title: A substance P antagonist reduces axonal injury and improves neurologic outcome when administered up to 12 hours after traumatic brain injury.
abstract: 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.
authors.affiliation: Discipline of Anatomy and Pathology, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: James J
authors.initials: JJ
authors.lastname: Donkin
authors.forename: Ibolja
authors.initials: I
authors.lastname: Cernak
authors.forename: Peter C
authors.initials: PC
authors.lastname: Blumbergs
authors.forename: Robert
authors.initials: R
authors.lastname: Vink
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020833:Diffuse Axonal Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P