Astragaloside IV protects blood-brain barrier integrity from LPS-induced disruption via activating Nrf2 antioxidant signaling pathway in mice
Astragaloside IV protects blood-brain barrier integrity from LPS-induced disruption via activating Nrf2 antioxidant signaling pathway in mice
复制标题
黄芪甲苷 IV 通过激活小鼠 Nrf2 抗氧化信号通路，保护血脑屏障完整性免受 LPS 诱导的破坏
DOI：
10.1016/j.taap.2017.12.019
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发表时间：
2018-02-01
影响因子：
3.8
通讯作者：
Wu, Xiaojun
中科院分区：
文献类型：
--
作者：
Li, Hongli;Wang, Ping;Wu, Xiaojun
脑微血管内皮细胞是血脑屏障（BBB）的重要组成部分，它们之间通过紧密连接（TJ）相互连接。脑疾病如缺血性中风、阿尔茨海默氏病、多发性硬化和创伤性脑损伤中的BBB破坏被认为加剧了疾病的进展。从黄芪中分离的黄芪甲苷（ASIV）可预防啮齿动物脑水肿和实验性自身免疫性脑脊髓炎引起的血脑屏障破坏。然而，其潜在的分子机制尚未阐明。本研究发现，ASIV可防止LPS诱导的小鼠血脑屏障渗漏，并伴有脑微血管中zo-1和occludin的增加，而VCAM-1的减少。类似地，在脑内皮细胞系bEnd.3细胞中，ASIV减轻了LPS诱导的渗透性增加，如TEER增加和荧光素钠外渗减少所证明的。ASIV还增强LPS刺激的bEnd.3细胞中TJ蛋白如zo-1、occludin和claudin-5的表达。同时，它抑制炎症反应，并防止单核细胞粘附到bEnd.3细胞在LPS刺激。进一步研究发现ASIV能降低bEnd. 3细胞内ROS水平，激活Nrf 2抗氧化通路。当Nrf 2被沉默时，ASIV的保护作用被取消。在LPS诱导的小鼠脑微血管中，ASIV还增强了Nrf 2抗氧化途径相关蛋白的表达。以上结果表明，ASIV对LPS诱导的小鼠血脑屏障具有保护作用，其机制可能与激活Nrf 2信号通路有关。提示ASIV可能是一种潜在的作用于血脑屏障的神经保护药物。
Endothelial cells of cerebral microvessels are one of the components of blood-brain-barrier (BBB), which are connected by tight junctions (TJs). BBB disruption in cerebral diseases such as ischemic stroke, Alzhemer's disease, multiple sclerosis and traumatic brain injury is implicated to exacerbate the disease progression. Astragaloside IV (ASIV) isolated from Astragalus membranaceus prevents BBB breakdown in rodents induced with cerebral edema and experimental autoimmune encephalomyelitis. However, its underlying molecular mechanism has not been elucidated yet. In present study, ASIV was found to prevent the leakage of BBB in LPS-induced mice, which was accompanied with increased zo-1 and occludin but reduced VCAM-1 in brain micro vessels. Similarly, in brain endothelial cell line bEnd.3 cells, ASIV mitigated the increased permeability induced by LPS, as evidenced by increased TEER and reduced sodium fluorescein extravasation. ASIV also enhanced the expression of TJ proteins such as zo-1, occludin and claudin-5 in LPS stimulated bEnd.3 cells. Meanwhile, it inhibited the inflammatory responses and prevented the monocyte adhesion onto bEnd.3 cells upon LPS stimulation. Further study disclosed that ASIV could alleviate ROS level and activate Nrf2 antioxidant pathway in bEnd.3 cells. When Nrf2 was silenced, the protective effect of ASIV was abolished. In brain microvessels of LPS-induced mice, ASIV also enhanced the expression of Nrf2 antioxidant pathway related proteins. Collectively, our results demonstrated that ASIV protected the integrity of BBB in LPS-induced mice, the mechanism of which might be mediated via activating Nrf2 signaling pathway. The findings suggested that ASIV might be a potential neuroprotective drug acting on BBB.