Ion Channels and Epilepsy

Abstract

The role of voltage-gated and ligand-gated ion channels in epileptogenesis of both genetic and acquired epilepsies, and as targets in the development of new antiepileptic drugs (AEDs) is reviewed. Voltage-gated Na+ channels are essential for action potentials, and their mutations are the substrate for generalised epilepsy with febrile seizures plus and benign familial neonatal infantile seizures; Na+ channel inhibition is the primary mechanism of carbamazepine, phenytoin and lamotrigine, and is a probable mechanism for many other classic and novel AEDs. Voltage-gated K+ channels are essential in the repolarisation and hyperpolarisation that follows paroxysmal depolarisation shifts (PDSs), and their mutations are the substrate for the benign neonatal epilepsy and episodic ataxia type 1; they are new targets for AEDs such as retigabine. Voltage-gated Ca2+ channels are involved in neurotransmitter release, in the sustained depolarisation-phase of PDSs, and in the generation of absence seizures; their mutations are a substrate for juvenile myoclonic epilepsy and the absence-like pattern seen in some mice; the antiabsence effect of ethosuximide is due to the inhibition of thalamic T-type Ca2+ channels. Voltage-gated Cl- channels are implicated in GABA(A) transmission, and mutations in these channels have been described in some families with juvenile myoclonic epilepsies, epilepsy with grand mal seizures on awakening or juvenile absence epilepsy. Hyperpolarisation-activated cation channels have been implicated in spike-wave seizures and in hippocampal epileptiform discharges. The Cl- ionophore of the GABA(A) receptor is responsible for the rapid post-PDS hyperpolarisation, it has been involved in epileptogenesis both in animals and humans, and mutations in these receptors have been found in families with juvenile myoclonic epilepsy or generalised epilepsy with febrile seizures plus; enhancement of GABA(A) inhibitory transmission is the primary mechanism of benzodiazepines and phenobarbital and is a mechanistic approach to the development of novel AEDs such as tiagabine or vigabatrin. Altered GABA(B)-receptor function is implicated in spike-wave seizures. Ionotropic glutamate receptors are implicated in the sustained depolarisation phase of PDS and in epileptogenesis both in animals and humans; felbamate, phenobarbital and topiramate block these receptors, and attenuation of glutamatergic excitatory transmission is another new mechanistic approach. Mutations in the nicotinic acetylcholine receptor are the substrates for the nocturnal frontal lobe epilepsy. The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.

GABA Receptors: Pharmacological Potential and Pitfalls

“…GABAB receptors differ from GABAA receptors by their structural and functional properties, but also exhibit numerous pharmacological effects, including central muscle relaxation, epileptogenesis, suppression of drug craving, antinociception, cognitive impairment and inhibition of hormone release [12,239].…”

The Use of Antiepileptic Drugs in Acute Neuropsychiatric Conditions: Focus on Traumatic Brain Injury, Pain, and Alcohol Withdrawal

“…A tricyclic anticonvulsant, carbamazepine inhibits voltage dependent sodium channels and activates the voltage-dependent potassium channels [66]. It has been found to suppress withdrawal-induced kindling in limbic structures [67] [68], and animal studies have also shown that carbamazepine is able to prevent alcohol withdrawal seizures [69] in addition to decreasing withdrawal symptoms [70].…”

Genome-wide identification of febrile seizure and related epilepsy phenotype loci

“…Novel susceptibility genes for FS, ADEFS+ and SMEI may exist in these loci. Fourteen loci common to all phenotypes may play a role in epileptogenesis [39], while genes located in loci belonging to Area I (5), Area II (3) and Area III (2) multi-factorial disorder because they are provoked by high fever or, in cases of SMEI, the first seizures are mostly associated with fever [10]. These data suggest that FS, ADEFS+ and SMEI represent a continuum of epileptic disorders; FS is the mild type, SMEI is the most severe type, and ADEFS+ is an intermediate phenotype between FS and SMEI spectrum.…”