The pathogenesis of stroke involves inflammation, apoptosis, and excitotoxicity, 
which is mediated in part by neuronal NO synthase (nNOS) activation. Ghrelin, an 
endogenous 28-amino acid peptide, is shown to exert antiapoptotic and 
anti-inflammatory properties. However, the effect of ghrelin in permanent focal 
cerebral ischemia and the role of the vagus nerve in its action remain unknown. 
To study this, male adult Sprague-Dawley rats underwent right-sided permanent 
middle cerebral artery occlusion (MCAO) with or without prior bilateral truncal 
vagotomy. This was followed by infusion of 4 nmol human ghrelin as treatment or 
saline as vehicle. Neurological deficit was assessed at 24 h after MCAO. Rats 
were killed thereafter, and brains were rapidly removed and analyzed for infarct 
size, markers of inflammation, excitotoxicity, and apoptosis. Compared with 
vehicle treatment, human ghrelin treatment in vagus nerve-intact rats after MCAO 
showed marked reduction in neurological deficit by 57% and infarct size by 25%. 
Middle cerebral artery occlusion resulted in increases in cerebral TNF-α, IL-6, 
neutrophil trafficking, matrix metalloproteinase 9 and nNOS gene expression, 
nitrotyrosine, and apoptosis. Human ghrelin treatment in vagus nerve-intact rats 
significantly decreased the above measurements. Human ghrelin treatment also 
improved 7-day survival and significantly decreased neurological deficit over 
the entire 7 days after MCAO in vagus nerve-intact rats compared with vehicle. 
Prior vagotomy, however, blunted human ghrelin's neuroprotective effects on 
neurological deficit, infarct size, TNF-α, neutrophil trafficking, 
nitrotyrosine, and apoptosis. Human ghrelin is thus a neuroprotective agent that 
inhibits inflammation, nNOS activity, and apoptosis in focal cerebral ischemia 
through a vagal pathway.