Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex

Abstract

We investigated the effect of zonisamide, a new antiepileptic drug, on voltage-dependent Ca 2+ currents in cultured neurons of rat cerebral cortex. Whole-cell voltage-clamp recordings demonstrated at least two distinct voltage-dependent Ca 2+ currents: 1. (1) a lowthreshold, rapidly inactivating component, T-type Ca 2+ current, which is sensitive to 100,μM Ni 2+, and 2. (2) a high-threshold, slowly inactivating (long-lasting) component, L-type Ca 2+ current. Zonisamide, a new anticonvulsant effective against maximal electroshock (MES) seizures in mice reduced T-type Ca 2+ current in a dose-dependent manner. The mean percentage of reduction was 59.5 ± 7.2% at 500 μM, but zonisamide had no effect on L-type Ca 2+ current. A methylated analog of zonisamide, which is ineffective against MES seizures in mice, was tested at a concentration of 500 μM, and reduced neither T-type nor L-type Ca 2+ current. These findings suggest that the effects of zonisamide against MES seizures might occur through the reduction of T-type Ca 2+ current. Because drugs that are effective against MES seizures are thought to prevent seizure discharge spread, T-type Ca 2+ channels could underlie a cellular mechanism of spreading activity in epileptic seizures.