title: Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration.
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.
authors.affiliation: Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Lochhead
authors.affiliation: 1] Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA [2] Clinical Neuroengineering Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wolak
authors.affiliation: 1] Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA [2] Clinical Neuroengineering Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Pizzo
authors.affiliation: 1] Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA [2] Clinical Neuroengineering Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA [3] Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA [4] Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA [5] The Institute for Clinical and Translational Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Thorne
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes / Q000008:administration & dosage*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D018613:Microscopy, Confocal; D061848:Optical Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005456:Fluorescent Dyes; D020780:Matrix Metalloproteinase 9