KEAP₁ inhibition is neuroprotective and suppresses the development of epilepsy

TY - JOUR

T1 - KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

AU - Shekh-Ahmad, Tawfeeq

AU - Eckel, Ramona

AU - Dayalan Naidu, Sharadha

AU - Higgins, Maureen

AU - Yamamoto, Masayuki

AU - Dinkova-Kostova, Albena

AU - Kovac, Stjepana

AU - Abramov, Andrey Y.

AU - Walker, Matthew C.

N1 - This work was supported by the European Union’s Seventh Framework Programme (FP7/2007- 2013) under grant agreement n°602102 (EPITARGET) and Epilepsy Research UK and the Biotechnology and Biological Sciences Research Council (Project Grant BB/L01923X/1).

PY - 2018/5

Y1 - 2018/5

N2 - 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.

AB - 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.

KW - epilepsy

KW - epileptogenesis

KW - mitochondrial dysfunction

KW - Nrf2-KEAP1 pathway

KW - oxidative stress

UR - https://www.scopus.com/pages/publications/85047058349

U2 - 10.1093/brain/awy071

DO - 10.1093/brain/awy071

M3 - Article

C2 - 29538645

SN - 0006-8950

VL - 141

SP - 1390

EP - 1403

JO - Brain

JF - Brain

IS - 5

ER -