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Keywords:

  • Topiramate;
  • Epilepsy;
  • Mechanism of action;
  • Patch-clamp techniques;
  • Excitatory amino acids;
  • Hippocampal neurons

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.