Sensitivity, specificity and limitation of in vitro hippocampal slice and neuron-based assays for assessment of drug-induced seizure liability.
Toxicol Appl Pharmacol
; 430: 115725, 2021 11 01.
Article
em En
| MEDLINE
| ID: mdl-34536444
ABSTRACT
An effective in vitro screening assay to detect seizure liability in preclinical development can contribute to better lead molecule optimization prior to candidate selection, providing higher throughput and overcoming potential brain exposure limitations in animal studies. This study explored effects of 26 positive and 14 negative reference pharmacological agents acting through different mechanisms, including 18 reference agents acting on glutamate signaling pathways, in a brain slice assay (BSA) of adult rat to define the assay's sensitivity, specificity, and limitations. Evoked population spikes (PS) were recorded from CA1 pyramidal neurons of hippocampus (HPC) in the BSA. Endpoints for analysis were PS area and PS number. Most positive references (24/26) elicited a concentration-dependent increase in PS area and/or PS number. The negative references (14/14) had little effect on the PS. Moreover, we studied the effects of 15 reference agents testing positive in the BSA on spontaneous activity in E18 rat HPC neurons monitored with microelectrode arrays (MEA), and compared these effects to the BSA results. From these in vitro studies we conclude that the BSA provides 93% sensitivity and 100% specificity in prediction of drug-induced seizure liability, including detecting seizurogenicity by 3 groups of metabotropic glutamate receptor (mGluR) ligands. The MEA results seemed more variable, both quantitatively and directionally, particularly for endpoints capturing synchronized electrical activity. We discuss these results from the two models, comparing each with published results, and provide potential explanations for differences and future directions.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Convulsões
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Testes de Toxicidade
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Convulsivantes
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Potenciais Evocados
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Hipocampo
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Neurônios
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article