Identification of compounds with anti-convulsant properties in a zebrafish model of epileptic seizures

Autor: Vincent T. Cunliffe, James M. Fox, Caroline A. Parkin, Philip W. Ingham, Paola L. Meza Santoscoy, Michael R. Harrison, Sarah Baxendale, Celia J. Holdsworth
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Central Nervous System
Embryo
Nonmammalian
medicine.medical_treatment
Neuroscience (miscellaneous)
Drug Evaluation
Preclinical
lcsh:Medicine
Medicine (miscellaneous)
In situ hybridization
Pharmacology
Motor Activity
General Biochemistry
Genetics and Molecular Biology
Small Molecule Libraries
03 medical and health sciences
Epilepsy
0302 clinical medicine
Immunology and Microbiology (miscellaneous)
Transcription (biology)
In vivo
lcsh:Pathology
medicine
Animals
Picrotoxin
Zebrafish
In Situ Hybridization
030304 developmental biology
Regulation of gene expression
0303 health sciences
biology
Muscles
lcsh:R
Gene Expression Regulation
Developmental
biology.organism_classification
medicine.disease
3. Good health
Disease Models
Animal
Anticonvulsant
Organ Specificity
Larva
Convulsant
Pentylenetetrazole
Anticonvulsants
030217 neurology & neurosurgery
lcsh:RB1-214
Research Article
Zdroj: Disease Models & Mechanisms
Disease Models & Mechanisms, Vol 5, Iss 6, Pp 773-784 (2012)
ISSN: 1754-8411
1754-8403
Popis: Summary The availability of animal models of epileptic seizures provides opportunities to identify novel anticonvulsants for the treatment of people with epilepsy. We found that exposure of 2-day-old zebrafish embryos to the convulsant agent pentylenetetrazole (PTZ) rapidly induces the expression of synaptic-activity-regulated genes in the CNS, and elicited vigorous episodes of calcium (Ca2+) 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 fos in 2-day-old (2 dpf) zebrafish embryos. Further analysis of a subset of these compounds, which included compounds with known and newly identified anticonvulsant properties, revealed that they exhibited concentration-dependent inhibition of both locomotor activity and PTZ-induced fos transcription, confirming their anticonvulsant characteristics. We conclude that this in situ hybridisation assay for fos transcription in the zebrafish embryonic CNS is a robust, high-throughput in vivo indicator of the neural response to convulsant treatment and lends itself well to chemical screening applications. Moreover, our results demonstrate that suppression of PTZ-induced fos expression provides a sensitive means of identifying compounds with anticonvulsant activities.
Databáze: OpenAIRE
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