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.