Evolutionary conservation of vertebrate blood-brain barrier chemoprotective mechanisms in Drosophila.
Evolutionary conservation of vertebrate blood-brain barrier chemoprotective mechanisms in Drosophila.
复制标题
DOI：
10.1523/jneurosci.5564-08.2009
复制
发表时间：
2009-03-18
期刊：
影响因子：
--
通讯作者：
Bainton RJ
中科院分区：
文献类型：
--
作者：
Mayer F;Mayer N;Chinn L;Pinsonneault RL;Kroetz D;Bainton RJ
由于血脑屏障（BBB）强大的药物排斥特性，许多脑疾病的药物治疗是困难的。脊椎动物脑的化学分离是通过BBB的高度整合、解剖学上紧凑和功能上重叠的化学分离过程来实现的。这些包括需要在紧密扩散连接和单向作用的异生物质转运蛋白之间协调的功能。对许多这些过程的理解受到阻碍，因为它们不能被BBB的离体模型很好地模拟，并且在完整的啮齿动物模型中进行实验困难且昂贵。在这里，我们表明，果蝇（Dm）体液/中枢神经系统屏障保存异生物质排斥特性发现在脊椎动物血管内皮。我们的特点飞ABC转运，Mdr 65，功能类似于哺乳动物异生物质血脑屏障转运，并表明，改变其水平仅在Dm血脑屏障的变化的固有敏感性的细胞毒性药物的屏障。此外，我们证明了mdr 65和脊椎动物的ABC转运蛋白之间的orthopathic功能，通过拯救化学保护的Dm脑与人类MDR 1/Pgp。这些数据表明，CNS化学保护的古老起源延伸到保守的分子手段和功能类似的解剖空间，共同促进CNS选择性药物分配。因此，Dm提出了一种实验上易于处理的系统，用于分析完整生物体中BBB的生理特性。
Pharmacologic remedy of many brain diseases is difficult because of the powerful drug exclusion properties of the blood-brain barrier (BBB). Chemical isolation of the vertebrate brain is achieved through the highly integrated, anatomically compact and functionally overlapping chemical isolation processes of the BBB. These include functions that need to be coordinated between tight diffusion junctions and unidirectionally-acting xenobiotic transporters. Understanding of many of these processes has been hampered, as they are not well mimicked by ex vivo models of the BBB and have been experimentally difficult and expensive to disentangle in intact rodent models. Here we show that the Drosophila melanogaster (Dm) humoral/CNS barrier conserves the xenobiotic exclusion properties found in the vertebrate vascular endothelium. We characterize a fly ABC transporter, Mdr65, that functions similar to mammalian xenobiotic BBB transporters and show that varying its levels solely in the Dm BBB changes the inherent sensitivity of the barrier to cytotoxic pharmaceuticals. Furthermore we demonstrate orthologous function between Mdr65 and vertebrate ABC transporters by rescuing chemical protection of the Dm brain with human MDR1/Pgp. These data indicate that the ancient origins of CNS chemoprotection extend to both conserved molecular means and functionally analogous anatomic spaces that together promote CNS selective drug partition. Thus, Dm presents an experimentally tractable system for analyzing physiological properties of the BBB in an intact organism.