blood–brain barrier

File:Blood Brain Barriere.jpg

File:Blood vessels brain english.jpg

The BBB results from the selectivity of the tight junctions between the endothelial cells of brain capillaries, restricting the passage of solutes. At the interface between blood and the brain, endothelial cells are adjoined continuously by these tight junctions, which are composed of smaller subunits of transmembrane proteins, such as occludin, claudins (such as Claudin-5), junctional adhesion molecule (such as JAM-A). Each of these tight junction proteins is stabilized to the endothelial cell membrane by another protein complex that includes scaffolding proteins such as tight junction protein 1 (ZO1) and associated proteins.

The BBB is composed of endothelial cells restricting passage of substances from the blood more selectively than endothelial cells of capillaries elsewhere in the body. Astrocyte cell projections called astrocytic feet (also known as "glia limitans") surround the endothelial cells of the BBB, providing biochemical support to those cells.{{cite journal | vauthors = Abbott NJ, Rönnbäck L, Hansson E | s2cid = 205500476 | title = Astrocyte-endothelial interactions at the blood-brain barrier | journal = Nature Reviews. Neuroscience | volume = 7 | issue = 1 | pages = 41–53 | date = January 2006 | pmid = 16371949 | doi = 10.1038/nrn1824 }} The BBB is distinct from the quite similar blood-cerebrospinal fluid barrier, which is a function of the choroidal cells of the choroid plexus, and from the blood-retinal barrier, which can be considered a part of the whole realm of such barriers.{{cite journal | vauthors = Hamilton RD, Foss AJ, Leach L | title = Establishment of a human in vitro model of the outer blood-retinal barrier | journal = Journal of Anatomy | volume = 211 | issue = 6 | pages = 707–16 | date = December 2007 | pmc = 2375847 | doi = 10.1111/j.1469-7580.2007.00812.x | pmid = 17922819 }}{{open access}}

Not all vessels in the human brain exhibit BBB properties. Some examples of this include the circumventricular organs, the roof of the third and fourth ventricles, capillaries in the pineal gland on the roof of the diencephalon and the pineal gland.

The BBB appears to be functional by the time of birth. P-glycoprotein, a transporter, exists already in the embryonal endothelium.{{cite journal | vauthors = Tsai CE, Daood MJ, Lane RH, Hansen TW, Gruetzmacher EM, Watchko JF | s2cid = 46815691 | title = P-glycoprotein expression in mouse brain increases with maturation | journal = Biology of the Neonate | volume = 81 | issue = 1 | pages = 58–64 | date = January 2002 | pmid = 11803178 | doi = 10.1159/000047185 }}

Measurement of brain uptake of various blood-borne solutes showed that newborn endothelial cells were functionally similar to those in adults,{{cite journal | vauthors = Braun LD, Cornford EM, Oldendorf WH | title = Newborn rabbit blood-brain barrier is selectively permeable and differs substantially from the adult | journal = Journal of Neurochemistry | volume = 34 | issue = 1 | pages = 147–52 | date = January 1980 | pmid = 7452231 | doi = 10.1111/j.1471-4159.1980.tb04633.x | s2cid = 21944159 }} indicating that a selective BBB is operative at birth.

