Neuropharmacology 42 (2002) 107–116 www.elsevier.com/locate/neuropharm Effect of phenytoin on sodium and calcium currents in hippocampal CA1 neurons of phenytoin-resistant kindled rats M. Jeub a , H. Beck a , E. Siep b , C. Ru ¨schenschmidt b , E.-J. Speckmann b , U. Ebert c , H. Potschka c , C. Freichel c , E. Reissmu ¨ller c , W. Lo ¨scher c,* a Department of Epileptology, University of Bonn, Bonn, Germany b Institute of Physiology, University of Mu ¨nster, Mu ¨nster, Germany c Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Bu ¨nteweg 17, Hannover 30559 Germany Received 2 January 2001; accepted 17 September 2001 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 antiepilep- tic 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, phenyto- in’s inhibitory effect on sodium currents was significantly reduced by kindling without difference between the responder and nonre- sponder subgroups. Further studies in phenytoin-resistant kindled rats may help to elucidate the mechanisms that can explain therapy resistance.  2002 Elsevier Science Ltd. All rights reserved. Keywords: Epilepsy; Pharmacoresistance; Ion channels; Antiepileptic drugs; Kindling 1. Introduction A substantial number of epileptic patients continue to have seizures in spite of adequate treatment with antiepi- leptic drugs (Johannessen et al., 1995). In such patients with pharmacoresistant epilepsy, brain surgery may be an alternative treatment. The largest group of surgical candidates comprises patients with complex partial seiz- * Corresponding author. Tel.: +49-511-856-8721; fax: +49-511- 953-8581. E-mail address: wolfgang.loescher@tiho-hannover.de (W. Lo ¨scher). 0028-3908/02/$ - see front matter  2002 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(01)00148-4 ures of temporal lobe origin (Theodore, 1992). Surgical resection of epileptogenic tissue, particularly the hippo- campus, often results in pharmacological seizure control after surgery (Theodore, 1992), indicating that the hippo- campus plays a crucial role in the pharmacoresistance of temporal lobe epilepsy (TLE) in these patients. The mechanisms underlying pharmacoresistance most likely involve the functional and morphologic changes developing in regions such as the hippocampus in the course of the disease (Heinemann et al., 1994). Drugs of primary choice for treatment of TLE such as pheny- toin or carbamazepine are thought to act via modulation of voltage-activated sodium and calcium channels