Abstracts

Rationale: Traumatic brain injury (TBI) is a leading cause of acquired epilepsies, yet there are still no clinical therapies available to prevent posttraumatic epileptogenesis (PTE) following TBI. In this study, we examined the neuroprotective potential of the antiepileptic drug levetiracteam (LEV) to prevent PTE in rats following controlled cortical impact (CCI) injury.Methods: Rats were subjected to severe CCI trauma (2.0 mm depth) and then given a single dose of LEV (150 mg/kg, i.p.) immediately after injury. Control animals were also subjected to CCI injury but received only sham-drug injections of the saline vehicle. At 2 3 weeks after injury, cortical hyperexcitability and epileptiform activity were assessed via in vitro electrophysiological recordings of brain slices from LEV-treated and control animals. Coronal slices (400 ?m; 5 slices per rat) of somatosensory cortex were prepared from regions adjacent to the injury site and maintained in an interface recording chamber at 31.0 1.0 C. Slices were examined for epileptiform activity via intracellular and extracellular recordings obtained from cortical layer V. Evoked responses were triggered by single, brief electrical stimuli (200 ?s) applied in layer VI.Results: Post-injury administration of a single dose of LEV prevented PTE in rat neocortex after CCI injury, with slices from LEV-treated rats showing a much lower incidence of evoked and spontaneous epileptiform activity than slices from sham-treated control rats. In slices from sham-treated rats, intracellular recordings of layer V pyramidal cells showed both evoked and spontaneous epileptiform firing that was synchronized with population events recorded extracellularly. Evoked epileptiform activity was characterized by bursts of action potentials (APs) that were usually followed by recurrent, repetitive after-discharges, suggestive of interictal-like firing. Spontaneous events consisted of prolonged (2 10 sec) bursts of APs that were correlated with long duration, ictal-like population events. Evoked epileptiform discharges were observed in slices from all (100%) sham-treated rats, with at least 1 slice from each animal showing epileptiform activity. Spontaneous epileptiform discharges were recorded in slices from 75% of sham-treated animals. In comparison, evoked epileptiform activity was observed in slices from 57% of LEV-treated rats, and spontaneous epileptiform discharges were recorded in slices from only 14.3% of LEV-treated animals. LEV treatment also reduced the mean number of slices per rat that displayed epileptiform activity. In sham-treated rats, evoked and spontaneous epileptiform activity was recorded from 4.25 0.48 (81%) slices per rat and 0.75 0.24 (14%) slices per rat, respectively. In LEV-treated rats, evoked epileptiform discharges were recorded in 1.00 0.44 (21%) slices per rat, and spontaneous discharges in 0.14 0.14 (3%) slices per rat.Conclusions: These results suggest that post-injury administration of a single dose of LEV can prevent or reduce posttraumatic epileptogenesis after severe cortical neurotrauma.