Cellular actions of topiramate: Blockade of kainate-evoked inward currentsin cultured hippocampal neurons

Purpose: This study was undertaken to evaluate the effects of topiramate (T PM) on excitatory amino acid-evoked currents. Methods: Kainate and N-methyl-D-aspartate (NMDA) were applied to cultured r at hippocampal neurons by using a concentration-clamp apparatus to selectiv ely activate the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)/kainate and NMDA receptor subtypes, respectively. The evoked membrane currents were recorded by using perforated-patch whole-cell voltage-clamp techniques. Results: TPM partially blocked kainate-evoked currents with an early-onset reversible phase (phase I) and a late-onset phase (phase II) that occurred after a 10- to 20-min delay and did not reverse during a 2-h washout period . Application of dibutyryl cyclic adenosine monophosphate (cAMP; 2 mM) duri ng washout after phase II block enhanced reversal, with the kainate current amplitude being restored by approximate to 50%. Phase II but not phase I b lock was prevented by prior application of okadaic acid (1 mu M), a broad-s pectrum phosphatase inhibitor, suggesting that phase II block may be mediat ed through interactions with intracellular intermediaries that alter the ph osphorylation state of kainate-activated channels. Topiramate at 100 mu M b locked kainate-evoked currents by 90% during phase II, but had no effect on NMDA-evoked currents. The median inhibitory concentration (IC50) values fo r phase I and II block of kainate currents were 1.6 and 4.8 mu M, respectiv ely, which are within the range of free serum levels of TPM in patients. Conclusions: The specific blockade of the kainate-induced excitatory conduc tance is consistent with the ability of TPM to reduce neuronal excitability and could contribute to the anticonvulsant efficacy of this drug.