Voltage gated ion channels: targets for anticonvulsant drugs

Abstract

Epilepsy is one of the most prevalent neurological syndromes in the world today. Epilepsy describes a group of brain disorders whose symptoms and causes are diverse and complicated, but all share a common behavioural manifestation: the seizure. Seizures result from the abnormal discharge of groups of neurons within the brain, usually within a focal point, that can result in the recruitment of large brain regions into epileptiform activity. Although the range of explanations for the development of seizures can be as varied as genetic composition to acute head trauma, the net result is often similar. The excitability of neurons is governed by the input they receive from their neighbours and the intrinsic excitability of the neuron. In this review we focus on elements that are crucial to determining the intrinsic excitability of neurons in the CNS, the voltage gated ion channels (VGICs). VGICs as well as being important for physiological function are critical in producing hyperexcitability such as that associated with seizure discharges. Many drugs routinely used in the clinical setting, as well as several novel experimental drugs, have shown interactions with VGICs that underpin, at least in part, their anticonvulsant action. We review the physiological roles of voltage gated ion channels that are selective for sodium, potassium and calcium conductance and attempt to highlight their role in the pathology of epilepsy. This is supplemented by the mechanisms of drug action at these important anticonvulsant targets for classical and clinically relevant compounds (e.g. phenytoin, ethosuximide) as well as some important second generation drugs (e.g. gabapentin, levetiracetam) and novel experimental agents (e.g. retigabine, losigamone, safinamide). We also briefly discuss the urgent need for new drugs in this arena and the potential of combinatorial methods and recombinant screening to identify leads.