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

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.

Pharmacodynamic rationale for the choice of antiseizure medications in the paediatric population

“…Perampanel (PER) is a non-competitive selective antagonist of AMPA receptors. Accordingly, it can reduce fast excitatory neurotransmission and thus limit the generation of seizures and the spread of seizure discharges [ 75 , 76 ]. Nonetheless, it is believed that PER, when administered at therapeutic doses, only blocks a minor fraction of the AMPA receptor current.…”

“…This amount is adequate to slow down epileptiform discharges while preserving most of the normal synaptic transmission. This is why PER has a narrow therapeutic window, and sometimes even a slight increase in the dosage can lead to neuropsychiatric AEs [ 23 , 76 ].…”

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

“…Given that AMPA receptors are a key mediator of glutamatergic neurotransmission involved in many functions, the AMPAr antagonist, perampanel (originally approved as an anti-seizure medication), has been used in a wide variety non-epilepsy or epilepsy associated conditions, including in autism with associated epilepsy ( 146 ). Several studies have looked at the efficacy of perampanel in rare epilepsies, including epilepsy associated with SYNGAP1-DEE ( 147 – 149 ).…”

Antiseizure Medications in Alzheimer’s Disease from Preclinical to Clinical Evidence

“…Although several mechanisms can be relevant, studies have also uncovered that epilepsy and AD are linked strictly to ion channel activity. The modification of ion channels, mainly because of mutations in genes encoding ion channel subunits [ 24 ], can lead to the dysregulation of E/I signaling, which results in the spread of aberrant discharges in epilepsy, and a variety of ion channels, such as NMDA and AMPA glutamate receptors, are putatively involved in the pathogenesis of AD and several other neuropsychiatric conditions [ 25 , 26 , 27 ]. Interestingly, it has been shown in an experimental mouse model of cerebral amyloidosis that the D1 receptor could be involved in mediating the epileptic effects of Aβ 1–42 .…”

“…Interestingly, the PER effects were linked to a reduction in the expression of some pro-inflammatory cytokines in this mice model [ 30 ]. Recently, a review summarizing preclinical and clinical data on AMPA antagonism supported the possibility of treating several neuropsychiatric conditions, beyond epilepsy, with PER [ 25 ].…”