Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish

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 aci...

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Autores principales:	Yifan Zhang, Michiel Vanmeert, Aleksandra Siekierska, Annelii Ny, Jubi John, Geert Callewaert, Eveline Lescrinier, Wim Dehaen, Peter A. M. de Witte, Rafal M. Kaminski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6ff38202a6df4a5db9aa95983d4e8524
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spelling	oai:doaj.org-article:6ff38202a6df4a5db9aa95983d4e85242021-12-02T15:05:30ZInhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish10.1038/s41598-017-06294-w2045-2322https://doaj.org/article/6ff38202a6df4a5db9aa95983d4e85242017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06294-whttps://doaj.org/toc/2045-2322Abstract 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.Yifan ZhangMichiel VanmeertAleksandra SiekierskaAnnelii NyJubi JohnGeert CallewaertEveline LescrinierWim DehaenPeter A. M. de WitteRafal M. KaminskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yifan Zhang Michiel Vanmeert Aleksandra Siekierska Annelii Ny Jubi John Geert Callewaert Eveline Lescrinier Wim Dehaen Peter A. M. de Witte Rafal M. Kaminski Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish
description	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.
format	article
author	Yifan Zhang Michiel Vanmeert Aleksandra Siekierska Annelii Ny Jubi John Geert Callewaert Eveline Lescrinier Wim Dehaen Peter A. M. de Witte Rafal M. Kaminski
author_facet	Yifan Zhang Michiel Vanmeert Aleksandra Siekierska Annelii Ny Jubi John Geert Callewaert Eveline Lescrinier Wim Dehaen Peter A. M. de Witte Rafal M. Kaminski
author_sort	Yifan Zhang
title	Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish
title_short	Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish
title_full	Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish
title_fullStr	Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish
title_full_unstemmed	Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish
title_sort	inhibition of glutamate decarboxylase (gad) by ethyl ketopentenoate (ekp) induces treatment-resistant epileptic seizures in zebrafish
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6ff38202a6df4a5db9aa95983d4e8524
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Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish

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