The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia.

Anderson Brito Da Silva,Koustav Chatterjee,Mark R Baker,David Bateman,Abhijit Joshi,Stuart D Greenhill,Hrishikesh Kumar,Jane Pennifold,Roland S G Jones,Roger W Whittaker,Mark O Cunningham,Richard Walsh,Ben Henley,Gavin L Woodhall,Stefano Seri,Claire Nicholson

doi:10.1002/epi4.12549

Abstract

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well‐tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients.

Highlights

Focal cortical dysplasia type IIb (FCD IIb) lesions are notoriously epileptogenic and associated with drug refractory epilepsy
Perampanel was observed to significantly reduce the degree of cross correlation between multi-unit activity and high frequency oscillations (HFOs) (Figure 2, I-L). These electrophysiological and pharmacological data demonstrate that the use of perampanel is effective in reducing seizure-like activity in neocortical slices resected from human patients with FCD, suggesting potential benefit for the use of this drug in treating pharmacoresistant epilepsy in this patient group
In cortical tissue removed from patients with partial-onset epilepsy, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density is increased,[17] and the sensitivity of the receptor to glutamate enhanced by altered RNA editing.[18]

Summary

Introduction

Focal cortical dysplasia type IIb (FCD IIb) lesions are notoriously epileptogenic and associated with drug refractory epilepsy. From a histological point of view, FCD IIb presents with cytoarchitectural abnormalities of the neocortex, often with the presence of balloon cells, dysmorphic neurons, and hypomyelinated white matter. Due to the propensity for pharmacoresistance in FCD IIb, a significant proportion of patients will undergo surgical resection of the lesion in order to control seizures. The ability to conduct a “complete” resection can be complicated by a number of factors. Due to the fact that FCD IIb lesions frequently occur close to eloquent cortex and important fiber tracts, it is not always possible to conduct a full resection as this may lead to post-surgical neurological deficits. Alternative therapeutic approaches for epilepsy arising from this particular type of lesion are required

Methods

Results

Conclusion