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The neurobiology of antiepileptic drugs

Key Points

  • Antiepileptic drugs (AEDs) protect against seizures by modulation of voltage-gated sodium and calcium channels, enhancement of GABAA (γ-aminobutyric acid, type A) receptor-mediated synaptic inhibition, and inhibition of ionotropic glutamate receptor-mediated synaptic excitation.

  • Sodium channel-blocking AEDs, including phenytoin, carbamazepine and lamotrigine, inhibit high-frequency repetitive spike firing during the spread of seizure activity without affecting ordinary ongoing neural activity. These drugs bind preferentially to depolarized sodium channels and induce a non-conducting state that is similar to channel inactivation, but from which recovery is much slower, allowing the block to accumulate during repetitive activation of the channel, as occurs with epileptic bursting. In addition, the drug binds slowly so that there is preferential block of firing during sustained epileptic depolarizations.

  • Persistent or non-inactivating sodium current represents only a fraction of the sodium current, but might contribute to the initiation and maintenance of epileptiform activity. Preferential inhibition of persistent sodium current probably contributes to the protective activity of phenytoin and possibly other sodium channel blocking AEDs.

  • Gabapentin binds with high affinity to the auxiliary calcium channel subunits α2δ-1 and α2δ-2. The functional consequences of this interaction are not fully defined, but recent studies indicate that gabapentin might inhibit calcium currents, resulting in reduced excitatory neurotransmission.

  • In the thalamus, T-type calcium channels are essential for the abnormal oscillatory behaviour that underlies generalized absence seizures. Ethosuximide inhibits these channels, accounting for its anti-absence activity.

  • Inhibitory GABAA receptor-mediated synaptic interactions are important in restraining the natural tendency of brain circuits in regions that are susceptible to epileptic activity (including the neocortex, hippocampus and amygdala) to undergo the transition into synchronized epileptiform activity. Many AEDs enhance GABAA receptor inhibition either through positive modulatory interactions with GABAA receptors (benzodiazepines, barbiturates, felbamate and topiramate) or by modifying the dynamics of GABA-mediated inhibitory synaptic function, as is the case for vigabatrin, an irreversible suicide inhibitor of the GABA degradative enzyme GABA transaminase, and tiagabine, an inhibitor of the high-affinity GABA transporter GAT1.

  • Several marketed AEDs might act partly by inhibition of ionotropic glutamate receptors, including felbamate, which inhibits NMDA (N-methyl-D-aspartate) receptors, and topiramate, which inhibits kainate receptors.

  • There is remarkable overlap between the ion channel targets of AEDs and human epilepsy genes, illustrating the pivotal importance of ion channels in epilepsy. In many cases, the AEDs and mutations induce functionally opposite effects on channel behaviour. So, whereas the mutations lead to increased seizure susceptibility through gain-of-function effects on voltage-gated sodium and calcium channel gating or reduced efficacy of GABAA receptors or potassium channels, AEDs inhibit sodium or calcium channels, or enhance the activity of GABAA receptors or potassium channels.

Abstract

Antiepileptic drugs (AEDs) provide satisfactory control of seizures for most patients with epilepsy. The drugs have the remarkable ability to protect against seizures while permitting normal functioning of the nervous system. AEDs act on diverse molecular targets to selectively modify the excitability of neurons so that seizure-related firing is blocked without disturbing non-epileptic activity. This occurs largely through effects on voltage-gated sodium and calcium channels, or by promoting inhibition mediated by GABAA (γ-aminobutyric acid, type A) receptors. The subtle biophysical modifications in channel behaviour that are induced by AEDs are often functionally opposite to defects in channel properties that are caused by mutations associated with epilepsy in humans.

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Figure 1: Lamotrigine selectively blocks epileptiform discharges without affecting ordinary action potential firing.
Figure 2: Antiepileptic drugs (AEDs) and sodium channels.
Figure 3: Stick and space-filling views showing diphenyl moiety common to the sodium-channel-blocking antiepileptic drugs phenytoin, lamotrigine and carbamazepine.
Figure 4: GABA receptors and antiepileptic drugs.

