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• W2890216918 abstract "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. 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 GABAA receptor. Given that epilepsy-linked mutations in human GABAA 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. 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. Our streamlined assay is AED-validated, feasible for higher throughput compound screens, and can facilitate insights into AED mechanisms of action. 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." @default.
• W2890216918 created "2018-09-27" @default.
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• W2890216918 date "2018-11-01" @default.
• W2890216918 modified "2023-10-16" @default.
• W2890216918 title "A Caenorhabditis elegans assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action" @default.
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• W2890216918 doi "https://doi.org/10.1016/j.jneumeth.2018.09.004" @default.
• W2890216918 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6200019" @default.
• W2890216918 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30189284" @default.
• W2890216918 hasPublicationYear "2018" @default.
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