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

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.

DHA and EPA Prevent Seizure and Depression‐Like Behavior by Inhibiting Ferroptosis and Neuroinflammation via Different Mode‐of‐Actions in a Pentylenetetrazole‐Induced Kindling Model in Mice

“…Recent research demonstrated that iron dyshomeostasis plays an important role in epilepsy and depression. [36,37] Generally, IRPs (IRP1 and IRP2) sense the iron concentration and increase intracellular active iron via upregulating TfR1, downregulating FTH1, and FPN1. However, an abnormal increase in IRPs can lead to intracellular iron accumulation, thereby promoting ferroptosis.…”

Attenuated iron stress and oxidative stress may participate in anti-seizure and neuroprotective roles of xenon in pentylenetetrazole-induced epileptogenesis

“…Iron metabolism in the brain is closely related to brain development and function. Past studies have confirmed a close relationship between iron levels and epilepsy ( Cai and Yang, 2021 ; Zimmer et al, 2021 ). Intracortical injections of Fe 3+ can induce seizures ( Das et al, 2017 ).…”

Enhanced sciatic nerve regeneration by relieving iron-overloading and organelle stress with the nanofibrous P(MMD-co-LA)/DFO conduits

“…It indicated that PDPLA/DFO alleviated iron overload during Wallerian Degeneration. The imbalance of iron homeostasis causes neuronal dysfunction, and iron accumulation causes a continuous pro-inflammatory environment [ 55 ]. According to morphological analysis, nerve respond differently to WD among groups.…”