The broad-spectrum activity of perampanel: state of the art and future perspective of AMPA antagonism beyond epilepsy

Fabio Perversi; Cinzia Costa; Angelo Labate; Simona Lattanzi; Claudio Liguori; Marta Maschio; Stefano Meletti; Lino Nobili; Francesca Felicia Operto; Andrea Romigi; Emilio Russo; Carlo Di Bonaventura

doi:10.3389/fneur.2023.1182304

The broad-spectrum activity of perampanel: state of the art and future perspective of AMPA antagonism beyond epilepsy

Front Neurol. 2023 Jul 6:14:1182304. doi: 10.3389/fneur.2023.1182304. eCollection 2023.

Authors

Fabio Perversi¹, Cinzia Costa^{2

3}, Angelo Labate⁴, Simona Lattanzi⁵, Claudio Liguori^{6

7}, Marta Maschio⁸, Stefano Meletti^{9

10}, Lino Nobili^{11

12}, Francesca Felicia Operto^{13

14}, Andrea Romigi^{15

16}, Emilio Russo¹⁴, Carlo Di Bonaventura¹⁷

Affiliations

¹ Polistudium s.r.l., Milan, Italy.
² Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
³ Neurological Clinic, S. Maria Della Misericordia Hospital, Perugia, Italy.
⁴ Neurophysiopatology and Movement Disorders Clinic, University of Messina, Messina, Italy.
⁵ Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy.
⁶ Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy.
⁷ Epilepsy Center, Neurology Unit, University Hospital "Tor Vergata", Rome, Italy.
⁸ Center for Tumor-Related Epilepsy, UOSD Neuro-Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
⁹ Neurology Department, University Hospital of Modena, Modena, Italy.
¹⁰ Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
¹¹ Child Neuropsychiatry Unit, IRCCS Istituto G. Gaslini, Genova, Italy.
¹² Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Child and Maternal Health (DINOGMI), University of Genova, Genova, Italy.
¹³ Child and Adolescent Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.
¹⁴ Department of Science of Health, School of Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy.
¹⁵ Sleep Medicine Center, Neurological Mediterranean Institute IRCCS Neuromed, Pozzilli, Italy.
¹⁶ Psychology Faculty, International Telematic University Uninettuno, Rome, Italy.
¹⁷ Epilepsy Unit, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.

Abstract

Glutamate is the brain's main excitatory neurotransmitter. Glutamatergic neurons primarily compose basic neuronal networks, especially in the cortex. An imbalance of excitatory and inhibitory activities may result in epilepsy or other neurological and psychiatric conditions. Among glutamate receptors, AMPA receptors are the predominant mediator of glutamate-induced excitatory neurotransmission and dictate synaptic efficiency and plasticity by their numbers and/or properties. Therefore, they appear to be a major drug target for modulating several brain functions. Perampanel (PER) is a highly selective, noncompetitive AMPA antagonist approved in several countries worldwide for treating different types of seizures in various epileptic conditions. However, recent data show that PER can potentially address many other conditions within epilepsy and beyond. From this perspective, this review aims to examine the new preclinical and clinical studies-especially those produced from 2017 onwards-on AMPA antagonism and PER in conditions such as mesial temporal lobe epilepsy, idiopathic and genetic generalized epilepsy, brain tumor-related epilepsy, status epilepticus, rare epileptic syndromes, stroke, sleep, epilepsy-related migraine, cognitive impairment, autism, dementia, and other neurodegenerative diseases, as well as provide suggestions on future research agenda aimed at probing the possibility of treating these conditions with PER and/or other AMPA receptor antagonists.

Keywords: AMPA antagonists; AMPA receptors; epilepsy; glutamate; migraine; perampanel; sleep.

Publication types

Review