Topiramate blocks kainate-evoked cobalt influx into cultured neurons.
This study evaluated topiramate (TPM) antagonism of glutamate receptors activated by kainate.



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).



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).



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
S
S
Anticonvulsant Screening Project, Department of Pharmacology and Toxicology, University of Utah, College of Pharmacy, Salt Lake City 84112, USA.
White
H S
HS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003035:Cobalt / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000378:metabolism; D000077236:Topiramate
D000927:Anticonvulsants; D002118:Calcium; D002413:Cations, Divalent; D003035:Cobalt; D018691:Excitatory Amino Acid Antagonists; D005632:Fructose; D007608:Kainic Acid; D008274:Magnesium; D011810:Quinoxalines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D000077236:Topiramate; C056723:FG 9041