Please use this identifier to cite or link to this item: http://localhost:8080/xmlui/handle/123456789/3189
Title: Inhibition of Glutamate Decarboxylase (GAD) by Ethyl Ketopentenoate (EKP) Induces Treatment-resistant Epileptic Seizures in Zebrafish
Authors: Zhang, Y
Vanmeert, M
Siekierska, A
Annelii, N
Jubi John
Callewaert, G
Eveline, L
Dehaen, W
De Witte, P A M
Kaminski, R M
Issue Date: 3-Aug-2017
Publisher: Nature
Citation: Scientific Reports, 7:7195
Abstract: Epilepsy is a chronic brain disorder characterized by recurrent seizures due to abnormal, excessive and synchronous neuronal activities in the brain. It affects approximately 65 million people worldwide, one third of which are still estimated to suffer from refractory seizures. Glutamic acid decarboxylase (GAD) that converts glutamate into GABA is a key enzyme in the dynamic regulation of neural network excitability. Importantly, clinical evidence shows that lowered GAD activity is associated with several forms of epilepsy which are often treatment resistant. In the present study, we synthetized and explored the possibility of using ethyl ketopentenoate (EKP), a lipid-permeable GAD-inhibitor, to induce refractory seizures in zebrafish larvae. Our results demonstrate that EKP evoked robust convulsive locomotor activities, excessive epileptiform discharges and upregulated c-fos expression in zebrafish. Moreover, transgenic animals in which neuronal cells express apoaequorin, a Ca2+-sensitive bioluminescent photoprotein, displayed large luminescence signals indicating strong EKP-induced neuronal activation. Molecular docking data indicated that this proconvulsant activity resulted from the direct inhibition of both gad67 and gad65. Limited protective efficacy of tested anti-seizure drugs (ASDs) demonstrated a high level of treatment resistance of EKP-induced seizures. We conclude that the EKP zebrafish model can serve as a high-throughput platform for novel ASDs discovery.
URI: http://10.10.100.66:8080/xmlui/handle/123456789/3189
Appears in Collections:2017

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