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KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

Shekh-Ahmad, T; Eckel, R; Dayalan Naidu, S; Higgins, M; Yamamoto, M; Dinkova-Kostova, AT; Kovac, S; ... Walker, MC; + view all (2018) KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain 10.1093/brain/awy071. (In press). Green open access

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Abstract

Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.

Type: Article
Title: KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awy071
Publisher version: http://doi.org/10.1093/brain/awy071
Language: English
Additional information: © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Epilepsy, epileptogenesis, Nrf2-KEAP1 pathway, oxidative stress, mitochondrial dysfunction
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: http://discovery.ucl.ac.uk/id/eprint/10046311
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