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Cited by 144Barrier Structure and Function StudiesDrug Transport and Resistance MechanismsCerebrospinal fluid and hydrocephalus

The DOI matches its Crossref record; 129 of the 129 references it cites were found in a registry or an index.

The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system?

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Saunders, Norman R., Habgood, Mark D., Møllgård, Kjeld, Dziegielewska, Katarzyna M.·2016·F1000Research
DOI 10.12688/f1000research.7378.1PMC PMC4786902
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Abstract

Barrier mechanisms in the brain are important for its normal functioning and development. Stability of the brain’s internal environment, particularly with respect to its ionic composition, is a prerequisite for the fundamental basis of its function, namely transmission of nerve impulses. In addition, the appropriate and controlled supply of a wide range of nutrients such as glucose, amino acids, monocarboxylates, and vitamins is also essential for normal development and function. These are all cellular functions across the interfaces that separate the brain from the rest of the internal environment of the body. An essential morphological component of all but one of the barriers is the presence of specialized intercellular tight junctions between the cells comprising the interface: endothelial cells in the blood-brain barrier itself, cells of the arachnoid membrane, choroid plexus epithelial cells, and tanycytes (specialized glial cells) in the circumventricular organs. In the ependyma lining the cerebral ventricles in the adult brain, the cells are joined by gap junctions, which are not restrictive for intercellular movement of molecules. But in the developing brain, the forerunners of these cells form the neuroepithelium, which restricts exchange of all but the smallest molecules between cerebrospinal fluid and brain interstitial fluid because of the presence of strap junctions between the cells. The intercellular junctions in all these interfaces are the physical basis for their barrier properties. In the blood-brain barrier proper, this is combined with a paucity of vesicular transport that is a characteristic of other vascular beds. Without such a diffusional restrain, the cellular transport mechanisms in the barrier interfaces would be ineffective. Superimposed on these physical structures are physiological mechanisms as the cells of the interfaces contain various metabolic transporters and efflux pumps, often ATP-binding cassette (ABC) transporters, that provide an important component of the barrier functions by either preventing entry of or expelling numerous molecules including toxins, drugs, and other xenobiotics. In this review, we summarize these influx and efflux mechanisms in normal developing and adult brain, as well as indicating their likely involvement in a wide range of neuropathologies. There have been extensive attempts to overcome the barrier mechanisms that prevent the entry of many drugs of therapeutic potential into the brain. We outline those that have been tried and discuss why they may so far have been largely unsuccessful. Currently, a promising approach appears to be focal, reversible disruption of the blood-brain barrier using focused ultrasound, but more work is required to evaluate the method before it can be tried in patients. Overall, our view is that much more fundamental knowledge of barrier mechanisms and development of new experimental methods will be required before drug targeting to the brain is likely to be a successful endeavor. In addition, such studies, if applied to brain pathologies such as stroke, trauma, or multiple sclerosis, will aid in defining the contribution of brain barrier pathology to these conditions, either causative or secondary.

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Research works printed but not linked: 2

  1. M Lewandowsky, 1900, Zur Lehre von der Cerebrospinalflüssgkeit., Z Clin Med., 40, 480-494
  2. G Cotzias, 1968, Experimental treatment of parkinsonism with L-Dopa., Neurology., 18, 276-277

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Metadata

Authors
Saunders, N. R., Habgood, M. D., Møllgård, K., & Dziegielewska, K. M.
Affiliations
  • The University of Melbourne (AU)
  • University of Copenhagen (DK)
Corresponding author
Saunders, Norman R.
ORCID
Venue
F1000Research
Publisher
F1000 Research Ltd
Published
2016-03-10
Volume
5
Pages
313
ISSN
2046-1402 (ISSN-L)
DOI
10.12688/f1000research.7378.1
PMC
PMC4786902
OpenAlex
W2337076198
Cited by
143
References
129
Citations by year
2026: 9 · 2025: 10 · 2024: 12 · 2023: 13 · 2022: 15 · 2021: 12 · 2020: 17 · 2019: 19 · 2018: 12 · 2017: 13 · 2016: 10
FWCI
1.58
Type
journal article
Language
en
Open access
Licence
Locations
  • F1000Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
Keywords
blood-brain barrier, brain drug delivery, tight junctions, ABC transporters, efflux pumps, circumventricular organs, choroid plexus epithelium, arachnoid membrane, tanycytes, neuroepithelium, gap junctions, strap junction, focused ultrasound, blood-brain barrier disruption

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