KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy
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.
The Botanical Garden of Department of Pharmacognosy, University of Vienna, Austria. Photo by Atanas G. Atanasov.
Lagoon of the seven cities, a twin lake in the crater of a dormant volcano in the western part of the São Miguel island (Azores, Portugal). Photo by Dr. Ana Sanches Silva.
Central Australian desert scene. Photo by Dr. Rohan Davis.
HEK293T cells. Photo by Atanas G. Atanasov.
Tropical rainforest, Queensland, Australia. Photo by Dr. Rohan Davis.
Australian ocean scene. Photo by Dr. Rohan Davis.
Laboratory equipment. Photo by Atanas G. Atanasov.
Rhododendron arboreum flower. Photo by Devesh Tewari.
The Valley of Flowers, Himalaya, India. Photo by Dr. Rajeshwari Singh.
Bryce Canyon, Utah, USA. Photo by Dr. Anupam Bishayee.
Euphorbia prolifera Buch. (Ham) Ex. Photo by Devesh Tewari.
Foothills of Himalaya, India. Photo by Devesh Tewari.
The Valley of Flowers, Himalaya, India. Photo by Dr. Rajeshwari Singh.
Eco-School Festival, Leiria-Portugal, Spring 2018
Polygonum maritimum (L.) (Polygonaceae)- Ourdania beach (Ain Temouchent- west Algeria)- taken by PhD. EL HACI Imad Abdelhamid
Flower blossoms at gardens by the bay Singapore-photo by Dr. Hemanth Kumar Boyina.
