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 microm) 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 microm. OXC (3 microm) 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.
Huang
Chin-Wei
CW
Department of Neurology, National Cheng Kung University School of Medicine, Tainan, Taiwan.
Huang
Chao-Ching
CC
Lin
Ming-Wei
MW
Tsai
Jing-Jane
JJ
Wu
Sheng-Nan
SN
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D007211:Indoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008959:Models, Neurological; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D000927:Anticonvulsants; D007211:Indoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C476610:oxcarbamazepine; D002220:Carbamazepine; D013779:Tetrodotoxin; D000242:Cyclic AMP; C061017:linopirdine