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 T.
AU - Kovac, Stjepana
AU - Abramov, Andrey Y.
AU - Walker, Matthew C.
PY - 2018/5/1
Y1 - 2018/5/1
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
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U2 - 10.1093/brain/awy071
DO - 10.1093/brain/awy071
M3 - Article
C2 - 29538645
AN - SCOPUS:85047058349
SN - 0006-8950
VL - 141
SP - 1390
EP - 1403
JO - Brain
JF - Brain
IS - 5
ER -