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

T S Zimmer; G Ciriminna; A Arena; J J Anink; A Korotkov; F E Jansen; W van Hecke; W G Spliet; P C van Rijen; J C Baayen; S Idema; N R Rensing; M Wong; J D Mills; E A van Vliet; E Aronica

doi:https://doi.org/10.1111/nan.12596

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

T S Zimmer, G Ciriminna, A Arena, J J Anink, A Korotkov, F E Jansen, W van Hecke, W G Spliet, P C van Rijen, J C Baayen, S Idema, N R Rensing, M Wong, J D Mills, E A van Vliet, E Aronica

Research output: Contribution to journal › Article › Academic › peer-review

20 Citations (Scopus)

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. Tsc1^GFAP-/- 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 Tsc1^GFAP-/- 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.

Original language	English
Pages (from-to)	546-563
Number of pages	18
Journal	Neuropathology and applied neurobiology
Volume	46
Issue number	6
Early online date	1 Jan 2019
DOIs	https://doi.org/10.1111/nan.12596
Publication status	Published - 1 Oct 2020

Keywords

epilepsy
focal cortical dysplasia
haem oxygenase 1
iron metabolism
oxidative stress
tuberous sclerosis complex

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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, 46(6), 546-563. https://doi.org/10.1111/nan.12596

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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 = "With supplementary file",

year = "2020",

month = oct,

day = "1",

doi = "https://doi.org/10.1111/nan.12596",

language = "English",

volume = "46",

pages = "546--563",

journal = "Neuropathology and applied neurobiology",

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publisher = "Wiley-Blackwell",

number = "6",

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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 & 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

TY - JOUR

T1 - Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations

AU - Zimmer, T S

AU - Ciriminna, G

AU - Arena, A

AU - Anink, J J

AU - Korotkov, A

AU - Jansen, F E

AU - van Hecke, W

AU - Spliet, W G

AU - van Rijen, P C

AU - Baayen, J C

AU - Idema, S

AU - Rensing, N R

AU - Wong, M

AU - Mills, J D

AU - van Vliet, E A

AU - Aronica, E

N1 - With supplementary file

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

KW - epilepsy

KW - focal cortical dysplasia

KW - haem oxygenase 1

KW - iron metabolism

KW - oxidative stress

KW - tuberous sclerosis complex

UR - https://pure.uva.nl/ws/files/54226140/nan12596_sup_0001_suppinfo.docx

UR - http://www.scopus.com/inward/record.url?scp=85077852608&partnerID=8YFLogxK

U2 - https://doi.org/10.1111/nan.12596

DO - https://doi.org/10.1111/nan.12596

M3 - Article

C2 - 31869431

SN - 0305-1846

VL - 46

SP - 546

EP - 563

JO - Neuropathology and applied neurobiology

JF - Neuropathology and applied neurobiology

IS - 6

ER -

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

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