The availability of animal models of epileptic seizures provides opportunities to identify novel anticonvulsants for treatment of people with epilepsy. We found that exposure of 2 day-old zebrafish embryos to the convulsant agent Pentylenetetrazole (PTZ) rapidly induced the expression of synaptic activity-regulated genes in the CNS, and elicited vigorous episodes of calcium flux in muscle cells as well as intense locomotor activity. We then screened a library of ~2000 known bioactive small molecules and identified 46 compounds that suppressed PTZ-induced transcription of the synaptic activity-regulated gene cfos in 2 day-old zebrafish embryos. Further analysis of a subset of these compounds, which included compounds with known and novel anticonvulsant properties, revealed that they exhibited concentration-dependent inhibition of both locomotor activity and PTZ-induced cfos transcription, confirming their anticonvulsant characteristics. We conclude that this in situ hybridisation assay for cfos transcription in the zebrafish embryonic CNS is a robust, high throughput in vivo indicator of the neural response to convulsant treatment which lends itself well to chemical screening applications. Moreover, our results demonstrate that suppression of PTZ-induced cfos expression provides a sensitive means of identifying compounds with novel anticonvulsant activities.
- Received April 18, 2012.
- Accepted June 16, 2012.
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