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Cited by 445Barrier Structure and Function StudiesDrug Transport and Resistance MechanismsExtracellular vesicles in disease

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

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Lochhead, Jeffrey J., Yang, Junzhi, Ronaldson, Patrick T., Davis, Thomas P.·2020·Frontiers in Physiology
DOI 10.3389/fphys.2020.00914PMC PMC7424030
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Abstract

The blood-brain barrier (BBB) allows the brain to selectively import nutrients and energy critical to neuronal function while simultaneously excluding neurotoxic substances from the peripheral circulation. In contrast to the highly permeable vasculature present in most organs that reside outside of the central nervous system (CNS), the BBB exhibits a high transendothelial electrical resistance along with a low rate of transcytosis and greatly restricted paracellular permeability. The property of low paracellular permeability is controlled by tight junction protein complexes that seal the paracellular route between apposing brain microvascular endothelial cells. Although tight junction protein complexes are principal contributors to physical barrier properties, they are not static in nature. Rather, tight junction protein complexes are highly dynamic structures where expression and/or localization of individual constituent proteins can be modified in response to pathophysiological stressors. These stressors induce modifications to tight junction protein complexes that involve de novo synthesis of new protein or discrete trafficking mechanisms. Such responsiveness of BBB tight junctions to diseases indicates that these protein complexes are critical for maintenance of CNS homeostasis. In fulfillment of this vital role, BBB tight junctions are also a major obstacle to therapeutic drug delivery to the brain. There is an opportunity to overcome this substantial obstacle and optimize neuropharmacology via acquisition of a detailed understanding of BBB tight junction structure, function, and regulation. In this review, we discuss physiological characteristics of tight junction protein complexes and how these properties regulate delivery of therapeutics to the CNS for treatment of neurological diseases. Specifically, we will discuss modulation of tight junction structure, function, and regulation both in the context of disease states and in the setting of pharmacotherapy. In particular, we will highlight how these properties can be potentially manipulated at the molecular level to increase CNS drug levels via paracellular transport to the brain.

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Cited by

Sorted by citations

Authors
Lochhead, J. J., Yang, J., Ronaldson, P. T., & Davis, T. P.
Affiliations
University of Arizona (US)
Corresponding author
Davis, Thomas P.
ORCID
Venue
Frontiers in Physiology
Publisher
Frontiers Media SA
Published
2020-08-06
Volume
11
Pages
914-914
ISSN
1664-042X (ISSN-L)
DOI
10.3389/fphys.2020.00914
PMC
PMC7424030
OpenAlex
W3049428549
Cited by
445
References
19
Citations by year
2026: 75 · 2025: 91 · 2024: 92 · 2023: 69 · 2022: 67 · 2021: 45 · 2020: 3 · 2015: 1 · 2012: 1
FWCI
4.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Physiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Heart Association (18CDA34110454)
  • National Institutes of Health (NS42652-17, DA51812-01, NS84941-06)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
blood-brain barrier, tight junctions, paracellular permeability, brain microvascular endothelial cells, transendothelial electrical resistance, brain drug delivery, neuropharmacology, tight junction regulation, neurological disorders, paracellular transport

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