Effects of dibenzazepine compounds on Nav1.2 channels and neuronal network activity: A systematic comparison.

Voltage-gated Na+ channels are critical therapeutic targets of anti-seizure medications. The anti-seizure medications such as carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine acetate (ESL) of the dibenzazepine family are structurally similar, but a comparative analysis under identical conditions is lacking. Here, we rigorously compared their effects on biophysical properties of Nav1.2 Na + channels and effects on network properties in primary neuron cultures. HEK 293T cells stably expressing human Nav1.2 channels were employed to assess biophysical profiles using whole-cell patch clamp techniques. Additionally, the impact on neuronal networks in primary cortical neurons was evaluated using microelectrode array recordings. CBZ and OXC exhibited similar effects on voltage-dependent fast inactivation and recovery from inactivation. ESL and its active metabolite S-licarbazepine (S-Lic) also influenced fast inactivation, but their effects were less pronounced than those observed with CBZ. Notably, S-Lic exhibited comparatively small effects on use-dependent block. In these in vitro settings, all compounds had a subtle effect on slow inactivation. With regards to neuronal network activity, CBZ, OXC, and ESL induced substantial changes in spiking, bursting, and synchrony. S-Lic elicited significant and selective effects on network synchrony without effects on other parameters. In conclusion, CBZ, OXC and ESL exhibited similar activity profiles on properties of Nav1.2 channels and neuronal networks. The structurally similar S-Lic showed significantly less use-dependent blocking effect, and a selective effect on distributed network bursts. These results emphasize that structurally similar dibenzazepine anti-seizure medications can exhibit substantial differences in activity on the ion channel and network level.