Passage of erythropoietic agents across the blood-brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa
Passage of erythropoietic agents across the blood-brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa
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DOI：
10.1016/j.ejphar.2004.10.035
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发表时间：
2004-11-28
影响因子：
5
通讯作者：
Heatherington, AC
中科院分区：
文献类型：
--
作者：
Banks, WA;Jumbe, NL;Heatherington, AC
研究表明，促红细胞生成素（EPO）可用于治疗动物和人类的中风。它被认为直接对大脑产生影响，治疗剂量的研究表明它可以穿过血脑屏障。在这里，我们比较了在一个盲目的方式的能力，三个促红细胞生成剂（海洋促红细胞生成素，人促红细胞生成素，和darbepopoietin alfa，一种类似物的人促红细胞生成素在临床上使用），以跨越血脑屏障的小鼠。高效液相色谱（HPLC）结果表明，所有三种红细胞生成剂在脑和血液中均具有酶抗性。通过多次回归分析测量的单向血脑内流速率（Ki）显示，所有红细胞生成剂以与白蛋白大致相同的速率穿过血脑屏障，表明它们通过细胞外途径穿过血脑屏障。未发现可饱和的内流成分，但间接证据表明存在脑-血外排系统。在三种红细胞生成剂中，每克脑摄取的静脉注射剂量百分比（%注射/g）范围为0.05 - 0.1%注射/g，在静脉注射后约3 h达到峰值。对于其他物质，已知该%注射/g范围对脑功能产生直接影响。我们的结论是红细胞生成剂通过细胞外途径穿过血脑屏障的数量可能足以解释其神经保护作用。(C)2004 Elsevier B. V.保留所有权利。
Studies have suggested that erythropoietin (EPO) may be used to treat stroke in both animals and humans. It is thought to exert its effects directly on the brain and studies with therapeutic doses have shown that it can cross the blood-brain barrier. Here, we compared in a blinded fashion the ability of three erythropoietic agents (marine erythropoietin, human erythropoietin, and darbepoetin alfa, an analog of human erythropoietin in clinical use) to cross the blood-brain barrier of the mouse. High-performance liquid chromatography (HPLC) results showed that all three erythropoietic agents were enzymatically resistant in brain and blood. The unidirectional blood-to-brain influx rates (K-i) as measured by multiple-time regression analysis showed that all the erythropoietic agents crossed the blood-brain barrier at about the same rate as albumin, suggesting that they cross the blood-brain barrier by way of the extracellular pathways. No saturable component to influx was found, but indirect evidence suggested a brain-to-blood efflux system. The percent of the intravenously injected dose taken up per gram of brain (%Inj/g) ranged from 0.05 to 0.1 %Inj/g among the three erythropoietic agents and peaked about 3 h after IV injection. For other substances, this range of %Inj/g is known to produce direct effects on brain function. We conclude that erythropoietic agents cross the blood-brain barrier by way of the extracellular pathways in amounts that are likely sufficient to explain their neuroprotective effects. (C) 2004 Elsevier B.V. All rights reserved.