A neurochemical study of the novel antiepileptic drug retigabine in mouse brain

The novel antiepileptic drug, retigabine, has been reported to have multipl e mechanisms of action, including potentiation of gamma -aminobutyric acid (GABA) and glutamate synthesis. We have investigated its effects on several GABA- and glutamate-related neurochemical parameters in mouse brain. Mice were administered retigabine either as a single dose or daily for 5 days. A t 4 h after dosing, brains were removed and analysed for GABA, glutamate, a nd glutamine concentrations and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single doses of retigabine significantly lowe red brain concentrations of glutamate and glutamine, Repeated treatment sig nificantly reduced the activity of GABA-transaminase. The drug was essentia lly without effect on all other parameters investigated. These results sugg est that retigabine blocks GABA metabolism rather than enhancing GABA synth esis. In addition, the drug may also lower brain concentrations of the exci tatory neurotransmitter glutamate and its precursor, glutamine. These effec ts may contribute to the antiepileptic action of retigabine. (C) 2000 Acade mic Press.