Effects of Topiramate on Sustained Repetitive Firing and Spontaneous Recurrent Seizure Discharges in Cultured Hippocampal Neurons

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Abstract
In this study, we examined the effects of topiramate (TPM) on the electrophysiologic properties of cultured rat hippocampal pyramidal neurons. Whole-cell current-clamp recording techniques were used to determine the effects of TPM on sustained repetitive firing (SRF), spontaneous epileptiform-burst firing, and spontaneous recurrent seizures (SRS). Topiramate at therapeutic concentrations (10-100 microM) significantly decreased or abolished SRF in a dose-dependent and partially reversible manner. When transiently exposed to a medium in which Mg2+ is omitted, hippocampal neurons in culture develop SRS ("epilepsy") and epileptiform discharges. Application of TPM at concentrations ranging from 10 to 100 microM to cells displaying seizure activity caused a concentration-dependent decrease in the number of action potentials within a burst and in the average duration of epileptiform activity. Both effects were partially reversed during a 5- to 30-min drug washout period. These effects on the electrophysiologic properties of cultured neurons are consistent with the concept that TPM exerts modulatory effects on voltage-dependent Na+ and/or Ca2+ conductances responsible for the generation and propagation of action potentials. Topiramate also may inhibit synaptic conductances responsible for transmission of epileptiform discharges.