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Glossary

ANTIEPILEPTIC DRUG

A drug that protects against the occurrence of epileptic seizures; an alternative to the term 'anticonvulsant drug'.

GENERALIZED ABSENCE SEIZURE

A non-convulsive seizure that typically occurs in childhood. It is characterized by a sudden, brief impairment of consciousness, cessation of ongoing activity without loss of postural tone, and 3 Hz rhythmic cortical discharges of geneneralized onset. The usual duration is 5–10 seconds; several episodes can occur daily.

PAROXYSMAL DEPOLARIZATION SHIFT

Abnormal prolonged depolarization with repetitive spiking characteristic of neurons in epileptic cortical zones that are reflected as interictal discharges in the electroencephalogram.

METABOTROPIC RECEPTOR

A G-protein-coupled receptor that may indirectly influence the activity of ion channels but does not itself serve as a channel.

GENERALIZED TONIC-CLONIC SEIZURE

A convulsive seizure involving the entire body, usually characterized by muscle rigidity, violent rhythmic muscle contractions and loss of consciousness.

PARTIAL SEIZURE

Seizure resulting from a localized brain disturbance; also referred to as 'focal seizure'.

SODIUM CHANNEL INACTIVATION

Entry of the sodium channel into a set of states that are distinct from the open and closed states that prevents the channel from reopening until there has been sufficient time for recovery, thereby preventing persistent sodium flux during long depolarizations.

GEFS+

A pleotropic autosomal dominant epilepsy syndrome in which there are febrile seizures in childhood and afebrile generalized seizures that persist beyond 6 years of age, including absences, myoclonic seizures, atonic seizures and myoclonic-astatic seizures. The syndrome is distinct from common benign febrile seizures.

ICTAL

Relating to an epileptic seizure.

INTERICTAL DISCHARGES

Distinctive waves or complexes that can be recorded between seizures in the electroencephalogram of individuals with epilepsy. Generally brief in duration, but can have various morphologies described as 'sharp wave', 'spike' or 'spike-and-slow-wave'.

PERSISTENT SODIUM CURRENT

A small component of the sodium current that does not inactivate.

POLYGENIC

A characteristic that is controlled by different genes, each of which has only a small role in the phenotype.

UREIDE RING

Heterocyclic ring formed from urea (CO(NH2)2) as in phenytoin and barbiturates. In ethosuximide, the hydantoin ureide ring of phenytoin is substituted for a succinimide ring with a single nitrogen atom.

IONOTROPIC RECEPTOR

Possessing an intrinsic channel (pore) that mediates transmembrane ion flux.

MYOCLONIC SEIZURE

Sudden, brief, involuntary spasm (contraction–relaxation) of the tongue or muscles of the face, trunk, arms, legs or the entire body.

DRAVET'S SYNDROME

A rare intractable epilepsy syndrome in which prolonged generalized tonic, clonic or tonic-clonic seizures occur between 2 and 9 months of age followed by myoclonic, tonic-clonic, absence and partial seizures in the second year of life. The syndrome is associated with delayed psychomotor and speech development, and ataxia.

JUVENILE MYOCLONIC EPILEPSY

A common generalized epilepsy syndrome presenting between the ages of 8 and 26 years with early morning myoclonus, mainly affecting the upper extremities, and often associated with generalized tonic-clonic seizures and less frequently with absence seizures.

STATUS EPILEPTICUS

Continuous seizure activity without recovery of consciousness or return to neurological function.

IRREVERSIBLE SUICIDE INHIBITOR

An inhibitor that is inactive until acted upon by the enzyme: the inhibitor binds to the enzyme as a substrate and a chemically reactive intermediate is generated that inactivates the enzyme.

LENNOX-GASTAUT SYNDROME

A devastating paediatric epilepsy syndrome usually beginning between ages 1 to 8 years. It is characterized by multiple seizure types including tonic, atonic, atypical absence and myoclonic seizures. There is often impaired intellectual functioning and behavioural disturbances.

ANTIEPILEPTOGENIC

Protection against the development of epilepsy, a state characterized by recurrent seizures.

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Rogawski, M., Löscher, W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5, 553–564 (2004). https://doi.org/10.1038/nrn1430

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