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

Abstract

About 20–30% of patients with epilepsy continue to have seizures despite carefully monitored treatment with antiepileptic drugs. The mechanisms explaining why some patients' respond and others prove resistant to antiepileptic drugs are poorly understood. It has been proposed that pharmacoresistance is related to reduced sensitivity of sodium channels in hippocampal neurons to antiepileptic drugs such as carbamazepine or phenytoin. In line with this proposal, a reduced effect of carbamazepine on sodium currents in hippocampal CA1 neurons was found in the rat kindling model of temporal lobe epilepsy (TLE), i.e. a form of epilepsy with the poorest prognosis of all epilepsy types in adult patients. To address directly the possibility that neuronal sodium currents in the hippocampus play a crucial role in the pharmacoresistance of TLE, we selected amygdala-kindled rats with respect to their in vivo anticonvulsant response to phenytoin into responders and nonresponders and then compared phenytoin's effect on voltage-activated sodium currents in CA1 neurons. 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. Electrode-implanted but not kindled rats were used as sham controls for comparison with the kindled rats. 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 significantly differ from respective data obtained in phenytoin responders, i.e. phenytoin resistance was not associated with a changed modulation of the sodium or calcium currents by this drug. Compared to sham controls, phenytoin's inhibitory effect on sodium currents was significantly reduced by kindling without difference between the responder and nonresponder subgroups. Further studies in phenytoin-resistant kindled rats may help to elucidate the mechanisms that can explain therapy resistance.