TY - JOUR
T1 - The synergistic inhibitory actions of oxcarbazepine on voltage-gated sodium and potassium currents in differentiated NG108-15 neuronal cells and model neurons
AU - Huang, Chin Wei
AU - Huang, Chao Ching
AU - Lin, Ming Wei
AU - Tsai, Jing Jane
AU - Wu, Sheng Nan
PY - 2008/8
Y1 - 2008/8
N2 - 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 (INa). The IC50 value required for the inhibition of INa by OXC was 3.1 μm. OXC (3 μm) could shift the steady-state inactivation of INa 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 INa inactivation. Additionally, OXC was effective in suppressing persistent INa (INa(P)) elicited by long ramp pulses. The blockade of INa by OXC does not simply reduce current magnitude, but alters current kinetics. Moreover, OXC could suppress the amplitude of delayed rectifier K+ current (IK(DR)), with no effect on M-type K+ current (IK(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 INa and IK(DR) may contribute to the underlying mechanisms through which OXC affects neuronal function in vivo.
AB - 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 (INa). The IC50 value required for the inhibition of INa by OXC was 3.1 μm. OXC (3 μm) could shift the steady-state inactivation of INa 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 INa inactivation. Additionally, OXC was effective in suppressing persistent INa (INa(P)) elicited by long ramp pulses. The blockade of INa by OXC does not simply reduce current magnitude, but alters current kinetics. Moreover, OXC could suppress the amplitude of delayed rectifier K+ current (IK(DR)), with no effect on M-type K+ current (IK(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 INa and IK(DR) may contribute to the underlying mechanisms through which OXC affects neuronal function in vivo.
KW - Delayed-rectifier K current
KW - Differentiated NG108-15 cell
KW - Oxcarbazepine
KW - Voltage-gated Na current
UR - http://www.scopus.com/inward/record.url?scp=46449083261&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=46449083261&partnerID=8YFLogxK
U2 - 10.1017/S1461145707008346
DO - 10.1017/S1461145707008346
M3 - Article
C2 - 18184444
AN - SCOPUS:46449083261
SN - 1461-1457
VL - 11
SP - 597
EP - 610
JO - International Journal of Neuropsychopharmacology
JF - International Journal of Neuropsychopharmacology
IS - 5
ER -