title: A substance P antagonist improves outcome when administered 4 h after onset of ischaemic stroke.
abstract: Previous studies have suggested that substance P (SP) plays a critical role in the development of brain oedema and functional deficits following traumatic brain injury and that SP receptor antagonism may improve outcome. No studies have described such a role in ischemic stroke. The present study characterized the effects of the NK1 tachykinin receptor antagonist, n-acetyl-L-tryptophan (NAT), on blood-brain barrier (BBB) breakdown, oedema formation, infarct volume and functional outcome following reversible ischemic stroke in rats. Ischemia was induced using a reversible thread model of middle cerebral artery occlusion where occlusion was maintained for 2 h before reperfusion. Animals received either NAT or equal volume saline vehicle intravenously at 2 h post-reperfusion. Ischaemic stroke resulted in increased perivascular SP immunoreactivity at 24 h. Administration of NAT significantly reduced oedema formation and BBB permeability at 24 h post-ischemia and significantly improved functional outcome as assessed over 7 days. There was no effect on infarct volume. We conclude that inhibition of SP activity with a NK1 tachykinin receptor antagonist is effective in reducing cerebral oedema, BBB permeability and functional deficits following reversible ischemia and may therefore represent a novel therapeutic approach to the treatment of ischaemic stroke.
authors.affiliation: Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia. Renee.Turner@adelaide.edu.au
authors.forename: Renée J
authors.initials: RJ
authors.lastname: Turner
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Helps
authors.forename: Emma
authors.initials: E
authors.lastname: Thornton
authors.forename: Robert
authors.initials: R
authors.lastname: Vink
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D011480:Protease Inhibitors; D018040:Receptors, Neurokinin-1; D013373:Substance P; C006392:N-acetyltryptophan; D014364:Tryptophan