TY  - JOUR
AU  - Zimmer, Till S
AU  - David, Bastian
AU  - Broekaart, Diede W M
AU  - Schidlowski, Martin
AU  - Ruffolo, Gabriele
AU  - Korotkov, Anatoly
AU  - van der Wel, Nicole N
AU  - van Rijen, Peter C
AU  - Mühlebner, Angelika
AU  - van Hecke, Wim
AU  - Baayen, Johannes C
AU  - Idema, Sander
AU  - François, Liesbeth
AU  - van Eyll, Jonathan
AU  - Dedeurwaerdere, Stefanie
AU  - Kessels, Helmut W
AU  - Surges, Rainer
AU  - Rüber, Theodor
AU  - Gorter, Jan A
AU  - Mills, James D
AU  - van Vliet, Erwin A
AU  - Aronica, Eleonora
TI  - Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy.
JO  - Acta neuropathologica
VL  - 142
IS  - 4
SN  - 1432-0533
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2021-01505
SP  - 729 - 759
PY  - 2021
AB  - 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.
KW  - Adult
KW  - Aged
KW  - Aged, 80 and over
KW  - Animals
KW  - Astrocytes: metabolism
KW  - Astrocytes: pathology
KW  - Case-Control Studies
KW  - Cell Culture Techniques
KW  - Disease Models, Animal
KW  - Epilepsy, Temporal Lobe: complications
KW  - Epilepsy, Temporal Lobe: metabolism
KW  - Epilepsy, Temporal Lobe: pathology
KW  - Female
KW  - Hippocampus: metabolism
KW  - Humans
KW  - Iron: metabolism
KW  - Iron Metabolism Disorders: etiology
KW  - Iron Metabolism Disorders: pathology
KW  - Male
KW  - Middle Aged
KW  - Oxidative Stress: physiology
KW  - Rats
KW  - Status Epilepticus: complications
KW  - Status Epilepticus: metabolism
KW  - Status Epilepticus: pathology
KW  - Astrocytes (Other)
KW  - Glutathione metabolism (Other)
KW  - Iron (Other)
KW  - Status epilepticus (Other)
KW  - Temporal lobe epilepsy with hippocampal sclerosis (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34292399
C2  - pmc:PMC8423709
DO  - DOI:10.1007/s00401-021-02348-6
UR  - https://pub.dzne.de/record/162850
ER  -