Diminished response of CA1 neurons to antiepileptic drugs in chronic epilepsy

Purpose: A substantial proportion of epilepsy patients (similar to 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 (I-Na)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 I-Na 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 mechanisins 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.