Adverse effect of cyclosporin a on barrier functions of cerebral microvascular endothelial cells after hypoxia-reoxygenation damage in vitro
Adverse effect of cyclosporin a on barrier functions of cerebral microvascular endothelial cells after hypoxia-reoxygenation damage in vitro
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DOI：
10.1007/s10571-007-9209-2
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发表时间：
2007-11-01
影响因子：
4
通讯作者：
Kataoka, Yasufumi
中科院分区：
文献类型：
--
作者：
Dohgu, Shinya;Nishioku, Tsuyoshi;Kataoka, Yasufumi
缺氧和缺氧后复氧诱导血脑屏障（BBB）的破坏。缺氧/复氧（H/R）损伤后血脑屏障功能的变化尚不清楚。环孢菌素A（CsA）是一种有效的免疫抑制剂，通过进入脑诱导神经毒性作用，尽管CsA穿过BBB的转运受到P-糖蛋白（P-gp）、多药外排泵和脑毛细血管内皮细胞的紧密连接的限制。本研究的目的是评估H/R损伤后的BBB是否容易受到CsA诱导的BBB功能障碍的影响。我们尝试用永生化小鼠脑毛细血管内皮细胞（MBEC 4）建立病理生理学BBB模型。观察CsA对MBEC 4细胞通透性和P-gp活性的影响。缺氧4 h复氧1 h（H/R（4 h/1h））后7 d，MBEC 4细胞的P-gp功能显著降低，而细胞活力和荧光素钠和伊文思蓝-白蛋白的渗透性无明显变化。在H/R（4 h/1 h）后7天，CsA诱导的MBEC 4单层的高通透性和P-gp功能障碍加重。必须考虑CsA穿透脑梗死附近功能不全的血脑屏障诱导神经毒性的可能性。
Hypoxia and post-hypoxic reoxygenation induces disruption of the blood-brain barrier (BBB). Alterations of the BBB function after hypoxia/reoxygenation (H/R) injury remain unclear. Cyclosporin A (CsA), a potent immunosuppressant, induces neurotoxic effects by entering the brain, although the transport of CsA across the BBB is restricted by P-glycoprotein (P-gp), a multidrug efflux pump, and tight junctions of the brain capillary endothelial cells. The aim of this study was to evaluate whether the BBB after H/R damage is vulnerable to CsA-induced BBB dysfunction. We attempted to establish a pathophysiological BBB model with immortalized mouse brain capillary endothelial (MBEC4) cells. The effects of CsA on permeability and P-gp activity of the MBEC4 cells were then examined. Exposure to hypoxia for 4 h and reoxygenation for 1 h (H/R (4 h/1h)) produced a significant decrease in P-gp function of MBEC4 cells, without changing cell viability and permeability for sodium fluorescein and Evan's blue-albumin at 7 days after H/R (4 h/1h). CsA-induced hyperpermeability and P-gp dysfunction in MBEC4 monolayers at 7 days after H/R (4 h/1h) were exacerbated. The possibility that CsA penetrates the BBB with incomplete functions in the vicinity of cerebral infarcts to induce neurotoxicity has to be considered.