Evidence that the EphA2 receptor exacerbates ischemic brain injury

John Thundyil, Silvia Manzanero, Dale Pavlovski, Tanya R Cully, Ker-Zhing Lok, Alexander Widiapradja, Prasad Chunduri, Dong-Gyu Jo, Masahide Asano, Bradley S Launikonis, Christopher Graeme Sobey, Mark G Coulthard, Thiruma Arumugam

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27 Citations (Scopus)

Abstract

Ephrin (Eph) signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT) and EphA2-deficient (EphA2(-/-)) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (24 or 72 h). Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/-) mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/-) brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3). Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/-) compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.
Original languageEnglish
Article numbere53528
Number of pages8
JournalPLoS ONE
Volume8
Issue number1
DOIs
Publication statusPublished - 2013

Cite this

Thundyil, J., Manzanero, S., Pavlovski, D., Cully, T. R., Lok, K-Z., Widiapradja, A., ... Arumugam, T. (2013). Evidence that the EphA2 receptor exacerbates ischemic brain injury. PLoS ONE, 8(1), [e53528]. https://doi.org/10.1371/journal.pone.0053528
Thundyil, John ; Manzanero, Silvia ; Pavlovski, Dale ; Cully, Tanya R ; Lok, Ker-Zhing ; Widiapradja, Alexander ; Chunduri, Prasad ; Jo, Dong-Gyu ; Asano, Masahide ; Launikonis, Bradley S ; Sobey, Christopher Graeme ; Coulthard, Mark G ; Arumugam, Thiruma. / Evidence that the EphA2 receptor exacerbates ischemic brain injury. In: PLoS ONE. 2013 ; Vol. 8, No. 1.
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title = "Evidence that the EphA2 receptor exacerbates ischemic brain injury",
abstract = "Ephrin (Eph) signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT) and EphA2-deficient (EphA2(-/-)) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (24 or 72 h). Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/-) mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/-) brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3). Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/-) compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.",
author = "John Thundyil and Silvia Manzanero and Dale Pavlovski and Cully, {Tanya R} and Ker-Zhing Lok and Alexander Widiapradja and Prasad Chunduri and Dong-Gyu Jo and Masahide Asano and Launikonis, {Bradley S} and Sobey, {Christopher Graeme} and Coulthard, {Mark G} and Thiruma Arumugam",
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Thundyil, J, Manzanero, S, Pavlovski, D, Cully, TR, Lok, K-Z, Widiapradja, A, Chunduri, P, Jo, D-G, Asano, M, Launikonis, BS, Sobey, CG, Coulthard, MG & Arumugam, T 2013, 'Evidence that the EphA2 receptor exacerbates ischemic brain injury', PLoS ONE, vol. 8, no. 1, e53528. https://doi.org/10.1371/journal.pone.0053528

Evidence that the EphA2 receptor exacerbates ischemic brain injury. / Thundyil, John; Manzanero, Silvia; Pavlovski, Dale; Cully, Tanya R; Lok, Ker-Zhing; Widiapradja, Alexander; Chunduri, Prasad; Jo, Dong-Gyu; Asano, Masahide; Launikonis, Bradley S; Sobey, Christopher Graeme; Coulthard, Mark G; Arumugam, Thiruma.

In: PLoS ONE, Vol. 8, No. 1, e53528, 2013.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Evidence that the EphA2 receptor exacerbates ischemic brain injury

AU - Thundyil, John

AU - Manzanero, Silvia

AU - Pavlovski, Dale

AU - Cully, Tanya R

AU - Lok, Ker-Zhing

AU - Widiapradja, Alexander

AU - Chunduri, Prasad

AU - Jo, Dong-Gyu

AU - Asano, Masahide

AU - Launikonis, Bradley S

AU - Sobey, Christopher Graeme

AU - Coulthard, Mark G

AU - Arumugam, Thiruma

PY - 2013

Y1 - 2013

N2 - Ephrin (Eph) signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT) and EphA2-deficient (EphA2(-/-)) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (24 or 72 h). Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/-) mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/-) brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3). Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/-) compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.

AB - Ephrin (Eph) signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT) and EphA2-deficient (EphA2(-/-)) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (24 or 72 h). Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/-) mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/-) brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3). Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/-) compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538581/pdf/pone.0053528.pdf

U2 - 10.1371/journal.pone.0053528

DO - 10.1371/journal.pone.0053528

M3 - Article

VL - 8

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 1

M1 - e53528

ER -

Thundyil J, Manzanero S, Pavlovski D, Cully TR, Lok K-Z, Widiapradja A et al. Evidence that the EphA2 receptor exacerbates ischemic brain injury. PLoS ONE. 2013;8(1). e53528. https://doi.org/10.1371/journal.pone.0053528