title: Vagus nerve mediates the protective effects of melanocortins against cerebral and systemic damage after ischemic stroke.
abstract: A vagus nerve-mediated, efferent cholinergic protective pathway activated by melanocortins is operative in circulatory shock and myocardial ischemia. Moreover, melanocortins have neuroprotective effects against brain damage after ischemic stroke. Here we investigated cerebral and systemic pathophysiologic reactions to focal cerebral ischemia in rats induced by intrastriatal microinjection of endothelin-1, and the possible protective role of the melanocortin-activated vagal cholinergic pathway. In the striatum and liver of saline-treated control rats, the activation of extracellular signal-regulated kinases, c-jun N-terminal kinases, and caspase-3, the increase in tumor necrosis factor-alpha (TNF-alpha) concentration and DNA fragmentation, as well as the increase in TNF-alpha plasma levels, occurred 10 and 20 h after the ischemic insult suggesting an activation of inflammatory and apoptotic responses. Treatment with [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH; 3 or 9 h after stroke) suppressed the inflammatory and apoptotic cascades at central and peripheral level. Bilateral vagotomy and pharmacologic blockade of peripheral nicotinic acetylcholine receptors blunted the protective effect of NDP-alpha-MSH. The present results show that focal brain ischemia in rats causes significant effects not only in the brain, but also in the liver. Moreover, our data support the hypothesis that a protective, melanocortin-activated, vagal cholinergic pathway is likely operative in conditions of ischemic stroke.
authors.affiliation: Section of Pharmacology, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Chiara
authors.initials: C
authors.lastname: Mioni
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: Domenica
authors.initials: D
authors.lastname: Altavilla
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; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002545:Brain Ischemia / Q000150:complications*; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D019332:Endothelin-1; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism; D020521:Stroke / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019332:Endothelin-1; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-