The tetronic acid derivative losigamone is a new anticonvulsant drug with a mechanism of action that was previously unknown. The drug decreases the frequency of spontaneous action potentials and suppresses repetitive firing of neurons. Here we tested the hypothesis that losigamone suppresses the persistent Na+ current (I(NaP)) in hippocampal neurons of rat brain slices and in cultured hippocampal neurons. Whole-cell voltage clamp recordings from neurons of juvenile rats (P15-P25) were performed with pipettes filled with Cs-gluconate or CsF. After pharmacological block of K+ and Ca2+ currents I(NaP) was revealed by applying slow depolarizing voltage ramps from -70 to 0 mV. Losigamone (100-200 microM) was dissolved in DMSO (0.1%) and was applied by bath application or local pressure application. Losigamone induced a decrease in amplitude of I(NaP) at depolarized membrane potentials which was reversible in cultured neurons. When tetrodotoxin (TTX) was added to the bath, I(NaP) was blocked and only a residual non-specific outward cation current (I(cat)) remained. Losigamone had no obvious effect on responses to voltage ramps under these conditions. Thus, losigamone did not affect I(cat) or induce any additional currents. The data suggest that losigamone decreases neuronal excitability via a decrease in I(NaP).