AMPA: α-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid
ASD: antiseizure drug
CSF: cerebrospinal fluid
DS: depolarization shift
ETSP: Epilepsy Therapy Screening Project
GABA: γ-aminobutyric acid
JME: juvenile myoclonic epilepsy
NMDA: N-methyl-D-aspartate receptor
SV2A: synaptic vesicle glycoprotein 2A
EPILEPSY AND ANTISEIZURE THERAPY
The epilepsies are common and frequently devastating disorders, affecting about 2.5 million people in the U.S. alone. More than 40 distinct forms of epilepsy have been identified. Seizures often cause transient impairment of awareness, leaving the individual at risk of bodily harm and often interfering with education and employment. Current therapy is symptomatic: available ASDs inhibit seizures; neither effective prophylaxis nor cure is available. Adherence to prescribed treatment regimens is a major problem because of the need for long-term therapy together with unwanted effects of many drugs.
The mechanisms of action of ASDs fall into these major categories (see also Porter et al., 2012):
Modulation of cation channels (Na+, K+, Ca2+). This can include prolongation of the inactivated state of voltage-gated Na+ channels, positive modulation of K+ channels, and inhibition of Ca2+ channels.
Enhancement of GABA neurotransmission through actions on GABAA receptors, modulation of GABA metabolism, and inhibition of GABA reuptake into the synaptic terminal.
Modulation of synaptic release through actions on the synaptic vesicle protein SV2A or Ca2+ channels containing the α2δ subunit.
Diminishing synaptic excitation mediated by ionotropic glutamate receptors (e.g., AMPA receptors).
Beyond these broad classifications, many ASDs act through mechanisms distinct from the primary known mode of action. Furthermore, ASDs with similar mechanistic categories may have disparate clinical uses.
Much effort is devoted to elucidating the genetic causes and the cellular and molecular mechanisms by which a neural circuit becomes prone to seizure activity, with the goal of providing molecular targets for both symptomatic and preventive therapies.
TERMINOLOGY AND SEIZURE CLASSIFICATION
The term seizure refers to a transient alteration of behavior due to the disordered, synchronous, and rhythmic firing of populations of brain neurons. The term epilepsy refers to a disorder of brain function characterized by the periodic and unpredictable occurrence of seizures. Seizures can be provoked (i.e., by chemical agents or electrical stimulation) or unprovoked; the condition of epilepsy denotes the occurrence of spontaneous, unprovoked seizures. While agents in current clinical use inhibit seizures, whether any of these prevent the development of epilepsy (epileptogenesis) is uncertain.