Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
CNS Neurosci Ther. 2019 Jun;25(6):704-713. doi: 10.1111/cns.13101. Epub 2019 Jan 24.
Hypoxia may damage blood-brain barrier (BBB). The neuroprotective effect of propofol has been reported. We aimed to identify whether and how propofol improved hypoxia-induced impairment of BBB integrity.
Mouse brain microvascular endothelial cells (MBMECs) and astrocytes were cocultured to establish in vitro BBB model. The effects of hypoxia and propofol on BBB integrity were examined. Further, zonula occludens-1 (ZO-1) expression and phosphorylation, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression, intracellular calcium concentration and Ca /calmodulin-dependent protein kinase II (CAMKII) activation were measured.
Hypoxia-impaired BBB integrity, which was protected by propofol. Hypoxia-reduced ZO-1 expression, while induced ZO-1 phosphorylation. These effects were attenuated by propofol. The expression of HIF-1α and VEGF was increased by hypoxia and was alleviated by propofol. The hypoxia-mediated suppression of ZO-1 and impaired BBB integrity was reversed by HIF-α inhibitor and VEGF inhibitor. In addition, hypoxia increased the intracellular calcium concentration and induced the phosphorylation of CAMKII, which were mitigated by propofol. The hypoxia-induced phosphorylation of ZO-1 and impaired BBB integrity was ameliorated by calcium chelator and CAMKII inhibitor.
Propofol could protect against hypoxia-mediated impairment of BBB integrity. The underlying mechanisms may involve the expression and phosphorylation of ZO-1.
缺氧可能会损害血脑屏障（BBB）。已报道丙泊酚具有神经保护作用。我们旨在确定丙泊酚是否以及如何改善缺氧引起的 BBB 完整性受损。
将小鼠脑微血管内皮细胞（MBMEC）和星形胶质细胞共培养以建立体外 BBB 模型。检测缺氧和丙泊酚对 BBB 完整性的影响。进一步测量了紧密连接蛋白-1（ZO-1）的表达和磷酸化、缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子（VEGF）的表达、细胞内钙浓度和钙/钙调蛋白依赖性蛋白激酶 II（CAMKII）的激活。
缺氧损害了 BBB 完整性，丙泊酚对此具有保护作用。缺氧降低了 ZO-1 的表达，同时诱导了 ZO-1 的磷酸化。丙泊酚减弱了这些作用。HIF-1α和 VEGF 的表达增加，缺氧增加了 ZO-1 的表达和受损的 BBB 完整性，并被 HIF-α抑制剂和 VEGF 抑制剂逆转。此外，缺氧增加了细胞内钙浓度并诱导了 CAMKII 的磷酸化，丙泊酚减轻了这种作用。钙螯合剂和 CAMKII 抑制剂改善了缺氧诱导的 ZO-1 磷酸化和受损的 BBB 完整性。
丙泊酚可防止缺氧引起的 BBB 完整性受损。其潜在机制可能涉及 ZO-1 的表达和磷酸化。
