Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant topiramate

The actions of the antiepileptic drug topiramate (TPM) on Na+ currents were assessed using whole-cell patch-clamp recordings in dissociated neocortica l neurons and intracellular recordings in neocortical slices. Relatively lo w TPM concentrations (25-30 mu M) slightly inhibited the persistent fractio n of Nai current in dissociated neurons and reduced the Na+-dependent long- tasting action potential shoulders, which can be evoked in layer V pyramida l neurons after Ca++ and K+ current blockade. Conversely, the same drug con centrations were ineffective in reducing the amplitude of the fast Na+-depe ndent action potentials evoked in slices or the peak of transient Na+ (I-Na f) current evoked in isolated neurons from a physiological holding potentia l. Consistent I-Naf inhibition became, however, evident only when the neuro nal membrane was kept depolarized to enhance resting Na+ channel inactivati on. TPM (100 mu M) was ineffective on the voltage dependence of activation but induced a leftward shift of the steady-state I-Naf inactivation curve. The drug-induced inhibitory effect increased with the duration of membrane depolarization, and the recovery of I-Naf after long membrane depolarizatio ns was slightly delayed in comparison with that observed under control cond itions. The obtained evidence suggests that the anticonvulsant action of TP M may operate by stabilizing channel inactivation, which can be induced by depolarizing events similar to those occurring in chronic epileptic conditi ons. Concurrently, the slight but significant inhibition of the persistent fraction of the Na+ current, obtained with the application of relatively lo w TPM concentrations, may contribute toward its anticonvulsant effectivenes s by modulating the near-threshold depolarizing events that are sustained b y this small current fraction.