The synergistic inhibitory actions of oxcarbazepine on voltage-gated sodium and potassium currents in differentiated NG108-15 neuronal cells and model neurons

Oxcarbazepine (OXC), one of the newer anti-epileptic drugs, has been demonstrating its efficacy on wide-spectrum neuropsychiatric disorders. However, the ionic mechanism of OXC actions in neurons remains incompletely understood. With the aid of patch-clamp technology, we first investigated the effects of OXC on ion currents in NG108-15 neuronal cells differentiated with cyclic AMP. We found OXC (0.3-30 μm) caused a reversible reduction in the amplitude of voltage-gated Na⁺ current (I_Na). The IC₅₀ value required for the inhibition of I_Na by OXC was 3.1 μm. OXC (3 μm) could shift the steady-state inactivation of I_Na to a more negative membrane potential by approximately -9 mV with no effect on the slope of the inactivation curve, and produce a significant prolongation in the recovery of I_Na inactivation. Additionally, OXC was effective in suppressing persistent I_Na (I_Na(P)) elicited by long ramp pulses. The blockade of I_Na by OXC does not simply reduce current magnitude, but alters current kinetics. Moreover, OXC could suppress the amplitude of delayed rectifier K⁺ current (I_K(DR)), with no effect on M-type K⁺ current (I_K(M)). In current-clamp configuration, OXC could reduce the amplitude of action potentials and prolong action-potential duration. Furthermore, the simulations, based on hippocampal pyramidal neurons (Pinsky-Rinzel model) and a network of the Hodgkin-Huxley model, were analysed to investigate the effect of OXC on action potentials. Taken together, our results suggest that the synergistic blocking effects on I_Na and I_K(DR) may contribute to the underlying mechanisms through which OXC affects neuronal function in vivo.