Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy

Till S Zimmer,Jan A Gorter,Theodor Rüber,Angelika Mühlebner,James D Mills,Liesbeth François,Johannes C Baayen,Gabriele Ruffolo,Jonathan Van Eyll,Rainer Surges,Nicole N Van Der Wel,Diede W M Broekaart,Wim Van Hecke,Peter C Van Rijen,Stefanie Dedeurwaerdere,Martin Schidlowski,Erwin A Van Vliet,Bastian David,A Korotkov ,Sander Idema,Helmut W Kessels,Eleonora Aronica

doi:10.1007/s00401-021-02348-6

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.

Highlights

Epilepsy is a common neurological disease that is characterized by “an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequences of this condition” [18, 19].Epileptogenesis describes the pathogenic process by which physiological and structural changes in the brain are induced, leading to increased seizure susceptibility and enhanced likelihood of spontaneous recurrent seizures (SRS) to occur [61]
This study aims to investigate (1) if iron accumulation and iron metabolism are altered after status epilepticus (SE) and in temporal lobe epilepsy (TLE) per se in conjunction with oxidative stress (OS) and antioxidant capacity, (2) which cell types are involved in iron regulation and (3) whether iron has ictogenic effects and could be involved in epileptogenesis
We evaluated OS and iron metabolism in post-mortem brain tissue of patients who died after SE and in surgically resected brain tissue from patients suffering from intractable TLE with hippocampal sclerosis (TLE-HS) to elucidate the effects of acute seizure activity and chronic epilepsy in iron metabolism, respectively

Summary

Introduction

Epilepsy is a common neurological disease that is characterized by “an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequences of this condition” [18, 19].Epileptogenesis describes the pathogenic process by which physiological and structural changes in the brain are induced, leading to increased seizure susceptibility and enhanced likelihood of spontaneous recurrent seizures (SRS) to occur [61]. Targeting OS by providing ROS scavenging antioxidants or by boosting endogenous antioxidant systems, the activity of the antioxidant transcription factor nuclear factor erythroid 2 like 2 (Nrf-2), was shown to have a beneficial disease-modifying effect in models of acquired epilepsy, delaying onset and progression of seizures [45, 58, 74, 76]. These effects were likely facilitated by proteins involved in the production and recycling of the primary intracellular antioxidant glutathione [7]

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