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Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex
S Suzuki1, K Kawakami, S Nishimura
1Shizuoka Higashi Hospital, National Epilepsy Center, Japan.
Abstract:
We investigated the effect of zonisamide, a new antiepileptic drug, on voltage-dependent Ca2+ currents in cultured neurons of rat cerebral cortex. Whole-cell voltage-clamp recordings demonstrated at least two distinct voltage-dependent Ca2+ currents: (1) a low-threshold, rapidly inactivating component, T-type Ca2+ current, which is sensitive to 100 microM Ni2+, and (2) a high-threshold, slowly inactivating (long-lasting) component, L-type Ca2+ current. Zonisamide, a new anticonvulsant effective against maximal electroshock (MES) seizures in mice reduced T-type Ca2+ current in a dose-dependent manner. The mean percentage of reduction was 59.5 +/- 7.2% at 500 microM, but zonisamide had no effect on L-type Ca2+ current. A methylated analog of zonisamide, which is ineffective against MES seizures in mice, was tested at a concentration of 500 microM, and reduced neither T-type nor L-type Ca2+ current. These findings suggest that the effects of zonisamide against MES seizures might occur through the reduction of T-type Ca2+ current. Because drugs that are effective against MES seizures are thought to prevent seizure discharge spread, T-type Ca2+ channels could underlie a cellular mechanism of spreading activity in epileptic seizures.
Insights
Zonisamide, an antiepileptic drug, effectively reduces T-type calcium currents in rat neurons. This action may explain its anticonvulsant effects against seizures by inhibiting seizure spread.
Area of Science:
- Neuroscience
- Pharmacology
- Epileptology
Background:
- Epilepsy is a neurological disorder characterized by recurrent seizures.
- Voltage-dependent calcium channels play a critical role in neuronal excitability and seizure generation.
- Zonisamide is a novel antiepileptic drug with demonstrated efficacy in animal models.
Purpose of the Study:
- To investigate the effects of zonisamide on voltage-dependent calcium (Ca2+) currents in cultured rat cerebral cortex neurons.
- To determine which specific calcium current subtypes are modulated by zonisamide.
- To explore the potential cellular mechanisms underlying zonisamide's anticonvulsant activity.
Main Methods:
- Whole-cell voltage-clamp recordings were utilized to measure calcium currents in cultured rat neurons.
- Neurons were exposed to varying concentrations of zonisamide and its analog.
- T-type and L-type calcium currents were identified and their sensitivity to zonisamide was assessed.
Main Results:
- Two distinct calcium currents were identified: low-threshold T-type and high-threshold L-type.
- Zonisamide dose-dependently reduced T-type Ca2+ current by up to 59.5% at 500 microM.
- Zonisamide exhibited no significant effect on L-type Ca2+ current.
- A non-anticonvulsant analog of zonisamide did not affect either current type.
Conclusions:
- Zonisamide selectively inhibits T-type calcium currents in rat cerebral cortex neurons.
- The reduction of T-type calcium current by zonisamide may be the primary mechanism for its anticonvulsant efficacy against maximal electroshock seizures.
- T-type calcium channels could represent a key cellular target for preventing seizure discharge spread in epilepsy.