Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence
Arena, Andrea; Zimmer, Till S; van Scheppingen, Jackelien; Korotkov, Anatoly; Anink, Jasper J; Mühlebner, Angelika; Jansen, Floor E; van Hecke, Wim; Spliet, Wim G; van Rijen, Peter C; Vezzani, Annamaria; Baayen, Johannes C; Idema, Sander; Iyer, Anand M; Perluigi, Marzia; Mills, James D; van Vliet, Erwin A; Aronica, Eleonora
(2019) Brain pathology (Zurich, Switzerland), volume 29, issue 3, pp. 351 - 365
(Article)
Abstract
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
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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 H 2 O 2 . 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 H 2 O 2 increased expression of TLR4, IL-1β and COX-2. We found that NF-κB signaling was activated only upon stimulation with 100 µM H 2 O 2 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.
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Keywords: Journal Article, epilepsy, focal cortical dysplasia, hemimegalencephaly, tuberous sclerosis complex, inflammation, oxidative stress, Oxidative Stress/physiology, Humans, Middle Aged, Tuberous Sclerosis, Child, Preschool, Epilepsy/metabolism, Infant, Male, Malformations of Cortical Development/metabolism, Adult, Female, Drug Resistant Epilepsy/metabolism, Child, Infant, Newborn, Cell Line, Malformations of Cortical Development, Group I, Seizures/physiopathology, Signal Transduction, Cerebral Cortex/metabolism, Hemimegalencephaly, Inflammation/metabolism, Neurons/metabolism, Adolescent, NF-kappa B/metabolism, Brain/metabolism, Clinical Neurology, General Neuroscience, Pathology and Forensic Medicine, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 1015-6305
Publisher: Wiley-Blackwell
Note: Funding Information: The research leading to these results has received funding from the European Union?s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602391 (EPISTOP; JvS, EA, FEJ) and no. 602102 (EPITARGET; AV, EAvV, EA), the Dutch Epilepsy Foundation, project number 16-05 (EAvV) and the European Union?s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 642881 (ECMED; AK, EA) and no. 722053 (EU-GliaPhD; TSZ, EA). Funding Information: The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602391 (EPISTOP; JvS, EA, FEJ) and no. 602102 (EPITARGET; AV, EAvV, EA), the Dutch Epilepsy Foundation, project number 16-05 (EAvV) and the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 642881 (ECMED; AK, EA) and no. 722053 (EU-GliaPhD; TSZ, EA). Publisher Copyright: © 2018 International Society of Neuropathology
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