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).
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RTA_paper_Final_Brain_2_clean.pdf - Accepted Version Download (5MB) | Preview |
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.
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