Effect of phenytoin on sodium and calcium currents in hippocampal CA1 neurons of phenytoin-resistant kindled rats

Animal Models of Limbic Epilepsies: What Can They Tell Us?

“…In all experiments, the interval between last kindled seizure and ion channel measurements was at least 5 weeks. In kindled rats with in vivo resistance to the anticonvulsant effect of phenytoin (phenytoin nonresponders), in vitro modulation of sodium and calcium currents by phenytoin in hippocampal CA1 neurons did not differ to any extent from respective data obtained in phenytoin responders, ie, phenytoin resistance was not associated with a changed modulation of the sodium or calcium currents by this drug (39). Compared to sham controls, phenytoin's inhibitory effect on sodium currents was significantly reduced by kindling without difference between the responder and non-responder subgroups.…”

“…To directly address the possibility that neuronal sodium currents in the hippocampus play a crucial role in the pharmacoresistance of TLE, amygdala kindled rats were selected with respect to their in vivo anticonvulsant response to phenytoin into responders and nonresponders and then phenytoin's effect on voltage-activated sodium currents was compared in CA1 neurons (39). Furthermore, in view of the potential role of calcium current modulation in the anticonvulsant action of phenytoin, the effect of phenytoin on high-voltage-activated calcium currents was studied in CA1 neurons.…”

Reciprocal Changes in Phosphorylation and Methylation of Mammalian Brain Sodium Channels in Response to Seizures

“…Nav channels, including Nav1.2, are also mutated in several forms of inherited epilepsy (15). Nav channels are targets for many of the most commonly used antiepileptic drugs (AEDs) (16), yet neurons in the epileptic brain display resistance to certain Nav channelspecific AEDs (17)(18)(19)(20). Pharmacoresistance may initially arise in response to acute seizures, and with a time course consistent with changes in Nav channel PTM and inconsistent with de novo expression of distinct Nav channel isoforms (21)(22)(23)(24).…”

Formulation of Spray-Dried Phenytoin Loaded Poly(ε-Caprolactone) Microcarrier Intended for Brain Delivery to Treat Epilepsy

“…15 Moreover, the modulation of postsynaptic calcium channels by PHT was also found in human hippocampal granule cells from intractable TLE patients and appears to contribute to its anticonvulsant action. 16 Therefore, it is conceivable that when present in locally therapeutic concentrations, PHT may be an efficient anticonvulsant in TLE patients that are pharmacoresistant to oral PHT.…”