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Exp Neurol. 2017 Oct;296:41-48. doi: 10.1016/j.expneurol.2017.07.003. Epub 2017 Jul 8.

Critical role of EphA4 in early brain injury after subarachnoid hemorrhage in rat.

Author information

1
Department of Neurology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China; Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, United States.
2
Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, United States.
3
Department of cerebrovascular, the Affiliated Hospital, Zunyi Medical University, Guizhou 563000, China.
4
Department of Neurology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China. Electronic address: chenym1997@sina.com.
5
Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, United States; Department of Anesthesiology, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, United States; Department of Neurosurgery, School of Medicine, Loma Linda University, Loma Linda, CA 92354, United States. Electronic address: jhzhang@llu.edu.

Abstract

Early brain injury (EBI) is reported as a primary cause of mortality in subarachnoid hemorrhage (SAH) patients. Eph receptor A4 (EphA4) has been associated with blood-brain barrier integrity and pro-apoptosis. We aimed to investigate a role of EphA4 in EBI after SAH. One hundred and seventy-nine male adult Sprague-Dawley rats were randomly divided into sham versus endovascular perforation model of SAH groups. SAH grade, neurological score, Evans blue dye extravasation, brain water content, mortality, Fluoro-Jade staining, immunofluorescence staining, and western blot experiments were performed after SAH. Small interfering RNA (siRNA) for EphA4, recombinant Ephexin-1 (rEphx-1), and Fasudil, a potent ROCK2 inhibitor, were used for intervention to study a role of EphA4 on EBI after SAH. The expression of EphA4, Ephexin-1, RhoA, and ROCK2 significantly increased after SAH. Knockdown of EphA4 using EphA4 siRNA injection intracerebroventricularly (i.c.v) reduced Evans blue extravasation, decreased brain water content, and alleviated neurobehavioral dysfunction after SAH. Additionally, the expression of Ephexin-1, RhoA, ROCK2 and cleaved caspase-3 were decreased. Tight junction proteins increased, and apoptotic neuron death decreased. The effects of EphA4 siRNA were abolished by rEphx-1. In contrast, Fasudil abolished the effects of rEphx-1. These results suggest that EphA4, a novel and promising target for treatment, exacerbates EBI through an Ephexin-1/ROCK2 pathway after SAH.

KEYWORDS:

Blood-brain barrier; EBI; EphA4; Neuronal apoptosis; Subarachnoid hemorrhage

PMID:
28698029
DOI:
10.1016/j.expneurol.2017.07.003
[Indexed for MEDLINE]

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