Diminished Response of CA1 Neurons to Antiepileptic Drugs in Chronic Epilepsy

• Published in: Epilepsia (Copenhagen) Vol. 48; no. 7; pp. 1339 - 1350
• Main Authors: Schaub, Christina, Uebachs, Mischa, Beck, Heinz
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.07.2007; Blackwell
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; CA1; Carbamazepine; Carbamazepine - pharmacology; Chronic Disease; Dentate Gyrus - drug effects; Dentate Gyrus - physiology; Disease Models, Animal; Drug effects; Drug Resistance; Drug toxicity and drugs side effects treatment; Epilepsy - chemically induced; Epilepsy - drug therapy; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus; Hippocampus - drug effects; Humans; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Nervous system (semeiology, syndromes); Neurology; Neurons - drug effects; Neurons - physiology; Neuropharmacology; Patch-Clamp Techniques; Patch‐clamp; Pharmacology. Drug treatments; Phenytoin; Phenytoin - pharmacology; Pilocarpine; Pyramidal Cells - drug effects; Pyramidal Cells - physiology; Rats; Sodium Channels - drug effects; Sodium Channels - physiology; Synaptic Transmission - drug effects; Antiglaucomatous agent; Agonist; Nervous system diseases; Epilepsy; Furan derivatives; Central nervous system; Anticonvulsant; Pilocarpine; Tricyclic compound; Hippocampus-Pilocarpine-Patchclamp-CA1-Carbamazepine-Phenytoin-Drug effects; Carbamazepine; Cerebral disorder; Parasympathomimetic; Cholinergic receptor; Chronic; Neuron; Mood stabilizer; Central nervous system disease; Muscarinic receptor; Dibenzazepine derivatives; Hippocampus; Phenytoin
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/j.1528-1167.2007.01103.x

Summary  Purpose: A substantial proportion of epilepsy patients (∼30%) continue to have seizures despite carefully optimized treatment with antiepileptic drugs (AEDs). One key concept to explain the development of pharmacoresistance is that epilepsy‐related changes in the properties of CNS drug targets result in AED‐insensitivity of these targets. These changes then contribute to drug‐resistance on a clinical level. We have tested this hypothesis in hippocampal CA1 neurons in experimental epilepsy. Methods: Using patch‐clamp techniques, we thoroughly examined the effects of carbamazepine (CBZ) and phenytoin (PHT) on voltage‐gated Na+ currents (INa) in hippocampal CA1 neurons of sham‐control and chronically epileptic rats. Results: We find that there were significant changes in the effects of PHT, but not CBZ on the voltage‐dependence of inactivation, resulting in a significant reduction in voltage‐dependent blocking effects in chronically epileptic animals. Conversely, CBZ effects on the time course of recovery from inactivation of INa were significantly less pronounced in epileptic compared to sham‐control animals, whereas PHT effects remained unaltered. Conclusions: Our findings indicate that AED‐sensitivity of Na+ currents is reduced in chronic epilepsy. The reduction in sensitivity is due to different biophysical mechanisms for CBZ and PHT. Furthermore, comparison to published work suggests that the loss of AED‐sensitivity is less pronounced in CA1 neurons than in dentate granule neurons. Thus, these results suggest that target mechanisms of drug resistance are cell type and AED specific. Unraveling these complex mechanisms is likely to be important for a better understanding of the cellular basis of drug‐resistant epilepsy.