Identification of compounds with novel anti-convulsant properties in a zebrafish model of epileptic seizures
- Authors
- Baxendale, S., Holdsworth, C.J., Santoscoy, P.M., Harrison, M.R., Fox, J., Parkin, C.A., Ingham, P.W., and Cunliffe, V.T.
- ID
- ZDB-PUB-120705-3
- Date
- 2012
- Source
- Disease models & mechanisms 5(6): 773-784 (Journal)
- Registered Authors
- Baxendale, Sarah, Cunliffe, Vincent, Harrison, Michael, Holdsworth, CJ, Ingham, Philip, Parkin, Caroline
- Keywords
- none
- MeSH Terms
-
- Animals
- Anticonvulsants/analysis*
- Anticonvulsants/pharmacology
- Anticonvulsants/therapeutic use*
- Central Nervous System/drug effects
- Central Nervous System/embryology
- Central Nervous System/pathology
- Disease Models, Animal*
- Drug Evaluation, Preclinical
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/pathology
- Epilepsy/drug therapy*
- Epilepsy/genetics
- Epilepsy/pathology
- Epilepsy/physiopathology
- Gene Expression Regulation, Developmental/drug effects
- In Situ Hybridization
- Larva/drug effects
- Motor Activity/drug effects
- Muscles/drug effects
- Muscles/embryology
- Muscles/metabolism
- Muscles/pathology
- Organ Specificity/drug effects
- Organ Specificity/genetics
- Pentylenetetrazole
- Picrotoxin/toxicity
- Small Molecule Libraries/analysis
- Small Molecule Libraries/pharmacology
- Small Molecule Libraries/therapeutic use
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/physiology*
- PubMed
- 22730455 Full text @ Dis. Model. Mech.
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.