Targeting Ionotropic Glutamate Receptors in the Treatment of Epilepsy

Abstract

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 nonconvulsive seizures to lay the groundwork for novel strategies for drug-resistant epilepsy. 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 Review’s scope. Results: iGlu receptors 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 dissecting those steps induced by iGlu receptors activation, which may be altered to provide antiepileptic efficacy without altering key physiological brain functions, thus improving 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.

Inhibition of AKT/GSK3β/CREB Pathway Improves the Responsiveness to AMPA Receptor Antagonists by Regulating GRIA1 Surface Expression in Chronic Epilepsy Rats

“…Since the activation and desensitization kinetics of AMPAR are much faster than those of NMDAR [38], AMPAR antagonists have been focused to prevent ictogenesis and steadily progressive seizure-related brain pathologic plasticity in the epileptic brain [5]. Indeed, AMPAR antagonists terminate SE and seizure activity that are uncontrolled by NMDAR antagonists [6][7][8].…”

“…Indeed, AMPAR antagonists terminate SE and seizure activity that are uncontrolled by NMDAR antagonists [6][7][8]. Among them, only perampanel is marketed for the treatment of focal epilepsy, which is a novel non-competitive AMPAR antagonist without affecting the NMDAR or kainate receptors [5], although its effects on signaling pathways remain to be elucidated. In the present study, both perampanel and GYKI 52466 ameliorated spontaneous seizure activity in 54% and 50% of animals (responders) in each group, concomitant with the reduced membrane expression of GRIA1 but not GRIA2.…”

“…A massive release of glutamate and the subsequent over-activation of glutamate receptors cause aberrant neuronal hyper-excitability, followed by delayed neuronal death and secondary injury [3,4]. Recently, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) has been focused on as one of the major therapeutic targets for treatment of epilepsy [5] since AMPAR antagonists, but not N-methyl-D-aspartate receptor (NMDAR) antagonists, terminate status epilepticus (SE, a prolonged seizure activity) and seizure activity in animal models and preferentially suppress seizure-related long-term consequences [6][7][8].…”

Src/CK2/PTEN-Mediated GluN2B and CREB Dephosphorylations Regulate the Responsiveness to AMPA Receptor Antagonists in Chronic Epilepsy Rats

“…Thus, the regulation of glutamate receptor activities is one of the major therapeutic targets to inhibit the seizure generation (ictogenesis). Among glutamate receptors, N-methyl-d-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and kainate receptor (KAR) have been reported as targets for treatment of epilepsy [8]. Furthermore, the interactions of NMDAR and AMPAR play an important role in synaptic plasticity in the normal brain.…”

Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

“…Previous studies have shown that glutamate levels increase in the extracellular fluid during seizures in temporal lobe epilepsy (TLE) and glutamate can directly activate NMDAR and induce neuroexcitatory toxicity (Albrecht and Zielińska, 2017). Meanwhile, it has been reported that NMDA, AMPA, and kainite (KA) can induce seizures in animal models, and glutamate receptor antagonists inhibit seizures in animals (Celli and Fornai, 2020). In the PTZ-induced status epilepticus (SE), GluN1, GluN2A, and GluN2B subunits are increased and synaptic plasticity impairs in the hippocampus of rats.…”