Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations

Autor: G. Ciriminna, James D. Mills, Nicholas Rensing, Eleonora Aronica, Wim G.M. Spliet, Andrea Arena, Anatoly Korotkov, Johannes C. Baayen, Sander Idema, Till S. Zimmer, E.A. van Vliet, W. Van Hecke, Jasper J. Anink, Floor E. Jansen, Michael Wong, P.C. van Rijen
Přispěvatelé: Neurosurgery, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Cellular and Computational Neuroscience (SILS, FNWI), Pathology, APH - Aging & Later Life, APH - Mental Health, Graduate School
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
tuberous sclerosis complex
medicine.disease_cause
Antioxidants
Tuberous sclerosis
Mice
0302 clinical medicine
Tuberous Sclerosis
iron metabolism
Cells
Cultured
Mice
Knockout
biology
3. Good health
Malformations of Cortical Development
Real-time polymerase chain reaction
Neurology
Immunohistochemistry
Encephalitis
Female
medicine.symptom
focal cortical dysplasia
Metabolic Networks and Pathways
congenital
hereditary
and neonatal diseases and abnormalities
Histology
Iron
Inflammation
In situ hybridization
Pathology and Forensic Medicine
03 medical and health sciences
Physiology (medical)
Glial Fibrillary Acidic Protein
medicine
Animals
Humans
Epilepsy
business.industry
Cortical dysplasia
medicine.disease
Ferritin
MicroRNAs
Oxidative Stress
030104 developmental biology
Malformations of Cortical Development
Group I
Ferritins
biology.protein
Cancer research
haem oxygenase 1
Neurology (clinical)
business
030217 neurology & neurosurgery
Oxidative stress
Heme Oxygenase-1
Zdroj: Zimmer, T S, Ciriminna, G, Arena, A, Anink, J J, Korotkov, A, Jansen, F E, van Hecke, W, Spliet, W G, van Rijen, P C, Baayen, J C, Idema, S, Rensing, N R, Wong, M, Mills, J D, van Vliet, E A & Aronica, E 2020, ' Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations ', Neuropathology and Applied Neurobiology, vol. 46, no. 6, pp. 546-563 . https://doi.org/10.1111/nan.12596
Neuropathology and Applied Neurobiology
Neuropathology and Applied Neurobiology, 46(6), 546-563. Wiley-Blackwell
Neuropathology and applied neurobiology, 46(6), 546-563. Wiley-Blackwell
ISSN: 1365-2990
0305-1846
DOI: 10.1111/nan.12596
Popis: 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.
Databáze: OpenAIRE
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