1. Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations.
- Author
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Zimmer TS, Ciriminna G, Arena A, Anink JJ, Korotkov A, Jansen FE, van Hecke W, Spliet WG, van Rijen PC, Baayen JC, Idema S, Rensing NR, Wong M, Mills JD, van Vliet EA, and Aronica E
- Subjects
- Animals, Cells, Cultured, Encephalitis genetics, Encephalitis metabolism, Epilepsy complications, Epilepsy genetics, Female, Ferritins metabolism, Glial Fibrillary Acidic Protein genetics, Heme Oxygenase-1 metabolism, Humans, Male, Malformations of Cortical Development genetics, Malformations of Cortical Development, Group I genetics, Malformations of Cortical Development, Group I metabolism, Mice, Mice, Knockout, MicroRNAs genetics, Oxidative Stress, Tuberous Sclerosis genetics, Tuberous Sclerosis metabolism, Antioxidants metabolism, Epilepsy metabolism, Iron metabolism, Malformations of Cortical Development complications, Malformations of Cortical Development metabolism, Metabolic Networks and Pathways
- 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 (Tsc1
GFAP-/- 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., (© 2019 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)- Published
- 2020
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