KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy.

Article Details

Citation

Shekh-Ahmad T, Eckel R, Dayalan Naidu S, Higgins M, Yamamoto M, Dinkova-Kostova AT, Kovac S, Abramov AY, Walker MC

KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy.

Brain. 2018 May 1;141(5):1390-1403. doi: 10.1093/brain/awy071.

PubMed ID
29538645 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
OmaveloxoloneKelch-like ECH-associated protein 1ProteinHumans
Unknown
Inhibitor
Details