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: Daniela Giuliani, Alessandra Ottani, Chiara Mioni, Carla Bazzani, Maria Galantucci, Letteria Minutoli, Alessandra Bitto, Davide Zaffe, Annibale R Botticelli, Francesco Squadrito, Salvatore Guarini
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 570 Issue 1-3 Pg. 57-65 (Sep 10 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17588564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• alpha-MSH
• MSH, 4-Nle-7-Phe-alpha-

Topics

• Animals
• Brain (drug effects, pathology, physiopathology)
• Brain Ischemia (drug therapy, physiopathology)
• Male
• Memory (drug effects)
• Neuroprotective Agents (therapeutic use)
• Psychomotor Performance (drug effects)
• Rats
• Rats, Wistar
• alpha-MSH (analogs & derivatives, therapeutic use)