Phenytoin Inhibits the Persistent Sodium Current in Neocortical Neurons by Modifying Its Inactivation Properties

The persistent Na+ current (I-NaP) is important for neuronal functions and can play a role in several pathologies, although it is small compared to the transient Na+ current (I-NaT). Notably, I-NaP is not a real persistent current because it undergoes inactivation with kinetics in the order of tens of seconds, but this property has often been overlooked. Na+ channel blockers, drugs used for treating epilepsy and other diseases, can inhibit I-NaP, but the mechanism of this action and the conditions in which I-NaP can be actually inhibited have not been completely clarified yet. We evaluated the action of phenytoin (PHT), a prototype anti-epileptic Na+ channel blocker, on I-NaP inactivation in pyramidal neurons of rat sensorimotor cortical slices at different concentrations, from 5 to 100 mu M. PHT did not modify I-NaP evoked with depolarizing voltage ramps of 50 or 100 mVs(-1), but decreased I-NaP evoked by slower voltage ramps (10 mVs(-1)). However, at all of the tested concentrations, PHT decreased I-NaP evoked by faster ramps when they were preceded by inactivating pre-pulses. Moreover, PHT shifted towards negative potentials the voltage-dependence of I-NaP inactivation and accelerated its kinetics of development also at depolarized potentials (+40 mV), not consistently with a simple inactivated state stabilizer. Therefore, our study shows a prominent PHT effect on I-NaP inactivation rather than an open channel block, which is instead often implied. I-NaP is inhibited by PHT only in conditions that induce major I-NaP inactivation. These results highlight the importance of I-NaP inactivation not only for physiological functions but also as drug target, which could be shared by other therapeutic drugs. Through this action PHT can reduce I-NaP-induced long-lasting pathological depolarisations and intracellular sodium overload, whereas shorter I-NaP actions should not be modified. These properties set the conditions of efficacy and the limits of PHT as I-NaP inhibitor.