Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy

Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy

Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neu...

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Main Authors: Tawfeeq Shekh-Ahmad, Andreas Lieb, Stjepana Kovac, Lukas Gola, W. Christian Wigley, Andrey Y. Abramov, Matthew C. Walker
Format: Article
Language:English
Published: Elsevier 2019-09-01
Series:Redox Biology
Online Access:http://www.sciencedirect.com/science/article/pii/S2213231719306731
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spelling doaj-cd9aa2fca8d745b69a2613ceb0b01fdd2020-11-24T22:06:49ZengElsevierRedox Biology2213-23172019-09-0126Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsyTawfeeq Shekh-Ahmad0Andreas Lieb1Stjepana Kovac2Lukas Gola3W. Christian Wigley4Andrey Y. Abramov5Matthew C. Walker6UCL Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N, UK; Faculty of Medicine, School of Pharmacy, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, IsraelUCL Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N, UK; Department of Pharmacology, Medical University of Innsbruck, Peter Mayr Strasse 1A, 6020, Innsbruck, AustriaDepartment of Neurology, University of Muenster, Muenster, 48149, GermanyDepartment of Neurology, University of Muenster, Muenster, 48149, GermanyReata Pharmaceuticals, 2801 Gateway Dr, Suite 150, Irving, TX, 75063, USAUCL Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N, UKUCL Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N, UK; Corresponding author.Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals. Keywords: Epileptogenesis, Spontaneous seizures, Oxidative stress, Keap1-Nrf2 pathway, NADPH oxidasehttp://www.sciencedirect.com/science/article/pii/S2213231719306731
collection DOAJ
language English
format Article
sources DOAJ
author Tawfeeq Shekh-Ahmad
Andreas Lieb
Stjepana Kovac
Lukas Gola
W. Christian Wigley
Andrey Y. Abramov
Matthew C. Walker
spellingShingle Tawfeeq Shekh-Ahmad
Andreas Lieb
Stjepana Kovac
Lukas Gola
W. Christian Wigley
Andrey Y. Abramov
Matthew C. Walker
Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy
Redox Biology
author_facet Tawfeeq Shekh-Ahmad
Andreas Lieb
Stjepana Kovac
Lukas Gola
W. Christian Wigley
Andrey Y. Abramov
Matthew C. Walker
author_sort Tawfeeq Shekh-Ahmad
title Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy
title_short Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy
title_full Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy
title_fullStr Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy
title_full_unstemmed Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy
title_sort combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy
publisher Elsevier
series Redox Biology
issn 2213-2317
publishDate 2019-09-01
description Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals. Keywords: Epileptogenesis, Spontaneous seizures, Oxidative stress, Keap1-Nrf2 pathway, NADPH oxidase
url http://www.sciencedirect.com/science/article/pii/S2213231719306731
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