Severe traumatic brain injury (TBI) induces seizures or status epilepticus (SE) in 20-30% of patients during the acute phase. We hypothesized that severe TBI induced with lateral fluid-percussion injury (FPI) triggers post-impact SE. Adult Sprague-Dawley male rats were anesthetized with isoflurane and randomized into the sham-operated experimental control or lateral FPI-induced severe TBI groups. Electrodes were implanted right after impact or sham-operation, then videoelectroencephalogram (EEG) monitoring was started. In addition, video-EEG was recorded from naïve rats. During the first 72 h post-TBI, injured rats had seizures that were intermingled with other epileptiform EEG patterns typical to nonconvulsive SE, including occipital intermittent rhythmic delta activity, lateralized or generalized periodic discharges, spike-and-wave complexes, poly-spikes, poly-spike-and-wave complexes, generalized continuous spiking, burst suppression, or suppression. Almost all (98%) of the electrographic seizures were recorded during 0-72 h post-TBI (23.2-17.4 seizures/rat). Mean latency from the impact to the first electrographic seizure was 18.4-15.1 h. Mean seizure duration was 86-57 sec. Analysis of high-resolution videos indicated that only 41% of electrographic seizures associated with behavioral abnormalities, which were typically subtle (Racine scale 1-2). Fifty-nine percent of electrographic seizures did not show any behavioral manifestations. In most of the rats, epileptiform EEG patterns began to decay spontaneously on Days 5-6 after TBI. Interestingly, also a few sham-operated and naïve rats had post-operation seizures, which were not associated with EEG background patterns typical to non-convulsive SE seen in TBI rats. To summarize, our data show that lateral FPI-induced TBI results in non-convulsive SE with subtle behavioral manifestations; this explains why it has remained undiagnosed until now. The lateral FPI model provides a novel platform for assessing the mechanisms of acute symptomatic non-convulsive SE and for testing treatments to prevent post-injury SE in a clinically relevant context.

P-glycoprotein (P-gp) has been associated with pharmacoresistance and mechanisms regulating the membrane potential. However, at present it is unknown if P-gp overexpression in brain is associated with changes in membrane depolarization in refractory epilepsy. Experiments were designed to evaluate the membrane depolarization and P-gp overexpression induced by repetitive pentilenetetrazole (PTZ)-induced-seizures. Wistar rats were daily treated with PTZ during 4 to 7 days (PTZ4 and PTZ7 groups), and the brain was used to evaluate membrane potential by in vitro electrophysiological procedures and using bis-oxonol dye, [bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4(3)], a fluorescence dye voltage-sensitive to membrane potentials. Rats with repetitive PTZ-induced seizures demonstrated lower phenytoin-induced anticonvulsant effects, increased number of DiBAC4(3) fluorescence cells and P-gp overexpression in hippocampus and neocortex, as well as augmentation of the induced fEPSP in CA1 field. These changes were more evident in PTZ7 group. Phenytoin or phenytoin plus nimodipine (a P-gp antagonist) avoided the enhanced fEPSP and decreased DiBAC4(3) fluorescence in animals from PTZ4 group. However, in PTZ7 group these effects were evident only when phenytoin was combined with nimodipine. An additional flow cytometry study demonstrated increased intracellular accumulation of DiBAC4(3) in K562 leukemic cells that overexpress MDR-1 and COX-2 genes, and are refractory to specific cytotoxic agents. These results represent the first evidence supporting the notion that brain P-gp overexpression contributes to a progressive seizure-related membranes depolarization in hippocampus and neocortex. Further experiments should be carried out to confirm the role of P-gp on membrane depolarization and epileptogenesis process.

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These findings suggest that acute infiltration of T-cells into the brain parenchyma after TBI is a contributing factor to poor post-injury recovery.

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