AMPA receptors and perampanel behind selected epilepsies: current evidence and future perspectives

ABSTRACT

Introduction: The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are the major mediators of glutamate-mediated excitatory neurotransmission, and are critical for synchronization and spread of epileptic activity.

Areas covered: AMPA receptor antagonists have been also developed as antiepileptic drugs and perampanel (PER) is the first highly selective, non-competitive AMPA-type glutamate receptor antagonist that is available on the market. It is approved as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalization, and for primary generalized tonic-clonic seizures in idiopathic generalized epilepsy, in patients aged ≥ 12 years. This article reviews the role of AMPA receptors in the neuronal hyperexcitability underlying epilepsy, the mechanism of action and clinical experience on the anti-seizure activity of PER. Moreover, the rationale for targeting AMPA receptor in specific epileptic disorders, including brain tumor-related epilepsy, mesial temporal lobe epilepsy with/without hippocampal sclerosis, and status epilepticus is evaluated. Finally, the pharmacological rationale for the development of AMPA receptor antagonists in other neurological disorders beyond epilepsy is considered.

Expert opinion: Further research aimed at better understanding the pharmacology and blocking mechanism of PER and other AMPA receptor antagonists will drive future development of therapeutic agents that target epilepsy and other neurological diseases.

KEYWORDS:

• AMPA receptor
• glutamate
• perampanel
• seizures
• temporal lobe epilepsy
• status epilepticus

Article highlights

• The role of glutamate in the excitatory neurotransmission through AMPA receptor-mediated excitatory synapses is well established.

• AMPA receptor antagonists have demonstrated anti-seizure activity in a broad range of seizure models.

• Perampanel is an AMPA receptor antagonist approved as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalized seizures in patients with epilepsy aged ≥ 12 years, and for the treatment of primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy.

• As the role of AMPA receptors becomes clearer, there seems to be a strong rationale for using AMPA receptor antagonists in specific types of epilepsy where ad hoc clinical studies are needed.

• There is a solid pharmacological rationale for the development of AMPA receptor antagonists in neurological disorders other than epilepsy.

This box summarizes key points contained in the article.

Acknowledgments

The authors wish to thank Luca Cantini (M.D.) for editorial assistance in preparing the manuscript for publication.

Declaration of interest

C. Di Bonaventura has received contribution for research activity or honoraria for speeches by UCB Pharma, Eisai and FB Health. A. Labate has received personal compensation from UCB and Eisai. M. Maschio has received support for travel to congresses from Eisai, has participated in scientific advisory boards for Eisai, has participated in pharmaceutical industry-sponsored symposia and has received research grants from UCB Pharma. S. Meletti has received Research grant support from the Emilia Romagna Region, Italian Ministry of Health; from the non-profit organization CarisMo Foundation; has received personal compensation from UCB Pharma and Eisai. E. Russo received personal compensation from Eisai. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.