Topiramate blocks kainate-evoked cobalt influx into cultured neurons

Purpose: This study evaluated topiramate (TPM) antagonism of glutamate rece ptors activated by kainate. Methods: The ability of TPM (3-30 mu M) to attenuate kainate (300 mu M)-act ivated cobalt (Co2+) flux through nonselective cation channels permeable to Co2+, Mn2+, and Ca2+ into cultured cerebellar granule neurons [9-14 days i n vitro (div)] was investigated. Results were compared with those obtained with the non-N-methyl-D-aspartate (non-NMDA) antagonist 6,7-dinitroquinoxal one-2,3-dione (DNQX) (10 mu M). 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 mu M, and complete inhibition was observed at 30 mu M Ma ximal inhibition of Co2+ uptake required pretreatment with TPM for greater than or equal to 30 minutes before stimulation by kainate. The effect of 30 mu M TPM on Co2+ uptake was similar to that of 10 mu M 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 e ffect of TPM on some types of alpha-amino-3-hydroxy-5-methylisoxazole-4-pro prionic acid (AMPA) and/or kainate receptors, and specifically suggest that TPM interacts with a Ca2+-permeable non-NMDA receptor that is developmenta lly regulated. This observation may provide insight into the molecular biol ogy underlying the pathophysiology of seizure disorders and antiepileptic d rug resistance.