Abstract
The effects of chemical injury with oxidizing agents on voltage-gated Na+ current (I(Na)) in differentiated NG108-15 neuronal cells were investigated in this study. In whole-cell patch-clamp recordings, the challenge of these cells with t-butyl hydroperoxide (t-BHP; 1 mM) decreased the peak amplitude of I(Na) with no modification in the current-voltage relationship. It caused a slowing of current inactivation, although there was no alteration in the activation time course of I(Na). Cell exposure to t-BHP also increased a non-inactivating I(Na) (I(Na(NI)) elicited by long-lasting ramp pulses. The t-BHP-induced increase of I(Na(NI)) was reversed by a further application of riluzole (10 microM) or oxcarbazepine (10 microM). When I(Na) was elicited by simulated waveforms of action potentials (APs), during exposure to t-BHP, the amplitude of this inward current was diminished, accompanied by a reduction in inactivation/deactivation rate and an increase in current fluctuations. Under current-clamp recordings, addition of t-BHP (0.3 mM) enhanced AP firing in combination with clustering-like activity and sub-threshold membrane oscillations. In the simulation study, when the fraction of non-inactivating Na(v) channels was elevated, the simulated window component of I(Na) in response to a long-lasting ramp pulse was reduced; however, the persistent I(Na) was markedly enhanced. Moreover, when simulated firing of APs was generated from a modeled neuron, changes of AP firing caused by the increased fraction of non-inactivating Na(v) channels used to mimic the t-BHP actions were similar to the experimental observations. Taken together, it is anticipated that the effects of oxidizing agents on I(Na(NI)) could be an important mechanism underlying their neurotoxic actions in neurons or neuroendocrine cells occurring in vivo.
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