A substance P antagonist reduces axonal injury and improves neurologic outcome when administered up to 12 hours after traumatic brain injury

James J Donkin; I Cernak; P C Blumbergs; R Vink

doi:10.1089/neu.2010.1632

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A substance P antagonist reduces axonal injury and improves neurologic outcome when administered up to 12 hours after traumatic brain injury

Journal article

Peer reviewed

A substance P antagonist reduces axonal injury and improves neurologic outcome when administered up to 12 hours after traumatic brain injury

James J Donkin, I Cernak, P C Blumbergs and R Vink

Journal of Neurotrauma, Vol.28(2), pp.217-224

2011

DOI: https://doi.org/10.1089/neu.2010.1632

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Abstract

neurogenic inflammation

neuropeptides

neurotrauma

neurokinin 1 (NK1) antagonist

Previous studies have demonstrated that the compound N-acetyl-L-tryptophan (NAT) reduces brain edema and improves functional outcome following traumatic brain injury (TBI). In this study we examined whether this effect was mediated via the neurokinin-1 receptor, and whether there was an effect on axonal injury. We also explored whether the compound was effective, even when administered at delayed time points. Male Sprague-Dawley rats were subject to acceleration-induced, diffuse TBI and administered NAT, its inactive D-enantiomer, or saline vehicle. In contrast to NAT (2.5 mg/kg), the inactive D-enantiomer was ineffective at improving rotarod motor performance after TBI. NAT also improved cognitive outcome as assessed by the Morris water maze and novel object recognition tests, and reduced axonal injury at 5 and 24 h after TBI as assessed by amyloid precursor protein immunohistochemistry. However, efficacy of the membrane-impermeable NAT was limited to administration within 5 h, whereas administration of a form of NAT, L-732,138 (47 mg/kg), in which a trifluoromethyl benzyl ester group has been added, making it highly lipid soluble and able to cross the intact blood-brain barrier, significantly improved motor outcome, even when administration was delayed by as much as 12 h. We conclude that the neuroprotective effects of NAT are receptor-mediated, and that administration of the membrane-permeable form of the compound can be effective even up to 12 h after TBI. © 2011, Mary Ann Liebert, Inc.

Details

Title: A substance P antagonist reduces axonal injury and improves neurologic outcome when administered up to 12 hours after traumatic brain injury
Authors: James J Donkin (Author) - University of Adelaide
I Cernak (Author) - Johns Hopkins University, United States
P C Blumbergs (Author) - University of Adelaide
R Vink (Author) - University of Adelaide
Publication details: Journal of Neurotrauma, Vol.28(2), pp.217-224
Publisher: Mary Ann Liebert, Inc. Publishers
Date published: 2011
DOI: 10.1089/neu.2010.1632
ISSN: 0897-7151
Organisation Unit: UniSC Clinical Trials Centre; University of the Sunshine Coast, Queensland
Language: English
Record Identifier: 99450426602621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Clinical Neurology; Critical Care Medicine; Neurosciences

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