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Cited by 358Barrier Structure and Function StudiesCerebrospinal fluid and hydrocephalusDrug Transport and Resistance Mechanisms

Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey.

Balin, Brian J., Broadwell, Richard D., Salcman, Michael, El‐Kalliny, Magdy·1986·Journal of Comparative Neurology
DOI 10.1002/cne.902510209
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Abstract

Pathways traversed by peripherally administered protein tracers for entry to the mammalian brain were investigated by light and electron microscopy. Native horseradish peroxidase (HRP) and wheat germ agglutinin (WGA) conjugated to peroxidase were administered intranasally, intravenously, or intraventricularly to mice; native HRP was delivered intranasally or intravenously to rats and squirrel monkeys. Unlike WGA-HRP, native HRP administered intranasally passed freely through intercellular junctions of the olfactory epithelia to reach the olfactory bulbs of the CNS extracellularly within 45-90 minutes in all species. The olfactory epithelium labeled with intravenously delivered HRP, which readily escaped vasculature supplying this epithelium. Blood-borne peroxidase also exited fenestrated vessels of the dura mater and circumventricular organs. This HRP in the mouse, but not in the other species, passed from the dura mater through patent intercellular junctions within the arachnoid mater; in time, peroxidase reaction product in the mouse brain was associated with the pial surface, the Virchow-Robin spaces of vessels penetrating the pial surface, perivascular clefts, and with phagocytic pericytes located on the abluminal surface of superficial and deep cerebral microvasculature. Blood-borne HRP was endocytosed avidly at the luminal face of the cerebral endothelium in all species. WGA-HRP and native HRP delivered intraventricularly to the mouse were not endocytosed appreciably at the abluminal surface of the endothelium; hence, the endocytosis of protein and internalization of cell surface membrane within the cerebral endothelium are vectorial. The low to non-existent endocytic activity and internalization of membrane from the abluminal endothelial surface suggests that vesicular transport through the cerebral endothelium from blood to brain and from brain to blood does not occur. The extracellular pathways through which probe molecules enter the mammalian brain offer potential routes of passage for blood-borne and air-borne toxic, carcinogenic, infectious, and neurotoxic agents and addictive drugs, and for the delivery of chemotherapeutic agents to combat CNS infections and deficiency states. Methodological considerations are discussed for the interpretation of data derived from application of peroxidase to study the blood-brain barrier.

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Crossref · 10.1002/cne.902510209

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97 of 97 references verified0 citation errors · 0 not checkable

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  • The pial vasculature has barrier properties and is part of the meninges blood-CSF barrier.

    “Several studies show this vasculature has barrier properties and are therefore part of the meninges blood-CSF barrier.”

    From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Balin et al., 1986

  • CNS penetration following intranasal administration occurs within minutes and delivery to the brain is thought to occur via an extracellular pathway.

    “CNS penetration following intranasal administration occurs within minutes and delivery to the brain is thought to occur via an extracellular pathway (e.g., patent intercellular clefts in the olfactory epithelium) (Balin et al., 1986)”

    From Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome (2012) · cites this paper as Balin et al., 1986

  • Endothelial cells comprising blood vessels in the dura mater lack tight junctions and allow extravasation of solutes as large as 43 kDa.

    “For example, endothelial cells comprising blood vessels in the dura mater lack tight junctions and allow extravasation of solutes as large as 43 kDa (Fig. 1A) (48).”

    From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [48]

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Authors
Balin, B. J., Broadwell, R. D., Salcman, M., & El‐Kalliny, M.
Affiliations
University of Maryland, Baltimore (US)
ORCID
Balin, Brian J.
Venue
Journal of Comparative Neurology
Publisher
Wiley
Published
1986-09-08
Volume
251
Issue
2
Pages
260-280
ISSN
  • 0021-9967 (ISSN-L)
  • 1096-9861
DOI
10.1002/cne.902510209
OpenAlex
W1967262708
Cited by
358
References
97
Citations by year
2026: 8 · 2025: 10 · 2024: 11 · 2023: 11 · 2022: 15 · 2021: 20 · 2020: 13 · 2019: 10 · 2018: 11 · 2017: 7 · 2016: 6 · 2015: 6 · 2014: 9 · 2013: 6 · 2012: 6
FWCI
10.42
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 6606 d)
Locations
  • The Journal of Comparative Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons - PCOM (Philadelphia College of Osteopathic Medicine) (submittedVersion)
Funders
U.S. Public Health Service (18030)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
blood-brain barrier, horseradish peroxidase, wheat germ agglutinin, olfactory epithelium, olfactory bulb, dura mater, circumventricular organs, arachnoid mater, cerebral microvasculature, pericytes, intranasal administration, intraventricular administration, intravenous administration, perivascular spaces, brain drug delivery
MeSH terms
Administration, Intranasal, Animals, Blood-Brain Barrier, Brain Mapping, Drug Administration Routes, Endothelium, Female, Horseradish Peroxidase, Injections, Intravenous, Male, Microscopy, Electron, Peroxidases, Rats, Inbred Strains, Saimiri, Wheat Germ Agglutinins, Mice, Rats

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