Summary:Purpose: This study evaluated the modulatory effects of topiramate (TPM) on various subtypes of recombinant rat y-aminobutyric acid A (GABA,) receptors expressed in Xenopus oocytes.Methods: Specific subunits of GABA, receptors were expressed in Xenopus oocytes. Voltage-clamp recordings of currents were performed after application of TPM (1-100 pM) to these oocytes in the presence or absence of GABA.
Results:In a concentration-dependent fashion, TPM (1-100 pM) reversibly inhibited GABA-evoked C1-currents in oocytes expressing either a , p2y2S and a2P2y2S recombinant GABA, receptors and reduced the current-fading rate in a, P,y,S-expressing oocytes. Topiramate was effective at GABA concentrations of 1-10 pM but not at 100 pM. Topiramate (1-100 @i') potentiated GABA-evoked C1-currents and increased the fading rate in oocytes expressing the a6p2y2S GABA, receptor. It had no effect on C1-currents mediated through the a4p2y2S receptor or through the mixed population of GABA, receptors expressed from rat brain mRNA. In general, the observed effects of TPM were more pronounced on fading rates than on peak C1-currents.Conclusions: These results indicate that TPM may affect desensitization of GABA, receptors as assessed by changes in the fading rates of GABA-evoked C1-currents, possibly by effects on second-messenger systems. Key Words: Topiramate-GABA, receptors-Epilepsy-Mechanism of action.Topiramate (TPM), a structurally novel antiepileptic drug (AED), has an unknown mechanism of action. In preclinical evaluations, TPM was effective in different models of epilepsy in rats and mice (1,2), suggesting potential utility in the clinic. In vitro experiments revealed that TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests, including those related to y-aminobutyric acid (GABA) receptor function (2). However, recent studies reveal that TPM has numerous effects that might account for its anticonvulsant actions: TPM decreased spontaneous epileptiform burst duration, inhibited voltage-activated Na+ channels, blocked kainate-type glutamate receptor currents in cultured rat hippocampal pyramidal neurons, and it potentiated GABA-evoked peak whole-cell currents in cortical neurons (see accompanying articles in this issue). TPM at anticonvulsant concentrations also enhanced GABA, receptor-mediated C1-flux in cultured cerebellar granule neurons (3). Several AEDs, among them the benzodiazepines (BZDs) and barbiturates, appear to act via enhancement of GABAA receptors (4). The actions of TPM on GABAA receptors reported by GABAA receptors are prevalent and widely distributed throughout the central nervous system (CNS), mediating inhibitory synaptic transmission. They are members of the superfamily of ligand-gated membrane ion channels and are themselves a family of chloride ion channels, composed of multiple related but different subunits (al-6, pl-3, yl-3, 6, E, pl-3). These GABAA receptors are heteropentameric receptor complexes with distinct pharmacologic properties (4-7). Because G...