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 again st maximal electroshock seizures, amygdala kindling, and spike-wave di scharges 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 a s a tool for estimating the effect of anticonvulsant drugs on GABA rec eptor function, topiramate was observed to enhance GABA-stimulated chl oride (Cl-) flux. Ar a therapeutic concentration, topiramate (10 mu M) enhanced GABA-stimulated (10 mu M) Cl- influx into cerebellar granule neurons but did not significantly increase Cl- influx alone. Phenytoi n (10 mu M) and acetazolamide (300 mu M) did not enhance GABA-stimulat ed Cl- influx. In patch-clamp electrophysiological studies, topiramate also enhanced GABA-evoked whole cell Cl- currents in mouse cerebral c ortical neurons in culture. In vivo anticonvulsant studies confirmed t hat topiramate, like phenytoin, is primarily effective against tonic e xtension seizures induced by maximal electroshock and is ineffective a gainst clonic seizures induced by the subcutaneously administered chem oconvulsants pentylenetetrazol (PTZ), bicuculline (Bic), and picrotoxi n (Pic). In contrast to phenytoin, topiramate, at a dose equivalent to the MES median effective dose (ED50), was found to elevate seizure th reshold as estimated by the intravenous PTZ seizure threshold test. Ta ken 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. (C) 1997 Elsevier Science B.V.