Imbalance of Systemic Redox Biomarkers in Children with Epilepsy: Role of Ferroptosis
Sara Petrillo,
Nicola Pietrafusa,
Marina Trivisano,
Costanza Calabrese,
Francesca Saura,
Maria Giovanna Gallo,
Enrico Silvio Bertini,
Federico Vigevano,
Nicola Specchio,
Fiorella Piemonte
Affiliations
Sara Petrillo
Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy
Nicola Pietrafusa
Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Piazza S. Onofrio 4, 00165 Rome, Italy
Marina Trivisano
Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Piazza S. Onofrio 4, 00165 Rome, Italy
Costanza Calabrese
Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Piazza S. Onofrio 4, 00165 Rome, Italy
Francesca Saura
Department of Laboratory Medicine, Children’s Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy
Maria Giovanna Gallo
Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy
Enrico Silvio Bertini
Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy
Federico Vigevano
Department of Neuroscience, Bambino Gesu Children’s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Piazza S. Onforio 4, 00165 Rome, Italy
Nicola Specchio
Department of Neuroscience, Bambino Gesu Children’s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Piazza S. Onforio 4, 00165 Rome, Italy
Fiorella Piemonte
Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy
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.
