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

This is the authors' abstract. We don't add key points for this paper.

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 Na v 1.2 Na + channels and effects on network properties in primary neuron cultures. HEK 293T cells stably expressing human Na v 1.2 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 Na v 1.2 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. • All tested compounds show significant effects on Na v 1.2 voltage-dependence. • Differential effects are observed for recovery from fast inactivation of Na v 1.2 channels. • All compounds show similar effects on slow inactivation processes of Na v 1.2 channels. • CBZ, OXC, and ESL exhibit broad effects on neuronal network. • Structurally similar dibenzazepine drugs may have different mechanisms of action.