• Bo Zhao, Jianping Zhu, Yuxiang Fei, Qiyang Yin, Weiyang Shen, Bingwen Liang, Xiong Zhu, and Yunman Li.
• State key laboratory of Nature Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
• Life Sci. 2020 Nov 1; 260: 118221.

AbstractJLX001, a new dihydrochloride of Cyclovirobuxine D (CVB-D), has bioactivities against ischemia injury. The blood-brain barrier (BBB) disruption is involved in the pathogeneses of ischemic stroke. This study was designed to explore the effect and potential mechanism of JLX001 on the BBB after ischemic stroke. Rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to mimic cerebral ischemia in vivo. In vitro, rat primary brain microvascular endothelial cells (PBMECs) were cultured and exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). Posttreatment of JLX001 for 15 days after MCAO/R improved the behavior, learning and memory ability. Pretreatment of JLX001 for 3 days significantly attenuated infarct volume, lessened brain edema, mitigated BBB disruption and decreased the neurological deficit score in MCAO/R rats. Moreover, JLX001 increased cell viability and reduced sodium fluorescein leakage after OGD/R injury. In addition, JLX001 increased the expressions of Claudin-5 and Occludin, decreased the expression of MMP-9 both in vivo and in vitro. Moreover, immunofluorescence staining and western immunoblotting results showed that JLX001 increased the expressions of tight junction proteins via activating Wnt/β-catenin signal pathway in vivo and in vitro, which may be associated with the activation of PI3K/Akt signaling. Besides, XAV939 (an inhibitor of the Wnt/β-catenin pathway) proved the connection of JLX001 and Wnt/β-catenin pathway. These results suggest that JLX001 alleviates BBB disruption after MCAO/R and OGD/R possibly by alleviating MMP-9 and activating the Wnt/β-catenin signaling pathway.Copyright © 2020. Published by Elsevier Inc.

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