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1 Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for the conversion of glutamate to glutamine, and for the detoxi®cation of ammonia. 2 We have investigated the eects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on GS activity in mouse brain. 3 Four hours after the ®nal dose, animals were sacri®ced and the brains removed for analysis of GS activity. 4 Both single and repeated doses of phenytoin and carbamazepine were found to reduce enzyme activity (P50.05). 5 Single doses of phenobarbitone, felbamate and topiramate were without eect, however repeated administration of these drugs dose-dependently reduced GS activity (P50.05). 6 Single and repeated doses of sodium valproate, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam and desglycinyl-remacemide were found to have no eect on GS activity. 7 The reduction in enzyme activity demonstrated is unlikely to be related to the anti-epileptic actions of these drugs, but may contribute to their toxicity.

These results contradict the reported increase in brain GABA concentrations with TPM. More detailed studies are required to determine the basis of this clinical observation and the extent to which it contributes to the antiepileptic activity of the drug.

Summary:Purpose: Topirainate (TPM) is a new antiepileptic agent with a multifactorial mechanism of action. The drug potentiates responses to y-aminobutyric acid (GABA) at the GABA, receptor and has inhibitory effects on neuronal sodium channels, the AMPA/kainate subtype of glutamate receptor, and carbonic anhydrase. Recent evidence has, however, suggested that the drug also increases brain GABA concentrations in humans. These studies were designed to investigate the neurochemical basis of this observation.Methods: Adult male mice were randomised into two groups and administered TPM (0-1,000 mg/kg) intraperitoneally either as a single dose or daily for 8 days. At 4 h after the final dose, brain tissues were analysed for concentrations of GABA, glutamate, and glutamine and for the activities of GABAtmnsaminase and glutamic acid decarboxylase. TPM levels in brain also were determined.Results: Single-dose and repeated TPM treatments were without effect on all of the parameters investigated, although the drug was detectable in the brain at doses of 3 1 0 mg/kg.Conclusions: These results contradict the reported increase in brain GABA concentrations with TPM. More detailed studies are required to determine the basis of this clinical observation and the extent to which it contributes to the antiepileptic activity of the drug. Key Words: Topiramate-Glutamate-GABA-Antiepileptic drugs-Epilepsy .Topiramate (TPM) is a new antiepileptic agent, licensed across the globe for the treatment of refractory epilepsy (1). It is a sugar sulphamate compound that has demonstrated efficacy in a range of experimental seizure models (2). TPM is effective against tonic extension induced by maximal electroshock (3) and prevents the motor manifestations of amygdaloid kindling (4). It elevates pentylenetetrazol (PTZ) seizure threshold in mice (3, but is only weakly effective against PTZ-induced clonic convulsions (3). In addition, the drug has shown efficacy in a rat model of ischaemia-induced epilepsy (6) and against tonic-and absence-like seizures in spontaneously epileptic rats and sound-induced seizures in DBAl2 mice (7).The mechanisms by which TPM exerts these anticonvulsant effects have been the subject of extensive research. The drug has a recognised inhibitory action at voltage-dependent sodium channels (8-10) and the AMPA/kainate subtype of glutamate receptor (1 1). TPM has also been proposed to potentiate responses to y-ami-

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