Abstract
To assess if ferroptosis, a new type of programmed cell death accompanied by iron accumulation, lipid peroxidation, and glutathione depletion, occurs in children with epilepsy, and in order to identify a panel of biomarkers useful for patient stratification and innovative-targeted therapies, we measured ferroptosis biomarkers in blood from 83 unrelated children with a clinical diagnosis of epilepsy and 44 age-matched controls. We found a marked dysregulation of three ferroptosis key markers: a consistent increase of 4-hydroxy-2-nonenal (4-HNE), the main by-product of lipid peroxidation, a significant decrease of glutathione (GSH) levels, and a partial inactivation of the enzyme glutathione peroxidase 4 (GPX4), the mediator of lipid peroxides detoxification. Furthermore, we found a significant increase of NAPDH oxidase 2 (NOX2) in the blood of children, supporting this enzyme as a primary source of reactive oxygen species (ROS) in epilepsy. Additionally, since the nuclear factor erythroid 2-related factor 2 (NRF2) induction protects the brain from epileptic seizure damage, we also evaluated the NRF2 expression in the blood of children. The antioxidant and anti-inflammatory transcription factor was activated in patients, although not enough to re-establish a correct redox homeostasis for counteracting ferroptosis. Ferroptosis-mediated oxidative damage has been proposed as an emergent mechanism underlying the pathogenesis of epilepsy. Overall, our study confirms a crucial role for ferroptosis in epilepsy, leading to the identification of a panel of biomarkers useful to find new therapeutic targets. Developing innovative drugs, which act by inhibiting the ferroptosis signaling axis, may represent a promising strategy for new anti-seizure medications.
Highlights
Oxidative stress, glutamate-mediated excitotoxicity and neuroinflammation underlie the neurobiology of epilepsy, leading to seizure-induced cell death, increased susceptibility to neuronal synchronization, and progressive degeneration of brain areas [1,2,3,4]
Several mechanisms trigger ferroptosis (GSH depletion, excess of glutamate, inhibition of glutathione peroxidase 4 (GPX4)), many approaches (GSH augmentation, iron chelation, lipid radical scavenging) can revert it, paving the way for new promising therapeutic targets [10,11]. In this pilot cross-sectional study, we investigated if ferroptosis occurs in children with epilepsy by measuring the blood content of the “pathogenic triad” of ferroptosis bio-markers [8,12,13,14]; (i) 4-HNE and 15(S)-HETE, the main lipid peroxidation byproducts [15,16]; (ii) GPX4, the principal lipid peroxides detoxifying enzyme [17]; and (iii)
As the activation of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) can revert ferroptosis [9,10,11], and NRF2 appears promising as a neuroprotective factor in epileptogenesis and chronic epilepsy animal models [15,18,19,20,21,22], we evaluated the gene expression of
Summary
Glutamate-mediated excitotoxicity and neuroinflammation underlie the neurobiology of epilepsy, leading to seizure-induced cell death, increased susceptibility to neuronal synchronization, and progressive degeneration of brain areas [1,2,3,4]. Oxidative stress and antioxidant levels are important modulators of ferroptosis, which has been recently proposed as an emergent mechanism underlying the susceptibility to epileptic seizures [7,8]. Ferroptosis is an iron- and lipid-mediated programmed cell death characterized by ROS accumulation, GSH depletion, GPX4 decreased activity, and lipid peroxides accumulation [9]. ROS can act as primer, and ferroptosis underlies the excitotoxic neuronal injury in seizures [6,7]
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