Affiliations: Department of Neurosurgery, University of
Pennsylvania, Philadelphia, PA,USA
Note: [] Corresponding author: Dr. Tracy K. McIntosh, Department of
Neurosur-gery, University of Pennsylvania, 3320 Smith Walk, Room 105-C Hayden
Hall, Philadelphia, PA 19104, USA. Tel.: +1 215 573 3156; Fax: +1 215 573 3808;
E-mail: mcintosh@eniac.seas.upenn.edu
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 (2.42.6 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.
