Molecular Targets for Antiepileptic Drug Development

Abstract

Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

Evidence for epistatic interactions in antiepileptic drug resistance

“…In brain, the transporter is crucial in terminating the action of the excitatory neurotransmitter glutamate. 20 Therefore, on the basis of the results from this study, it can be inferred that the excitatory/inhibitory imbalance in the epileptic brain, resulting from alterations in both ambient glutamate/GABA concentration and their receptor sites, may underlie the pathogenesis of AED resistance.…”

Advances in diagnosis, treatments, and molecular mechanistic studies of traumatic brain injury

“…The most extensively researched biomarkers in the blood are glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1). A receiver operating characteristic (ROC) analysis has indicated that the area under the curve is greater than 0.87 for medication is used only if seizures occur (34,35). Numerous studies have indicated that phenytoin (PHT) can be used to prevent seizures soon after TBI, but other anti-seizure drugs such as levetiracetam (LEV) are also being used in clinical practice.…”

Animal Models for Pre-Clinical Antiepileptic Drug Research

“…Pharmacologically PTZ is an analeptic agent; possible common mechanism of action is ability to alter movement of chloride ions across neuronal membrane (Kaminski et al, 2007). It is reported that mice lacking δ subunit exhibit spontaneous seizure and greater sensitivity PTZ, demonstrating a role of the δ subunit containing GABA A receptor in regulating seizure susceptibility (Meldrum and Rogawski, 2007). It is believed to be PTZ act by antagonizing the inhibitory GABAergic neurotransmission but binding site is unknown (Huang et al, 2001).…”