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: Alessandra Ottani, Daniela Giuliani, Chiara Mioni, Maria Galantucci, Letteria Minutoli, Alessandra Bitto, Domenica Altavilla, Davide Zaffe, Annibale R Botticelli, Francesco Squadrito, Salvatore Guarini
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 29 Issue 3 Pg. 512-23 (Mar 2009) ISSN: 1559-7016 [Electronic] United States
• PMID: 19018269 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Endothelin-1
• Receptors, Nicotinic
• Tumor Necrosis Factor-alpha
• alpha-MSH
• MSH, 4-Nle-7-Phe-alpha-

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Brain Ischemia (complications)
• Corpus Striatum (drug effects, enzymology, metabolism, pathology)
• DNA Fragmentation (drug effects)
• Endothelin-1
• Liver (drug effects, enzymology, metabolism, pathology)
• Male
• Rats
• Rats, Wistar
• Receptors, Nicotinic (metabolism)
• Stroke (etiology, metabolism, pathology, prevention & control)
• Tumor Necrosis Factor-alpha (blood)
• Vagotomy
• Vagus Nerve (physiology)
• alpha-MSH (analogs & derivatives, pharmacology, therapeutic use)