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Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence.

  • Arena, Andrea1, 2
  • Zimmer, Till S1
  • van Scheppingen, Jackelien1
  • Korotkov, Anatoly1
  • Anink, Jasper J1
  • Mühlebner, Angelika1
  • Jansen, Floor E3
  • van Hecke, Wim4
  • Spliet, Wim G4
  • van Rijen, Peter C5
  • Vezzani, Annamaria6
  • Baayen, Johannes C7
  • Idema, Sander7
  • Iyer, Anand M1
  • Perluigi, Marzia2
  • Mills, James D1
  • van Vliet, Erwin A1, 8
  • Aronica, Eleonora1, 9
  • 1 Department of (Neuro-)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, the Netherlands. , (Netherlands)
  • 2 Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy. , (Italy)
  • 3 Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, the Netherlands. , (Netherlands)
  • 4 Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. , (Netherlands)
  • 5 Department of Neurosurgery, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. , (Netherlands)
  • 6 Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy. , (Italy)
  • 7 Department of Neurosurgery, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
  • 8 Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
  • 9 Stichting Epilepsie Instellingen Nederland (SEIN), the Netherlands. , (Netherlands)
Published Article
Brain Pathology
Wiley (Blackwell Publishing)
Publication Date
May 01, 2019
DOI: 10.1111/bpa.12661
PMID: 30303592


Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co-occurred also in resected brain tissue of patients with epileptogenic cortical malformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug-resistant epilepsy of different etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX-2 and NF-κB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH-SY5Y in which OS was induced using H2 O2 . OS markers were higher in dysmorphic neurons and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100 µM, but not 50 µM, of H2 O2 increased expression of TLR4, IL-1β and COX-2. We found that NF-κB signaling was activated only upon stimulation with 100 µM H2 O2 leading to upregulation of TLR4 signaling and IL-1β. The NF-κB inhibitor TPCA-1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF-κB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once. © 2018 International Society of Neuropathology.

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