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PURPOSE: This study evaluated topiramate (TPM) antagonism of glutamate receptors activated by kainate. METHODS: The ability of TPM (3-30 microM) to attenuate kainate (300 microM)-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 microM). 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 microM, and complete inhibition was observed at 30 microM. Maximal inhibition of Co2+ uptake required pretreatment with TPM for > or =30 minutes before stimulation by kainate. The effect of 30 microM TPM on Co2+ uptake was similar to that of 10 microM 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 alpha-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 developmentally regulated. This observation may provide insight into the molecular biology underlying the pathophysiology of seizure disorders and antiepileptic drug resistance.
Skradski et al. (Sat,) studied this question.