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Lookup NU author(s): Dr Andrei Ilie, Ashan Jayasekera, Christopher CowieORCiD, Professor Andrew Trevelyan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. Objective: Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. Methods: We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. Results: Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm γ-aminobutyric acid type A (GABAA) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. Significance: These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions.
Author(s): Jones A, Barker-Haliski M, Ilie AS, Herd MB, Baxendale S, Holdsworth CJ, Ashton J-P, Placzek M, Jayasekera BAP, Cowie CJA, Lambert JJ, Trevelyan AJ, White HS, Marson AG, Cunliffe VT, Sills GJ, Morgan A
Publication type: Article
Publication status: Published
Journal: Epilepsia
Year: 2020
Volume: 61
Issue: 10
Pages: 2106-2118
Print publication date: 01/10/2020
Online publication date: 14/08/2020
Acceptance date: 21/07/2020
Date deposited: 15/10/2020
ISSN (print): 0013-9580
ISSN (electronic): 1528-1167
Publisher: Wiley Periodicals, Inc.
URL: https://doi.org/10.1111/epi.16644
DOI: 10.1111/epi.16644
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