Concentration-effect studies with topiramate on selected enzymes and intermediates of the GABA shunt

Purpose: Topiramate (TPM) is a new antiepileptic agent with a multifactoria l mechanism of action. The drug potentiates responses to gamma-aminobutyric acid (GABA) at the GABA(A) receptor and has inhibitory effects on neuronal . sodium channels, the AMPA/kainate subtype of glutamate receptor, and carb onic 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 T PM (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 concent rations of GABA, glutamate, and glutamine and for the activities of GABA-tr ansaminase and glutamic acid decarboxylase. TPM levels in brain also were d etermined. Results: Single-dose and repeated TPM treatments were without effect on all of the parameters investigated, although the drug was detectable in the br ain at doses of greater than or equal to 10 mg/kg. Conclusions: These results contradict the reported increase in brain GABA c oncentrations 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.