The Configuration of the Perivascular System Transporting Macromolecules in the CNS (PREPRINT)

TL;DR

This study maps the extensive network of perivascular channels in the CNS, revealing their potential as a widespread route for delivering macromolecular therapeutics across the brain and spinal cord.

Contribution

It provides detailed mapping of perivascular pathways in rats and primates, highlighting their extensive reach and potential for CNS drug delivery.

Findings

Perivascular channels extend throughout the CNS parenchyma.

Average density of channels is about 40 per mm².

Channels reach deep into CNS tissues, excluding ventricles.

Abstract

Large blood vessels entering the CNS are surrounded by perivascular spaces that communicate with the cerebrospinal fluid and, at their termini, with the interstitial space. Solutes and particles can translocate along these perivascular conduits, reportedly in both directions. Recently, this prompted a renewed interest in the intrathecal therapy delivery route for CNS-targeted therapeutics. However, the extent of the CNS coverage by the perivascular system is unknown, making the outcome of drug administration to the CSF uncertain. We traced the translocation of model macromolecules from the CSF into the CNS of rats and non-human primates. Conduits transporting macromolecules were found to extend throughout the parenchyma from both external and internal (fissures) CNS boundaries, excluding ventricles, in large numbers, on average ca. 40 channels per mm2 in rats and non-human primates. The high density and depth of extension of the perivascular channels suggest that the perivascular route can be suitable for delivery of therapeutics to parenchymal targets throughout the CNS.