title: Neuroprotection in focal cerebral ischemia owing to delayed treatment with melanocortins.
abstract: In gerbils subjected to transient global cerebral ischemia, melanocortin peptides produce long-lasting protection with a broad time window, and through the activation of central nervous system melanocortin MC(4) receptors. Here we aimed to investigate whether melanocortins are neuroprotective also in a rat model of focal cerebral ischemia induced by intrastriatal microinjection of endothelin-1. The vasoconstrictor agent endothelin-1 caused a significant impairment in spatial learning and memory, as well as in sensory-motor orientation and limb use, associated with severe striatal morphological damage including intense neuronal death and an almost complete myelin degradation. Treatment of ischemic rats with a nanomolar dose (340 microg/kg/day i.p. for 11 days, beginning 3 h or 9 h after endothelin-1 microinjection) of the melanocortin analog [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) significantly reduced striatal damage, and improved subsequent functional recovery, with all scheduled NDP-alpha-MSH treatments. Pharmacological blockade of melanocortin MC(4) receptors prevented the protective effect of NDP-alpha-MSH. Our findings give evidence that melanocortins are neuroprotective, with a broad time window, also in a severe model of focal cerebral ischemia, and suggest that melanocortin MC(4) receptor agonists could produce neuroprotection in different experimental models of ischemic stroke.
authors.affiliation: Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.forename: Chiara
authors.initials: C
authors.lastname: Mioni
authors.forename: Carla
authors.initials: C
authors.lastname: Bazzani
authors.forename: Maria
authors.initials: M
authors.lastname: Galantucci
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Davide
authors.initials: D
authors.lastname: Zaffe
authors.forename: Annibale R
authors.initials: AR
authors.lastname: Botticelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008568:Memory / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-