Exocytosis mechanism as a new targeting site for mechanisms of action of antiepileptic drugs.

Carbamazepine (CBZ) and zonisamide (ZNS) are effective antiepileptic drugs (AEDs) for the treatment of epilepsy and mood disorder. One of the mechanisms of action of CBZ and ZNS is inactivation of voltage-gated Na+ channel (VGSC). However, the major mechanism(s) of action of these AEDs is not clear yet. We have been exploring novel targeting mechanisms for the antiepileptic actions of CBZ and ZNS during the past ten years. In this report, we describe our hypothesis regarding the new targeting mechanisms for the antiepileptic action of AEDs. We determined an interaction between these AEDs and inhibitors of both voltage-sensitive Ca2+ channels (VSCCs) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) on neurotransmitter exocytosis using microdialysis. Perfusion with therapeutic concentrations of CBZ and ZNS increased basal neurotransmitter release. This stimulatory action was predominantly inhibited by inhibitors of N-type VSCC and syntaxin. CBZ and ZNS increased Ca2+-evoked release, an action selectively inhibited by inhibitors of N-type VSCC and syntaxin. CBZ and ZNS reduced K+-evoked release, an action predominantly inhibited by inhibitors of P-type VSCCs and synaptobrevin. These actions of CBZ and ZNS on neurotransmitter exocytosis could be observed under the condition of inhibition of VGSC using perfusion with tetrodotoxin. Our findings enhance our understanding of the mechanisms of action of CBZ and ZNS as AEDs, which possibly reduce P-type VSCCs/synaptobrevin-related exocytosis mechanisms during the depolarization stage, and simultaneously enhance N-type VSCCs/syntaxin-related exocytosis mechanisms at the resting stage.