Background: A dysfunction in glutamate neurotransmission is critical for seizure. Glutamate
is the major excitatory drive in the cerebral cortex, where seizures occur. Glutamate acts via
(i) ionotropic (iGlu) receptors, which are ligand-gated ion channels mediating fast excitatory synaptic
transmission; and (ii) G proteins coupled metabotropic (mGlu) receptors.
Objective: To overview the evidence on the role of iGlu receptors in the onset, duration, and severity
of convulsive and non-convulsive seizures to lay the groundwork for novel strategies for drug-resistant
Methods: We used PubMed crossed-search for “glutamate receptor and epilepsy” (sorting 3,170 reports),
searched for “ionotropic glutamate receptors”, “AMPA receptors”, “NMDA receptors”, “kainate
receptors”, “convulsive seizures”, “absence epilepsy”, and selected those papers focusing this
Results: iGlu receptor antagonists inhibit, whereas agonists worsen experimental seizures in various
animal species. Clinical development of iGlu receptor antagonists has been limited by the occurrence
of adverse effects caused by inhibition of fast excitatory synaptic transmission. To date,
only one drug (perampanel) selectively targeting iGlu receptors is marketed for the treatment of focal
epilepsy. However, other drugs, such as topiramate and felbamate, inhibit iGlu receptors in addition
to other mechanisms.
Conclusion: This review is expected to help dissect those steps induced by iGlu receptors activation,
which may be altered to provide antiepileptic efficacy without altering key physiological
brain functions, thus improving the safety and tolerability of iGlu-receptor directed antiepileptic
agents. This effort mostly applies to drug resistant seizures, which impact the quality of life and often
lead to status epilepticus, which is a medical urgency.