The novel antiepileptic agent RWJ-333369-A, but not its analog
RWJ-333369, reduces regional cerebral edema without affecting neurobehavioral
outcome or cell death following experimental traumatic brain injury
Affiliations: Traumatic Brain Injury Laboratory, Department of
Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania | Department of Biobehavioral Nursing and Health
Systems, University of Washington, Seattle, WA, USA | A. I. Virtanen Institute for Molecular Sciences,
University of Kuopio, Kuopio, Finland | Department of Neurology, Kuopio University Hospital,
Finland | Veterans Administration Medical Center, Philadelphia,
Pennsylvania | The R.W. Johnson Pharmaceutical Research Institute
Spring House, Pennsylvania
Note: [] Corresponding author: Hilaire J. Thompson, PhD, Box 357266,
Seattle, WA 98195-7266, USA. Tel.: +1 206 616 5641; Fax: +1 206 543 3779;
E-mail: hilairet@u.washington.edu
Abstract: Purpose: To evaluate the therapeutic efficacy of two antiepileptic
compounds, RWJ-333369 and RWJ-333369-A in a well-established experimental model
of lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat. Methods: Anethestized Male Sprague-Dawley rats (n=227) were subjected to
lateral FP brain injury or sham-injury. Animals were randomized to receive
treatment with RWJ-333369 (60 mg/kg, p.o.) or its analog RWJ-333369-A
(60 mg/kg, p.o.), or vehicle (equal volume) at 15 minutes, 4, 8, and 24 hours
post-injury. In Study I, animals were assessed at 48 hours for acute motor and
cognitive function and then sacrificed to evaluate regional cerebral edema. In
Study II, animals were evaluated post-injury for motor function at 48 hours and
weekly thereafter from 1 to 4 weeks. Post-traumatic learning ability was
assessed 4 weeks post-injury, followed by evaluation of hemispheric tissue
loss. Results: In Study I, no improvement in acute memory or motor
function was observed following administration of either RWJ-333369 or
RWJ-333369-A in brain-injured animals compared to vehicle-treated,
brain-injured animals. However, brain-injured animals receiving treatment with
RWJ-333369-A had a significant reduction in post-traumatic cerebral edema in
both injured and contralateral hippocampus compared to brain-injured,
vehicle-treated controls (p<0.05). In Study II, treatment with either
compound did not result in any improvement of neuromotor function, learning
ability or change in lesion volume following brain injury.
