Design and evaluation of EphrinA1 mutants with cerebral protective effect
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CitationZhu, Yuanjun, Yuanqing Gao, Danping Zheng, Mengyang Shui, Kuai Yu, Xiaoyan liu, Yuan Lin, Li Su, Wenxing Yang, and Yinye Wang. 2017. “Design and evaluation of EphrinA1 mutants with cerebral protective effect.” Scientific Reports 7 (1): 1881. doi:10.1038/s41598-017-02091-7. http://dx.doi.org/10.1038/s41598-017-02091-7.
AbstractThe activation of EphA2 receptor by its natural ligand EphrinA1 causes blood brain barrier dysfunction, and inactivation of EphA2 reduces BBB damage in ischemic stroke. Thus, EphA2 targeted antagonists may serve as neuroprotective agents. We engineered four mutants of EphrinA1, EM1, EM2, EM3 and EM4, respectively. The computational analysis showed that these four mutants were capable of interacting with EphA2. Their potential neuroprotective effects were examined in mouse focal ischemia/reperfusion (I/R) model. EM2 exhibited strong neuroprotective effects, including reduced brain infarct volume, neuronal apoptosis, cerebral edema, and improved neurological scores. The EM2-mediated protection was associated with a comparative decrease in BBB leakage, inflammatory infiltration, and higher expression levels of tight junction proteins, such as zonula occludens-1 and Occludin. I/R-induced high expression of Rho-associated protein kinase 2 (ROCK2) was down-regulated after EM2 treatment. Moreover, EM2 reduced agonist doxazosin-induced EphA2 phosphorylation and cells rounding in PC3 cells, indicating EphA2-antagonizing activity of EM2. These finding provided evidences of the neuroprotection of EphA2 antagonist and a novel approach for ischemic stroke treatment. These results also suggested that a receptor agonist can be switched to an antagonist by substituting one or more relevant residues.
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