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.
authors: School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia.
authors: John
authors: J
authors: Thundyil
authors: Silvia
authors: S
authors: Manzanero
authors: Dale
authors: D
authors: Pavlovski
authors: Tanya R
authors: TR
authors: Cully
authors: Ker-Zhing
authors: KZ
authors: Lok
authors: Alexander
authors: A
authors: Widiapradja
authors: Prasad
authors: P
authors: Chunduri
authors: Dong-Gyu
authors: DG
authors: Jo
authors: Chie
authors: C
authors: Naruse
authors: Masahide
authors: M
authors: Asano
authors: Bradley S
authors: BS
authors: Launikonis
authors: Christopher G
authors: CG
authors: Sobey
authors: Mark G
authors: MG
authors: Coulthard
authors: Thiruma V
authors: TV
authors: Arumugam
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D036342:Ephrins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D036104:Receptor, EphA2 / Q000172:deficiency / Q000235:genetics*; D015427:Reperfusion Injury / Q000473:pathology; D015398:Signal Transduction; D013778:Tetrazolium Salts; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D036342:Ephrins; D013778:Tetrazolium Salts; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D051028:bcl-2-Associated X Protein; C009591:triphenyltetrazolium; D036104:Receptor, EphA2; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9; D005947:Glucose