A <i>Caenorhabditis elegans</i> assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action

Wong, Shi Quan, Jones, Alistair, Dodd, Steven, Grimes, Douglas ORCID: 0000-0002-1034-6625, Barclay, Jeff W, Marson, Anthony G ORCID: 0000-0002-6861-8806, Cunliffe, Vincent T, Burgoyne, Robert D ORCID: 0000-0002-9219-0387, Sills, Graeme J ORCID: 0000-0002-3389-8713 and Morgan, Alan ORCID: 0000-0002-0346-1289 (2018) A <i>Caenorhabditis elegans</i> assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action. JOURNAL OF NEUROSCIENCE METHODS, 309. pp. 132-142. ISSN 0165-0270, 1872-678X

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Official URL: https://doi.org/10.1016/j.jneumeth.2018.09.004

Abstract

<h4>Background</h4>Epilepsy affects around 1% of people, but existing antiepileptic drugs (AEDs) only offer symptomatic relief and are ineffective in approximately 30% of patients. Hence, new AEDs are sorely needed. However, a major bottleneck is the low-throughput nature of early-stage AED screens in conventional rodent models. This process could potentially be expedited by using simpler invertebrate systems, such as the nematode Caenorhabditis elegans.<h4>New method</h4>Head-bobbing convulsions were previously reported to be inducible by pentylenetetrazol (PTZ) in C. elegans with loss-of-function mutations in unc-49, which encodes a GABA<sub>A</sub> receptor. Given that epilepsy-linked mutations in human GABA<sub>A</sub> receptors are well documented, this could represent a clinically-relevant system for early-stage AED screens. However, the original agar plate-based assay is unsuited to large-scale screening and has not been validated for identifying AEDs. Therefore, we established an alternative streamlined, higher-throughput approach whereby mutants were treated with PTZ and AEDs via liquid-based incubation.<h4>Results</h4>Convulsions induced within minutes of PTZ exposure in unc-49 mutants were strongly inhibited by the established AED ethosuximide. This protective activity was independent of ethosuximide's suggested target, the T-type calcium channel, as a null mutation in the worm cca-1 ortholog did not affect ethosuximide's anticonvulsant action.<h4>Comparison with existing method</h4>Our streamlined assay is AED-validated, feasible for higher throughput compound screens, and can facilitate insights into AED mechanisms of action.<h4>Conclusions</h4>Based on an epilepsy-associated genetic background, this C. elegans unc-49 model of seizure-like activity presents an ethical, higher throughput alternative to conventional rodent seizure models for initial AED screens.

Item Type:	Article
Uncontrolled Keywords:	Caenorhabditis elegans, Calcium channel, Drug screens, Epilepsy, Ethosuximide, GABA receptor, Pentylenetetrazol, Anticonvulsant
Depositing User:	Symplectic Admin
Date Deposited:	11 Sep 2018 14:22
Last Modified:	07 Dec 2024 04:48
DOI:	10.1016/j.jneumeth.2018.09.004
Open Access URL:	https://doi.org/10.1016/j.jneumeth.2018.09.004
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3026125