Neuroprotection in focal cerebral ischemia owing to delayed treatment with melanocortins.
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.
Giuliani
Daniela
D
Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy.
Ottani
Alessandra
A
Mioni
Chiara
C
Bazzani
Carla
C
Galantucci
Maria
M
Minutoli
Letteria
L
Bitto
Alessandra
A
Zaffe
Davide
D
Botticelli
Annibale R
AR
Squadrito
Francesco
F
Guarini
Salvatore
S
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
D018696:Neuroprotective Agents; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-