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The AMPA receptor as a therapeutic target in epilepsy: preclinical and clinical evidence

Authors Hanada T

Received 18 June 2014

Accepted for publication 14 August 2014

Published 18 September 2014 Volume 2014:7 Pages 39—50


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 5

Editor who approved publication: Professor Trevor W. Stone

Takahisa Hanada,1,2

1Neuroscience and General Medicine Product Creation Unit, Eisai Co., Ltd., Tsukuba, Japan; 2Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan

Abstract: Epilepsy affects around 0.5%–1% of the general population. The most established hypothesis for its underlying pathophysiology is the imbalance of excitatory and inhibitory neuronal activity. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor has significant roles in fast excitatory neuronal transmission in the central nervous system (CNS) and the plasticity of synaptic strength. Based on this, AMPA-receptor modulation could be a way of adjusting the excitatory–inhibitory balance. The role of the AMPA receptor in epilepsy and epileptogenesis, and its potential as a target for antiepileptic drugs, has been supported by studies in a range of animal models, as well as clinical investigation in humans. However, it has been difficult to develop drugs that target AMPA-receptor activity, especially without considerable CNS-related side effects. In the case of AMPA-receptor antagonists, CNS-depressant side effects had to be overcome before they could be considered viable drugs. Recently, the first selective AMPA receptor antagonist on the market, perampanel, was approved as an adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older. Further research into the role of AMPA receptors, particularly in the process of epileptogenesis, and the development of AMPA-targeted drugs is warranted.

Keywords: anticonvulsant, antiepileptic, drug discovery research, epileptogenesis, glutamate, perampanel, seizure, synaptic plasticity

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