The "perivascular pump" driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain
The "perivascular pump" driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain
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DOI：
10.1016/j.ymthe.2006.02.018
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发表时间：
2006-07-01
影响因子：
12.4
通讯作者：
Bankiewicz, K
中科院分区：
文献类型：
--
作者：
Hadaczek, P;Yamashita, Y;Bankiewicz, K
我们研究了高血压和低血压（BP）/心率大鼠以及输注前即刻处死的大鼠（无心脏活动）的中枢神经系统（CNS）内输注大分子的运动。通过对流增强递送（CED）将腺相关病毒2（AAV 2）、荧光脂质体或牛血清白蛋白注入大鼠纹状体（每组6个半球）。输注后，评价分布容积。具有高BP/心率的大鼠在注射部位内显示出输注分子的显著更大的分布，并且这些分子更广泛地转运到苍白球。这种差异对于AAV 2尤其明显，对于AAV 2，在具有高BP/心率的大鼠中观察到的病毒衣壳分布是在没有心跳的大鼠中的16.5倍。对于脂质体观察到类似的结果，尽管它们的直径较大。在所有低血流量或无血流量的大鼠中，所有输注分子的分布仅限于脑血管周围的空间。这些发现表明，CNS内通过血管周围空间的液体循环是通过CED施用的病毒颗粒和其他治疗剂在脑内扩散的主要机制，并且心脏收缩为该过程提供动力。
We investigated the movement of interstitially infused macromolecules within the central nervous system (CNS) in rats with high and low blood pressure (BP)/heart rate and in rats euthanized immediately before infusion (no heart action). Adeno-associated virus 2 (AAV2), fluorescent liposomes, or bovine serum albumin was infused into rat striatum (six hemispheres per group) by convection-enhanced delivery (CED). After infusion, distribution volumes were evaluated. The rats with high BP/heart rate displayed a significantly larger distribution of the infused molecules within the injected site and more extensive transport of those molecules to the globus pallidus. This difference was particularly apparent for AAV2, for which a 16.5-fold greater distribution of viral capsids was observed in the rats with high BP/heart rate than in the rats with no heartbeat. Similar results were observed for liposomes, despite their larger diameter. The distribution of all infused molecules in all rats that had low or no blood flow was confined to the space around brain blood vessels. These findings show that fluid circulation within the CNS through the perivascular space is the primary mechanism by which viral particles and other therapeutic agents administered by CED are spread within the brain and that cardiac contractions power this process.