Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration.

TitleRapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration.
Publication TypeJournal Article
Year of Publication2015
AuthorsLochhead JJ, Wolak DJ, Pizzo ME, Thorne RG
JournalJ Cereb Blood Flow Metab
Volume35
Issue3
Pagination371-81
Date Published2015 Mar
ISSN1559-7016
KeywordsAdministration, Intranasal, Animals, Blood-Brain Barrier, Brain, Enzyme-Linked Immunosorbent Assay, Female, Fluorescent Antibody Technique, Fluorescent Dyes, Matrix Metalloproteinase 9, Microscopy, Confocal, Optical Imaging, Rats, Rats, Sprague-Dawley
Abstract

The intranasal administration route is increasingly being used as a noninvasive method to bypass the blood-brain barrier because evidence suggests small fractions of nasally applied macromolecules may reach the brain directly via olfactory and trigeminal nerve components present in the nasal mucosa. Upon reaching the olfactory bulb (olfactory pathway) or brainstem (trigeminal pathway), intranasally delivered macromolecules appear to rapidly distribute within the brains of rodents and primates. The mechanisms responsible for this distribution have yet to be fully characterized. Here, we have used ex vivo fluorescence imaging to show that bulk flow within the perivascular space (PVS) of cerebral blood vessels contributes to the rapid central distribution of fluorescently labeled 3 and 10 kDa dextran tracers after intranasal administration in anesthetized adult rats. Comparison of tracer plasma levels and fluorescent signal distribution associated with the PVS of surface arteries and internal cerebral vessels showed that the intranasal route results in unique central access to the PVS not observed after matched intravascular dosing in separate animals. Intranasal targeting to the PVS was tracer size dependent and could be regulated by modifying nasal epithelial permeability. These results suggest cerebral perivascular convection likely has a key role in intranasal drug delivery to the brain.

DOI10.1038/jcbfm.2014.215
Alternate JournalJ. Cereb. Blood Flow Metab.
PubMed ID25492117
PubMed Central IDPMC4348383
Grant ListUL1 TR000427 / TR / NCATS NIH HHS / United States
KL2TR00428 / TR / NCATS NIH HHS / United States
UL1TR000427 / TR / NCATS NIH HHS / United States
KL2 TR000428 / TR / NCATS NIH HHS / United States
P50-AG033514 / AG / NIA NIH HHS / United States
T32 EB011434 / EB / NIBIB NIH HHS / United States
P50 AG033514 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Jeffrey J. Lochhead, PhD