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Validation of the Zebrafish Pentylenetetrazol Seizure Model: Locomotor versus Electrographic Responses to Antiepileptic Drugs

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Zebrafish have recently emerged as an attractive in vivo model for epilepsy. Seven-day-old zebrafish larvae exposed to theGABAA antagonist pentylenetetrazol (PTZ) exhibit increased locomotor activity, seizure-like behavior, and epileptiformelectrographic activity. A previous study showed that 12 out of 13 antiepileptic drugs (AEDs) suppressed PTZ-mediatedincreases in larval movement, indicating the potential utility of zebrafish as a high-throughput in vivo model for AEDdiscovery. However, a question remained as to whether an AED-induced decrease in locomotion is truly indicative ofanticonvulsant activity, as some drugs may impair larval movement through other mechanisms such as general toxicity orsedation. We therefore carried out a study in PTZ-treated zebrafish larvae, to directly compare the ability of AEDs to inhibitseizure-like behavioral manifestations with their capacity to suppress epileptiform electrographic activity. We re-tested the13 AEDs of which 12 were previously reported to inhibit convulsions in the larval movement tracking assay, administeringconcentrations that did not, on their own, impair locomotion. In parallel, we carried out open-field recordings on larvalbrains after treatment with each AED. For the majority of AEDs we obtained the same response in both the behavioral andelectrographic assays. Overall our data correlate well with those reported in the literature for acute rodent PTZ tests,indicating that the larval zebrafish brain is more discriminatory than previously thought in its response to AEDs withdifferent modes of action. Our results underscore the validity of using the zebrafish larval locomotor assay as a rapid firstpassscreening tool in assessing the anticonvulsant and/or proconvulsant activity of compounds, but also highlight theimportance of performing adequate validation when using in vivo models.
Tijdschrift: PloS one
ISSN: 1932-6203
Issue: 1
Volume: 8
Aantal pagina's: 9
Jaar van publicatie:2013