Cellular Actions of Topiramate: Blockade of Kainate-Evoked Inward Currents in Cultured Hippocampal Neurons

Authors


Address correspondence and reprint requests to Dr. D. A. Coulter at Department of Neurology, University School of Medicine, 3516 Civic Center Blvd. Philadelphia, PA 19104-4318.

Summary:

Purpose: This study was undertaken to evaluate the effects of topiramate (TPM) on excitatory amino acid-evoked currents.

Methods:Kainate and N-methyl-d-aspartate (NMDA) were applied to cultured rat hippocampal neurons by using a concentration-clamp apparatus to selectively activate the AMPA (α-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 2-min delay and did not reverse during a 2-h washout period. Application of dibutyryl cyclic adenosine monophosphate (cAMP; 2 mM) during washout after phase II block enhanced reversal, with the kainate current amplitude being restored by =50%. Phase II but not phase I block was prevented by prior application of okadaic acid (1 μM), a broad-spectrum phosphatase inhibitor, suggesting that phase II block may be mediated through interactions with intracellular intermediaries that alter the phosphorylation state of kainate-activated channels. Topiramate at 100 μM blocked kainate-evoked currents by 90% during phase II, but had no effect on NMDA-evoked currents. The median inhibitory concentration (IC50) values for phase I and II block of kainate currents were 1·6 and 4·8 μM, respectively, which are within the range of free serum levels of TPM in patients.

Conclusions:The specific blockade of the kainate-induced excitatory conductance is consistent with the ability of TPM to reduce neuronal excitability and could contribute to the anti-convulsant efficacy of this drug.

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