Vol. 288, Issue 3, 960-968, March 1999

Inhibition of Transient and Persistent Na⁺ Current Fractions by the New Anticonvulsant Topiramate

S. Taverna, G. Sancini, M. Mantegazza, S. Franceschetti and G. Avanzini

Istituto Neurologico C. Besta, Milano, Italy

The actions of the antiepileptic drug topiramate (TPM) on Na⁺ currents were assessed using whole-cell patch-clamp recordings in dissociated neocortical neurons and intracellular recordings in neocortical slices. Relatively low TPM concentrations (25-30 µM) slightly inhibited the persistent fraction of Na⁺ current in dissociated neurons and reduced the Na⁺-dependent long-lasting action potential shoulders, which can be evoked in layer V pyramidal neurons after Ca⁺⁺ and K⁺ current blockade. Conversely, the same drug concentrations were ineffective in reducing the amplitude of the fast Na⁺-dependent action potentials evoked in slices or the peak of transient Na⁺ (I_Naf) current evoked in isolated neurons from a physiological holding potential. Consistent I_Naf inhibition became, however, evident only when the neuronal membrane was kept depolarized to enhance resting Na⁺ channel inactivation. TPM (100 µM) 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 depolarizations was slightly delayed in comparison with that observed under control conditions. The obtained evidence suggests that the anticonvulsant action of TPM may operate by stabilizing channel inactivation, which can be induced by depolarizing events similar to those occurring in chronic epileptic conditions. Concurrently, the slight but significant inhibition of the persistent fraction of the Na⁺ current, obtained with the application of relatively low TPM concentrations, may contribute toward its anticonvulsant effectiveness by modulating the near-threshold depolarizing events that are sustained by this small current fraction.