Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold.
The anticonvulsant topiramate is effective in laboratory animals against maximal electroshock seizures, amygdala kindling, and spike-wave discharges and has demonstrated efficacy in humans for the treatment of complex partial seizures. However, its mechanism of action has yet to be clearly elucidated. When the chloride-sensitive fluorescent probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) was used as a tool for estimating the effect of anticonvulsant drugs on GABA receptor function, topiramate was observed to enhance GABA-stimulated chloride (Cl-) flux. At a therapeutic concentration, topiramate (10 microM) enhanced GABA-stimulated (10 microM) Cl- influx into cerebellar granule neurons but did not significantly increase Cl- influx alone. Phenytoin (10 microM) and acetazolamide (300 microM) did not enhance GABA-stimulated Cl- influx. In patch-clamp electrophysiological studies, topiramate also enhanced GABA-evoked whole cell Cl- currents in mouse cerebral cortical neurons in culture. In vivo anticonvulsant studies confirmed that topiramate, like phenytoin, is primarily effective against tonic extension seizures induced by maximal electroshock and is ineffective against clonic seizures induced by the subcutaneously administered chemoconvulsants pentylenetetrazol (PTZ), bicuculline (Bic), and picrotoxin (Pic). In contrast to phenytoin, topiramate, at a dose equivalent to the MES median effective dose (ED50), was found to elevate seizure threshold as estimated by the intravenous PTZ seizure threshold test. Taken together these results support the conclusion that enhancement of GABA-mediated Cl- flux may represent one mechanism that contributes to the anticonvulsant activity of topiramate.
White
H S
HS
Department of Pharmacology and Toxicology, University of Utah, College of Pharmacy, Salt Lake City 84112, USA. swhite@msscc.med.utah.edu
Brown
S D
SD
Woodhead
J H
JH
Skeen
G A
GA
Wolf
H H
HH
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects*; D003292:Convulsants; D004357:Drug Synergism; D005456:Fluorescent Dyes; D005632:Fructose / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced; D000077236:Topiramate; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D018118:Chloride Channels; D003292:Convulsants; D005456:Fluorescent Dyes; D000077236:Topiramate; D005632:Fructose; D005680:gamma-Aminobutyric Acid; D010433:Pentylenetetrazole