KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

Tawfeeq Shekh-Ahmad, Ramona Eckel, Sharadha Dayalan Naidu, Maureen Higgins, Masayuki Yamamoto, Albena T. DInkova-Kostova, Stjepana Kovac, Andrey Y. Abramov, Matthew C. Walker

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1390-1403
Number of pages14
JournalBrain
Volume141
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Status Epilepticus
Epilepsy
Reactive Oxygen Species
Sclerosis
Seizures
Cell Death
Antioxidants
Adenosine Triphosphate
Brain
Kelch-Like ECH-Associated Protein 1
N-(11-cyano-2,2,6a,6b,9,9,12a-heptmethyl-10,14-dioxo-1,3,4,5,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picen-4a-yl)-2-2-difluoropropionamide

Keywords

  • epilepsy
  • epileptogenesis
  • mitochondrial dysfunction
  • Nrf2-KEAP1 pathway
  • oxidative stress

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Shekh-Ahmad, T., Eckel, R., Dayalan Naidu, S., Higgins, M., Yamamoto, M., DInkova-Kostova, A. T., ... Walker, M. C. (2018). KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain, 141(5), 1390-1403. https://doi.org/10.1093/brain/awy071

KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. / Shekh-Ahmad, Tawfeeq; Eckel, Ramona; Dayalan Naidu, Sharadha; Higgins, Maureen; Yamamoto, Masayuki; DInkova-Kostova, Albena T.; Kovac, Stjepana; Abramov, Andrey Y.; Walker, Matthew C.

In: Brain, Vol. 141, No. 5, 01.05.2018, p. 1390-1403.

Research output: Contribution to journalArticle

Shekh-Ahmad, T, Eckel, R, Dayalan Naidu, S, Higgins, M, Yamamoto, M, DInkova-Kostova, AT, Kovac, S, Abramov, AY & Walker, MC 2018, 'KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy', Brain, vol. 141, no. 5, pp. 1390-1403. https://doi.org/10.1093/brain/awy071
Shekh-Ahmad T, Eckel R, Dayalan Naidu S, Higgins M, Yamamoto M, DInkova-Kostova AT et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain. 2018 May 1;141(5):1390-1403. https://doi.org/10.1093/brain/awy071
Shekh-Ahmad, Tawfeeq ; Eckel, Ramona ; Dayalan Naidu, Sharadha ; Higgins, Maureen ; Yamamoto, Masayuki ; DInkova-Kostova, Albena T. ; Kovac, Stjepana ; Abramov, Andrey Y. ; Walker, Matthew C. / KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. In: Brain. 2018 ; Vol. 141, No. 5. pp. 1390-1403.
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