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

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.