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Vascular dementia (VD) is a syndrome characterized by progressive cognitive decline. According to previous studies, stroke is considered to be a risk factor for VD. The disruption of the blood-brain barrier (BBB) is pivotal to the pathology of stroke, as it contributes to post-stroke inflammation and edema. It has been reported that the Eph/Ephrin signaling pathway serves an important role in central nervous system injury. However, the role of EphrinA1/EphA4 signaling in BBB damage following ischemic stroke has not yet been reported. Oxygen-glucose deprivation/reperfusion was performed to detect changes in EphrinA1 and EphA4 expression in human brain microvascular endothelial cells (HBMECs). Male mice were randomly divided into four groups [Sham, ischemia-reperfusion (I/R), I/R+EphrinA1 and I/R+EphA4] to observe the role of EphrinA1 and EphA4 under I/R conditions in vivo . The results of the present study revealed that the expression of EphrinA1 and EphA4 was significantly increased following I/R in vitro and in vivo . The administration of soluble ligand EphrinA1 enhanced CD68 + cell accumulation, brain edema and dysfunction of the BBB, with lower expression levels of zonula occludens-1 (ZO-1) and Claudin-5. In addition, EphrinA1-treated mice had a higher level of caspase-3 and a lower level of phosphorylated-protein kinase B. However, the effects of EphrinA1 were abolished by EphA4-Fc, an inhibitor of EphA4. These results suggested that EphrinA1 exerted its effects on I/R injury via the activated EphA4 receptor. In addition, EphrinA1 decreased ZO-1 and Claudin-5 expression through the Rho/Rho associated kinase (ROCK) signaling pathway, which was attenuated by the pharmacological inhibition of Rho (C3 transferase) or ROCK (Y-27632). In conclusion, the present study provides evidence that the activation of EphA4 induced by EphrinA1 contributes to BBB damage following ischemic stroke through the Rho/ROCK signaling pathway, which highlights a potential therapeutic strategy for ischemic stroke and may help the development of preventative interventions for VD.

experimental and therapeutic medicine

Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway