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- Title
Imbalance of Systemic Redox Biomarkers in Children with Epilepsy: Role of Ferroptosis.
- Authors
Petrillo, Sara; Pietrafusa, Nicola; Trivisano, Marina; Calabrese, Costanza; Saura, Francesca; Gallo, Maria Giovanna; Bertini, Enrico Silvio; Vigevano, Federico; Specchio, Nicola; Piemonte, Fiorella
- 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.
- Subjects
CHILDHOOD epilepsy; ENZYME inactivation; APOPTOSIS; DRUG target; TRANSCRIPTION factors; LIPIDS; GLUTATHIONE transferase; OXIDATION
- Publication
Antioxidants, 2021, Vol 10, Issue 8, p1267
- ISSN
2076-3921
- Publication type
Article
- DOI
10.3390/antiox10081267