1. Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy
- Author
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James D. Mills, Eleonora Aronica, Wim Van Hecke, Till S. Zimmer, Stefanie Dedeurwaerdere, Johannes C. Baayen, Sander Idema, Nicole N. van der Wel, Anatoly Korotkov, Jonathan van Eyll, Peter C. van Rijen, Rainer Surges, Erwin A. van Vliet, Helmut W. Kessels, Jan A. Gorter, Diede W. M. Broekaart, Angelika Mühlebner, Martin Schidlowski, Theodor Rüber, Bastian David, Gabriele Ruffolo, Liesbeth François, Cellular and Computational Neuroscience (SILS, FNWI), Graduate School, APH - Aging & Later Life, APH - Mental Health, ANS - Cellular & Molecular Mechanisms, Pathology, Medical Biology, ANS - Neurodegeneration, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
Male ,Astrocytes ,Glutathione metabolism ,Iron ,Status epilepticus ,Temporal lobe epilepsy with hippocampal sclerosis ,0301 basic medicine ,Cell Culture Techniques ,Hippocampus ,metabolism [Hippocampus] ,Hippocampal formation ,physiology [Oxidative Stress] ,Epilepsy ,0302 clinical medicine ,etiology [Iron Metabolism Disorders] ,pathology [Astrocytes] ,metabolism [Iron] ,Aged, 80 and over ,metabolism [Astrocytes] ,biology ,Middle Aged ,metabolism [Status Epilepticus] ,medicine.anatomical_structure ,pathology [Status Epilepticus] ,Female ,metabolism [Epilepsy, Temporal Lobe] ,medicine.symptom ,Astrocyte ,Adult ,medicine.medical_specialty ,pathology [Epilepsy, Temporal Lobe] ,complications [Status Epilepticus] ,Pathology and Forensic Medicine ,Temporal lobe ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Internal medicine ,medicine ,Animals ,Humans ,ddc:610 ,Aged ,Original Paper ,Hippocampal sclerosis ,business.industry ,complications [Epilepsy, Temporal Lobe] ,medicine.disease ,Iron Metabolism Disorders ,Rats ,Ferritin ,Oxidative Stress ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Epilepsy, Temporal Lobe ,Case-Control Studies ,pathology [Iron Metabolism Disorders] ,biology.protein ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02348-6.
- Published
- 2021