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: Renée J Turner, Stephen C Helps, Emma Thornton, Robert Vink
• Journal: Brain research (Brain Res) Vol. 1393 Pg. 84-90 (Jun 01 2011) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 21466790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Neurokinin-1 Receptor Antagonists
• Protease Inhibitors
• Receptors, Neurokinin-1
• Substance P
• N-acetyltryptophan
• Tryptophan

Topics

• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Brain Edema (drug therapy)
• Brain Ischemia (drug therapy)
• Disease Models, Animal
• Drug Administration Schedule
• Infarction, Middle Cerebral Artery (drug therapy)
• Male
• Neurokinin-1 Receptor Antagonists
• Protease Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Neurokinin-1 (metabolism)
• Recovery of Function (drug effects, physiology)
• Substance P (antagonists & inhibitors, metabolism)
• Time Factors
• Tryptophan (analogs & derivatives, pharmacology)