Targets for antiepileptic drugs in the synapse

Abstract

Antiepileptic drugs (AEDs) have many proposed mechanisms of action and are still not fully understood. AEDs are widely used today to treat epilepsy, migraine, neuropathic pain, and bipolar disorder, and other disorders are also being investigated. The focus in this review is the main targets for AEDs in the GABAergic and glutamatergic synapses and possible future sites of action for AEDs to clarify their wide spectrum of activity. The study is a review of recently published investigations of the mechanisms of action of AEDs. The main targets for AEDs in the synapses include enhancement of GABAergic inhibitory neurotransmission, decrease in glutamatergic excitatory neurotransmission directly or via inhibition of voltage-dependent sodium and calcium channels, and interference with intracellular signaling pathways. Vigabatrin, tiagabine, and valproate possess their main actions in the GABAergic synapse. Levetiracetam, topiramate, lamotrigine, carbamazepine, oxcarbazepine, gabapentin, pregabalin, felbamate, and zonisamide decrease glutamatergic excitability. In addition, valproate, carbamazepine, and oxcarbazepine modulate intracellular signaling pathways. Several AEDs of a new generation based on the existing drugs are in development. Future targets to decrease excitability may include GABA and glutamate ionotropic and metabotropic receptors and astrocytes. Knowledge of the sites of action of AEDs in the synapse is important to improve our understanding of their broad spectrum of clinical efficacy and to develop future effective drugs for the treatment of both epilepsy and other neurological and psychiatric disorders.