Reference : Pharmacological characterization of an antisense knockdown zebrafish model of Dravet ...
Scientific journals : Article
Human health sciences : Multidisciplinary, general & others
http://hdl.handle.net/10993/27294
Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: Inhibition of epileptic seizures by the serotonin agonist fenfluramine
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Zhang, Yang mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Computer Science and Communications Research Unit (CSC)]
Kecskés, A. [Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium]
Copmans, D. [Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium]
Langlois, Melanie mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Crawford, Alexander Dettmar mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Ceulemans, B. [Department of Neurology-Child Neurology, University Hospital Antwerp, University of Antwerp, Antwerp, Belgium]
Lagae, L. [Department of Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium]
De Witte, P. A. M. [Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium]
Esguerra, C. V. [Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium, Chemical Neuroscience Group, Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway]
2015
PLoS ONE
Public Library of Science
10
5
Yes (verified by ORBilu)
19326203
[en] Article ; Animalia ; Danio rerio
[en] Dravet syndrome (DS) is one of the most pharmacoresistant and devastating forms of childhood epilepsy syndromes. Distinct de novo mutations in the SCN1A gene are responsible for over 80% of DS cases. While DS is largely resistant to treatment with existing anti-epileptic drugs, promising results have been obtained in clinical trials with human patients treated with the serotonin agonist fenfluramine as an add-on therapeutic. We developed a zebrafish model of DS using morpholino antisense oligomers (MOs) targeting scn1Lab, the zebrafish ortholog of SCN1A. Zebrafish larvae with an antisense knockdown of scn1Lab (scn1Lab morphants) were characterized by automated behavioral tracking and high-resolution video imaging, in addition to measuring brain activity through local field potential recordings. Our findings reveal that scn1Lab morphants display hyperactivity, convulsive seizure-like behavior, loss of posture, repetitive jerking and a myoclonic seizure-like pattern. The occurrence of spontaneous seizures was confirmed by local field potential recordings of the forebrain, measuring epileptiform discharges. Furthermore, we show that these larvae are remarkably sensitive to hyperthermia, similar to what has been described for mouse models of DS, as well as for human DS patients. Pharmacological evaluation revealed that sodium valproate and fenfluramine significantly reduce epileptiform discharges in scn1Lab morphants. Our findings for this zebrafish model of DS are in accordance with clinical data for human DS patients. To our knowledge, this is the first study demonstrating effective seizure inhibition of fenfluramine in an animal model of Dravet syndrome. Moreover, these results provide a basis for identifying novel analogs with improved activity and significantly milder or no side effects. © 2015 Zhang et al.
Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group)
http://hdl.handle.net/10993/27294
10.1371/journal.pone.0125898

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