Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy
Tawfeeq Shekh-Ahmad,
Andreas Lieb,
Stjepana Kovac,
Lukas Gola,
W. Christian Wigley,
Andrey Y. Abramov,
Matthew C. Walker
Affiliations
Tawfeeq Shekh-Ahmad
UCL 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, Israel
Andreas Lieb
UCL 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, Austria
Stjepana Kovac
Department of Neurology, University of Muenster, Muenster, 48149, Germany
Lukas Gola
Department of Neurology, University of Muenster, Muenster, 48149, Germany
W. Christian Wigley
Reata Pharmaceuticals, 2801 Gateway Dr, Suite 150, Irving, TX, 75063, USA
Andrey Y. Abramov
UCL Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N, UK
Matthew C. Walker
UCL 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 oxidase
