Plasticity of antiepileptic drug targets.
The mechanisms underlying the development of drug resistance in epilepsy are complex and, at this time, not fully understood. It is widely accepted that the efficacy of an antiepileptic drug (AED) is determined by its ability to cross the blood-brain barrier (BBB) and bind to intraparenchymal target sites. According to the target hypothesis, pharmacoresistance occurs when target sites are structurally and/or functionally modified in such a way that they become less sensitive to AEDs. A large number of targets for AEDs have been identified in the brain, many of which undergo molecular changes during chronic epilepsy. So far, a reduced sensitivity of drug targets to AEDs in chronic human and experimental epilepsy has been suggested for the voltage-gated Na(+) channel and the GABA(A) receptor. At the molecular level, altered drug targets may arise due to the transcriptional regulation of ion channel subunit genes. Alternatively, ion channel subunits may be modified by redox modulation or phosphorylation, a set of mechanisms that may be invoked much more rapidly than transcriptional changes. In addition to functional experiments, genetic studies are currently attempting to identify polymorphisms that are specifically associated with the functional phenotypes of drug resistance and drug responsiveness in the epileptic population. It is hoped that our increased understanding of the target mechanisms underlying pharmacoresistance will lead to the development of novel therapeutic strategies that will improve treatment outcomes in individuals with refractory epilepsy.
Beck
Heinz
H
Department of Epileptology, University of Bonn, Bonn, Germany. heinz.beck@ukb.uni-bonn.de
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002220:Carbamazepine / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D004351:Drug Resistance / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D010597:Pharmacogenetics; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism
D000927:Anticonvulsants; D026901:Membrane Transport Proteins; D015222:Sodium Channels; D002220:Carbamazepine