KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Anticonvulsants / chemistry
  • Anticonvulsants / therapeutic use*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Disease Models, Animal
  • Epilepsy / chemically induced
  • Epilepsy / metabolism*
  • Epilepsy / therapy*
  • Excitatory Amino Acid Agonists / toxicity
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Glutathione / metabolism
  • Kainic Acid / toxicity
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / genetics
  • Mice, Transgenic
  • Mutation / genetics
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Triterpenes / chemistry
  • Triterpenes / therapeutic use

Substances

  • Anticonvulsants
  • Excitatory Amino Acid Agonists
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Triterpenes
  • Omaveloxolone
  • Glutathione
  • Kainic Acid