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ZIRC
ZFIN ID: ZDB-PUB-120705-3
Identification of compounds with novel anti-convulsant properties in a zebrafish model of epileptic seizures
Baxendale, S., Holdsworth, C.J., Santoscoy, P.M., Harrison, M.R., Fox, J., Parkin, C.A., Ingham, P.W., and Cunliffe, V.T.
Date: 2012
Source: Disease models & mechanisms   5(6): 773-784 (Journal)
Registered Authors: Baxendale, Sarah, Cunliffe, Vincent, 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.
FIGURES
ABSTRACT

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.

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