lastname: Galantucci
authors.forename: Laura
authors.initials: L
authors.lastname: Neri
authors.forename: Miranda
authors.initials: M
authors.lastname: Contri
authors.forename: Roberto
authors.initials: R
authors.lastname: Pizzala
authors.forename: Roberto
authors.initials: R
authors.lastname: D'Amico
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sandrini
authors.forename: Davide
authors.initials: D
authors.lastname: Zaffe
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D005849:Gerbillinae; D053823:Hedgehog Proteins / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000378:metabolism; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000089622:Doublecortin Domain Proteins; D053823:Hedgehog Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D044105:Receptor, Melanocortin, Type 4; D060509:Wnt3A Protein; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-