title: Lubeluzole treatment does not attenuate neurobehavioral dysfunction or CA3 hippocampal neuronal loss following traumatic brain injury in rats.
abstract: PURPOSE: One of the downstream consequences of glutamate-induced NMDA (N-methyl-D-aspartate) receptor activation following trau-matic brain injury (TBI) is production of nitric oxide (NO). In this study, we evaluated the ability of lubeluzole, a novel neuroprotective com-pound which downregulates the glutamate-activated nitric oxide pathway and blocks sodium and voltage-sensitive calcium channels, to improve behavioral and histological outcome in rats following TBI. METHODS: Rats were anesthetized and subjected to moderate lateral fluid percussion brain injury (2.4-2.6 atm) or were surgically prepared but not injured (sham). Fifteen minutes after injury, animals received a bolus of either vehicle (n = 12 injured, n = 14 uninjured) or lubeluzole (0.31 mg/kg, n = 12 injured, n = 8 uninjured) through the jugular vein followed by a one hour infusion of vehicle or lubeluzole (0.31 mg/kg). Animals were tested at 48 hours post-injury for cognitive performance in the Morris water maze, neuromotor function, and limb placing func-tion, and then sacrificed. RESULTS: While brain injury resulted in significant cognitive and motor deficits, injured animals treated with lubeluzole did not differ in spa-tial memory performance, neuromotor score, or limb placing function from injured, vehicle-treated animals. Furthermore, there was no differ-ence in the mean number of ipsilateral hippocampal CA3 neurons between injured rats treated with vehicle and those treated with lubeluzole. CONCLUSIONS: This single-dose study failed to demonstrate a beneficial effect of lubeluzole on the acute behavioral or histological sequelae following TBI.
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA,USA.
authors.forename: Dianne M.
authors.initials: DM
authors.lastname: O'Dell
authors.forename: Judith K.
authors.initials: JK
authors.lastname: Muir
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Florence M.
authors.initials: FM
authors.lastname: Bareyre
authors.forename: Kathryn E.
authors.initials: KE
authors.lastname: Saatman
authors.forename: Ramesh
authors.initials: R
authors.lastname: Raghupathi
authors.forename: Frank
authors.initials: F
authors.lastname: Welsh
authors.forename: Tracy K.
authors.initials: TK
authors.lastname: McIntosh