Abstracts

Rationale: The results of clinical trials using antiepileptic drugs (AEDs) to prevent posttraumatic epileptogenesis (PTE) have been disappointing. Effective prophylactic therapies remain elusive. In this study we tested the efficacy of the antiepileptic agent brivaracetam (BRV), a 4-n-propyl analogue of levetiracetam, in the controlled cortical impact (CCI) model of traumatic brain injury (TBI) in the rat. Methods: Rats were subjected to severe CCI trauma and then given a single dose of BRV after injury. Briefly, Sprague-Dawley rats (75 – 100g) were anesthetized with 2 – 5% isoflurane and placed in the stereotaxic frame. A 6.0 mm craniotomy centered between the lambda and the bregma was made over the right somatosensory cortex. A cortical impactor (5.0 mm diameter) was driven to a depth of 2.0 mm at a velocity of 4.0 m/s to induce a TBI. A single dose of BRV (21 mg/kg or 100 mg/kg, i.p.) was administered to rats immediately (0 – 2 min) or 30 min after injury. Control animals were also subjected to CCI injury, but received only the saline vehicle. At 3 – 4 weeks after TBI, rats were euthanized and coronal slices (400 µm thick; 4 slices per rat) of somatosensory cortex were prepared from regions proximal to the injury site from each rat for electrophysiological assessment. Slices were maintained in vitro and examined for spontaneous and stimulus-evoked epileptiform activity. Results: BRV-21 mg/kg administered immediately after injury significantly reduced the number of rats that exhibited evoked epileptiform discharges by approximately 50%, from 100.0% of saline-treated CCI rats (n=19) to 53.8 ± 13.8% of BRV-21 rats (n=13; mean ± SEM). BRV-21 treatment also reduced the proportion of total brain slices from CCI rats that exhibited evoked epileptiform bursts, from 74.4 ± 4.7% of slices ( n=86) in saline-treated controls to 19.6 ± 5.6% of slices (n=51) from BRV-21 rats. In addition, BRV-21 significantly inhibited the development of spontaneous epileptiform activity, with 7.7 ± 7.4% of BRV-21-treated rats exhibiting interictal- or ictal-like discharges compared to 44.4 ± 11.7% of saline controls; a nearly six-fold reduction. BRV-21 also reduced the proportion of brain slices that exhibited spontaneous epileptiform discharges, from 25.0 ± 8.8% of slices in saline controls to 2.0 ± 1.9% of slices from BRV-treated rats. The efficacy of BRV-100 mg/kg administered to rats at 30 min after injury was tested, and was found to be as efficacious as BRV-21 given immediately after injury. BRV-100 significantly reduced the proportion of CCI-injured rats that expressed evoked epileptiform activity (to 66.7 ± 13.6%; n=12 rats), as well as the percentage of total brain slices exhibiting evoked epileptiform burst discharges (20.8% ± 5.9%, n=48 slices). Most strikingly, BRV-100 prevented the development of spontaneous epileptiform activity after cortical trauma, with no BRV-100 treated rats exhibiting spontaneous interictal- or ictal-like discharges. Conclusions: A single dose of BRV administered immediately (21 mg/kg) or 30 min (100 mg/kg) after cortical injury significantly reduced the development of both evoked and spontaneous epileptiform activity in rats. These results suggest that BRV may effectively interfere with PTE. Funding: Supported by a grant from UCB Biopharma.