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Keywords:

  • Topiramate;
  • Kainate;
  • Antiepileptic drugs;
  • Epilepsy

Summary:

Purpose: This study evaluated topiramate (TPM) antagonism of glutamate receptors activated by kainate.

Methods: The ability of TPM (3–30 μM) to attenuate kainate (300 μM)-activated cobalt (Co2+) flux through nonselective cation channels permeable to Co2+, Mn2+, and Ca2+ into cultured cerebellar granule neurons [9–14 days in vitro (div)] was investigated. Results were compared with those obtained with the non-N-methyl-d-aspartate (non-NMDA) antagonist 6,7-dinitroquinoxalone-2,3-dione (DNQX) (10 μM).

Results: Topiramate produced a concentration- and time-dependent inhibition of Co2+ uptake into cerebellar granule cells cultured 9–11 div. Inhibition was evident at 10 μM, and complete inhibition was observed at 30 μM. Maximal inhibition of Co2+ uptake required pretreatment with TPM for ges;30 minutes before stimulation by kainate. The effect of 30 μM TPM on Co2+ uptake was similar to that of 10 μM DNQX. However, TPM, unlike DNQX, did not affect kainate-evoked Co2+ uptake into older neurons (i.e., 13–14 div).

Conclusions: These results provide additional support for an antagonistic effect of TPM on some types of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and/or kainate receptors, and specifically suggest that TPM interacts with a Ca2+-permeable non-NMDA receptor that is develop-mentally regulated. This observation may provide insight into the molecular biology underlying the pathophysiology of seizure disorders and antiepileptic drug resistance.