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.

Antioxidant treatment after epileptogenesis onset prevents comorbidities in rats sensitized by a past stressful event

“…Maintaining social contact provides different results, arguably modeling a different aspect of patient diversity. This argument may also explain the difference of our results with the reported positive effect of antioxidant treatment or targeting the Nrf2 pathway in experimental epilepsy in socially isolated animals . It will be interesting to test whether the positive effects found in the latter studies are due to the removal of the social isolation component of oxidative stress by the treatment, which would be highly clinically relevant.…”

“…Thus, in the SDL group, SE will occur in a context of oxidative stress. Because there is a tight relationship between ROS accumulation and epilepsy, we reasoned that SE should amplify oxidative stress in the SDL group, and tested whether the antioxidant treatment would prevent excessive ROS accumulation. We first assessed the antioxidant/detoxifying systems in animals 6 weeks after SE (Figure C).…”

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

“…Moreover, ROS modulate nuclear factor‐κB (NFκB)‐mediated transcriptional activation of various inflammatory genes and may provoke oxidative damage to proteins, lipids, and DNA. The available data support a vicious cycle that links ROS production and neuroinflammation to neuronal and glial dysfunction, thus representing a potential mechanism of epileptogenesis …”

“…The treatment delayed the time of onset of epilepsy by 30%, achieved a 70% reduction in seizure frequency compared to controls, and resolved cognitive deficits . A similar therapeutic response occurred in kainate‐induced SE models with the small molecule RTA 408, which removes the inhibitory control of the chaperon protein Keap1 on Nrf2, given alone or in combination with 4‐(2‐aminoethyl)benzenesulfonyl fluoride hydrochloride, a NADPH oxidase inhibitor, and with 1400W, a highly selective inhibitor of inducible nitric oxide synthase . These therapeutic effects outlasted the end of treatment by several weeks, suggesting disease‐modifying effects.…”

“…The available data support a vicious cycle that links ROS production and neuroinflammation to neuronal and glial dysfunction, thus representing a potential mechanism of epileptogenesis. 120,127,[134][135][136][137] Reduction of oxidative stress in animal models of epilepsy with small molecules reduces SE-induced neuronal damage and cognitive deficits. A recent hippocampal electrical SE study in rats used a combination of NAC and sulforaphane to increase both the acute endogenous antioxidant response and the longer-term antioxidant system through the transcriptional factor Nrf2, which induces the major antioxidant enzymes.…”