@article{2f840790f13447aa809385c063e1d139,
title = "Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations",
abstract = "Aims: Oxidative stress is evident in resected epileptogenic brain tissue of patients with developmental brain malformations related to mammalian target of rapamycin activation: tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCD IIb). Whether chronic activation of anti-oxidant pathways is beneficial or contributes to pathology is not clear. Methods: We investigated oxidative stress markers, including haem oxygenase 1, ferritin and the inflammation associated microRNA-155 in surgically resected epileptogenic brain tissue of TSC (n = 10) and FCD IIb (n = 8) patients and in a TSC model (Tsc1GFAP−/− mice) using immunohistochemistry, in situ hybridization, real-time quantitative PCR and immunoblotting. Using human foetal astrocytes we performed an in vitro characterization of the anti-oxidant response to acute and chronic oxidative stress and evaluated overexpression of the disease-relevant pro-inflammatory microRNA-155. Results: Resected TSC or FCD IIb tissue displayed higher expression of oxidative stress markers and microRNA-155. Tsc1GFAP−/− mice expressed more microRNA-155 and haem oxygenase 1 in the brain compared to wild-type, preceding the typical development of spontaneous seizures in these animals. In vitro, chronic microRNA-155 overexpression induced haem oxygenase 1, iron regulatory elements and increased susceptibility to oxidative stress. Overexpression of iron regulatory genes was also detected in patients with TSC, FCD IIb and Tsc1GFAP−/− mice. Conclusion: Our results demonstrate that early and sustained activation of anti-oxidant signalling and dysregulation of iron metabolism are a pathological hallmark of FCD IIb and TSC. Our findings suggest novel therapeutic strategies aimed at controlling the pathological link between both processes.",
keywords = "epilepsy, focal cortical dysplasia, haem oxygenase 1, iron metabolism, oxidative stress, tuberous sclerosis complex",
author = "Zimmer, {T. S.} and G. Ciriminna and A. Arena and Anink, {J. J.} and A. Korotkov and Jansen, {F. E.} and {van Hecke}, W. and Spliet, {W. G.} and {van Rijen}, {P. C.} and Baayen, {J. C.} and S. Idema and Rensing, {N. R.} and M. Wong and Mills, {J. D.} and {van Vliet}, {E. A.} and E. Aronica",
note = "Funding Information: TSZ, GC, AA, AK and JDM performed the experiments, data collection and analysis. WvH, WGS, PCvR, JCB, SI and EA helped with the selection and collection of human brain tissues and clinical data. NRR and MW collected Tsc1 GFAP −/− mouse tissue. EA, EAvV and JDM conceived the study and participated in its design and coordination. TSZ, JDM, EAvV and EA drafted and prepared the manuscript. All authors read, revised and approved the final manuscript. The research leading to these results has received funding from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007‐2013) under grant agreement no. 602391 (EPISTOP; EA, FJ) and no. 602102 (EPITARGET; EAvV, EA), the Dutch Epilepsy Foundation, project number 16‐05 (EAvV), the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska‐Curie grant agreement no. 642881 (ECMED; AK, EA) and no. 722053 (EU‐GliaPhD; TS, EA) and the United States National Institutes of Health NS056872 (MW). Funding Information: TSZ, GC, AA, AK and JDM performed the experiments, data collection and analysis. WvH, WGS, PCvR, JCB, SI and EA helped with the selection and collection of human brain tissues and clinical data. NRR and MW collected Tsc1GFAP?/? mouse tissue. EA, EAvV and JDM conceived the study and participated in its design and coordination. TSZ, JDM, EAvV and EA drafted and prepared the manuscript. All authors read, revised and approved the final manuscript. 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; EA, FJ) and no. 602102 (EPITARGET; EAvV, EA), the Dutch Epilepsy Foundation, project number 16-05 (EAvV), 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; TS, EA) and the United States National Institutes of Health NS056872 (MW). Publisher Copyright: {\textcopyright} 2019 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society",
year = "2020",
month = oct,
day = "1",
doi = "10.1111/nan.12596",
language = "English",
volume = "46",
pages = "546--563",
journal = "Neuropathology and Applied Neurobiology",
issn = "0305-1846",
publisher = "Wiley-Blackwell",
number = "6",
}