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@ARTICLE{Zimmer:162850,
      author       = {Zimmer, Till S and David, Bastian and Broekaart, Diede W M
                      and Schidlowski, Martin and Ruffolo, Gabriele and Korotkov,
                      Anatoly and van der Wel, Nicole N and van Rijen, Peter C and
                      Mühlebner, Angelika and van Hecke, Wim and Baayen, Johannes
                      C and Idema, Sander and François, Liesbeth and van Eyll,
                      Jonathan and Dedeurwaerdere, Stefanie and Kessels, Helmut W
                      and Surges, Rainer and Rüber, Theodor and Gorter, Jan A and
                      Mills, James D and van Vliet, Erwin A and Aronica, Eleonora},
      title        = {{S}eizure-mediated iron accumulation and dysregulated iron
                      metabolism after status epilepticus and in temporal lobe
                      epilepsy.},
      journal      = {Acta neuropathologica},
      volume       = {142},
      number       = {4},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2021-01505},
      pages        = {729 - 759},
      year         = {2021},
      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.},
      keywords     = {Adult / Aged / Aged, 80 and over / Animals / Astrocytes:
                      metabolism / Astrocytes: pathology / Case-Control Studies /
                      Cell Culture Techniques / Disease Models, Animal / Epilepsy,
                      Temporal Lobe: complications / Epilepsy, Temporal Lobe:
                      metabolism / Epilepsy, Temporal Lobe: pathology / Female /
                      Hippocampus: metabolism / Humans / Iron: metabolism / Iron
                      Metabolism Disorders: etiology / Iron Metabolism Disorders:
                      pathology / Male / Middle Aged / Oxidative Stress:
                      physiology / Rats / Status Epilepticus: complications /
                      Status Epilepticus: metabolism / Status Epilepticus:
                      pathology / Astrocytes (Other) / Glutathione metabolism
                      (Other) / Iron (Other) / Status epilepticus (Other) /
                      Temporal lobe epilepsy with hippocampal sclerosis (Other)},
      cin          = {AG Stöcker},
      ddc          = {610},
      cid          = {I:(DE-2719)1013026},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34292399},
      pmc          = {pmc:PMC8423709},
      doi          = {10.1007/s00401-021-02348-6},
      url          = {https://pub.dzne.de/record/162850},
}