The "Perivascular Pump" Driven by Arterial Pulsation Is a Powerful Mechanism for the Distribution of Therapeutic Molecules within the Brain

Piotr Hadaczek; Yoji Yamashita; Hanna Mirek; Laszlo Tamas; Martha C. Bohn; Charles Noble; John W. Park; Krystof Bankiewicz

doi:10.1016/j.ymthe.2006.02.018

The "Perivascular Pump" Driven by Arterial Pulsation Is a Powerful Mechanism for the Distribution of Therapeutic Molecules within the Brain

Piotr Hadaczek^*, Yoji Yamashita, Hanna Mirek, Laszlo Tamas, Martha C. Bohn, Charles Noble, John W. Park, Krystof Bankiewicz

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

253 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	69-78
Number of pages	10
Journal	Molecular Therapy
Volume	14
Issue number	1
DOIs	https://doi.org/10.1016/j.ymthe.2006.02.018
State	Published - Jul 2006

Funding

This work was supported by National Institutes of Health Award U54NS045309. Special thanks to Lisa Tesch (Northwestern University, Chicago, IL, USA) for preparing the AAV vector and Susan Eastwood ELS(D) (University of California at San Francisco ret.), who edited the manuscript. We are also grateful to John Forsayeth (University of California at San Francisco) for helpful discussions concerning preparation and organization of the manuscript.

Keywords

AAV2
brain
convection-enhanced delivery
liposomes
perivascular space
transport

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1016/j.ymthe.2006.02.018

Cite this

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abstract = "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.",

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note = "Funding Information: This work was supported by National Institutes of Health Award U54NS045309. Special thanks to Lisa Tesch (Northwestern University, Chicago, IL, USA) for preparing the AAV vector and Susan Eastwood ELS(D) (University of California at San Francisco ret.), who edited the manuscript. We are also grateful to John Forsayeth (University of California at San Francisco) for helpful discussions concerning preparation and organization of the manuscript.",

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AU - Tamas, Laszlo

AU - Bohn, Martha C.

AU - Noble, Charles

AU - Park, John W.

AU - Bankiewicz, Krystof

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The "Perivascular Pump" Driven by Arterial Pulsation Is a Powerful Mechanism for the Distribution of Therapeutic Molecules within the Brain

Abstract

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Keywords

ASJC Scopus subject areas

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