Lubeluzole treatment does not attenuate neurobehavioral dysfunction or CA3 hippocampal neuronal loss following traumatic brain injury in rats

Purpose: One of the downstream consequences of glutamate-induced NMDA (N-methyl-D-aspartate) receptor activation following traumatic brain injury (TBI) is production of nitric oxide (NO). In this study, we evaluated the ability of lubeluzole, a novel neuroprotective compound 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 function, and then sacrificed. Results: While brain injury resulted in significant cognitive and motor deficits, injured animals treated with lubeluzole did not differ in spatial memory performance, neuromotor score, or limb placing function from injured, vehicle-treated animals. Furthermore, there was no difference 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.