Melanocortin peptides have been shown to produce neuroprotection in experimental
ischemic stroke. The aim of the present investigation was to identify the therapeutic treatment window of
melanocortins, and to determine whether these
neuropeptides chronically protect against damage consequent to
brain ischemia. A 10-min period of global
cerebral ischemia in gerbils, induced by occluding both common carotid arteries, caused impairment in spatial learning and memory (Morris test: four sessions from 4 to 67 days after the ischemic episode), associated with neuronal death in the hippocampus. Treatment with a nanomolar dose (340 microg/kg i.p., every 12 h for 11 days) of the
melanocortin analog [Nle(4), D-Phe(7)]
alpha-melanocyte-stimulating hormone (
NDP-alpha-MSH), starting 3-18 h after the ischemic episode, reduced hippocampal damage with improvement in subsequent functional recovery. The protective effect was long-lasting (67 days, at least) with all schedules of
NDP-alpha-MSH treatment; however, in the latest treated (18 h) gerbils, some spatial memory deficits were detected. Pharmacological blockade of
melanocortin MC(4) receptors prevented the protective effects of
NDP-alpha-MSH. Our findings indicate that, in conditions of
brain ischemia,
melanocortins can provide strong and long-lasting protection with a broad therapeutic treatment window, and with involvement of
melanocortin MC(4) receptors, 18 h being the approximately time-limit for
stroke late treatment to be effective.