{{See also|Neuroimmune system}}

The blood–brain barrier acts effectively to protect brain tissue from circulating pathogens and other potentially toxic substances.{{cite journal | vauthors = Abdullahi W, Tripathi D, Ronaldson PT | title = Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection | journal = American Journal of Physiology. Cell Physiology | volume = 315 | issue = 3 | pages = C343–C356 | date = September 2018 | pmid = 29949404 | pmc = 6171039 | doi = 10.1152/ajpcell.00095.2018 }} Accordingly, blood-borne infections of the brain are rare. Infections of the brain that do occur are often difficult to treat. Antibodies are too large to cross the blood–brain barrier, and only certain antibiotics are able to pass.{{cite journal | vauthors = Raza MW, Shad A, Pedler SJ, Karamat KA | title = Penetration and activity of antibiotics in brain abscess | journal = Journal of the College of Physicians and Surgeons--Pakistan | volume = 15 | issue = 3 | pages = 165–167 | date = March 2005 | pmid = 15808097 | url = https://www.researchgate.net/publication/7928383 }} In some cases, a drug has to be administered directly into the cerebrospinal fluid where it can enter the brain by crossing the blood-cerebrospinal fluid barrier.{{cite journal | vauthors = Pardridge WM | title = Drug transport in brain via the cerebrospinal fluid | journal = Fluids and Barriers of the CNS | volume = 8 | issue = 1 | pages = 7 | date = January 2011 | pmid = 21349155 | pmc = 3042981 | doi = 10.1186/2045-8118-8-7 | doi-access = free }}{{cite journal | vauthors = Chen Y, Imai H, Ito A, Saito N | title = Novel modified method for injection into the cerebrospinal fluid via the cerebellomedullary cistern in mice | journal = Acta Neurobiologiae Experimentalis | volume = 73 | issue = 2 | pages = 304–311 | year = 2013 | doi = 10.55782/ane-2013-1938 | pmid = 23823990 | doi-access = free }}

{{Main |Circumventricular organs}}

Circumventricular organs (CVOs) are individual structures located adjacent to the fourth ventricle or third ventricle in the brain, and are characterized by dense capillary beds with permeable endothelial cells unlike those of the blood–brain barrier.{{cite journal | vauthors = Gross PM, Weindl A | title = Peering through the windows of the brain | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 7 | issue = 6 | pages = 663–72 | date = December 1987 | pmid = 2891718 | doi = 10.1038/jcbfm.1987.120 | doi-access = free }}{{cite book | vauthors = Gross PM | title = Circumventricular Organs and Brain Fluid Environment - Molecular and Functional Aspects | chapter = Chapter 31: Circumventricular organ capillaries | series = Progress in Brain Research | volume = 91 | pages = 219–33 | year = 1992 | pmid = 1410407 | doi = 10.1016/S0079-6123(08)62338-9 | isbn = 9780444814197 }} Included among CVOs having highly permeable capillaries are the area postrema, subfornical organ, vascular organ of the lamina terminalis, median eminence, pineal gland, and three lobes of the pituitary gland.{{cite journal | vauthors = Miyata S | title = New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains | journal = Frontiers in Neuroscience | volume = 9 | pages = 390 | year = 2015 | pmid = 26578857 | pmc = 4621430 | doi = 10.3389/fnins.2015.00390 | doi-access = free }}

Permeable capillaries of the sensory CVOs (area postrema, subfornical organ, vascular organ of the lamina terminalis) enable rapid detection of circulating signals in systemic blood, while those of the secretory CVOs (median eminence, pineal gland, pituitary lobes) facilitate transport of brain-derived signals into the circulating blood. Consequently, the CVO permeable capillaries are the point of bidirectional blood–brain communication for neuroendocrine function.{{cite journal | vauthors = Rodríguez EM, Blázquez JL, Guerra M | title = The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid | journal = Peptides | volume = 31 | issue = 4 | pages = 757–76 | date = April 2010 | pmid = 20093161 | doi = 10.1016/j.peptides.2010.01.003 | s2cid = 44760261 | url = https://www.researchgate.net/publication/41111270 }}

The border zones between brain tissue "behind" the blood–brain barrier and zones "open" to blood signals in certain CVOs contain specialized hybrid capillaries that are leakier than typical brain capillaries, but not as permeable as CVO capillaries. Such zones exist at the border of the area postrema—nucleus tractus solitarii (NTS),{{cite journal | vauthors = Gross PM, Wall KM, Pang JJ, Shaver SW, Wainman DS | title = Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius | journal = The American Journal of Physiology | volume = 259 | issue = 6 Pt 2 | pages = R1131-8 | date = December 1990 | pmid = 2260724 | doi = 10.1152/ajpregu.1990.259.6.R1131 }} and median eminence—hypothalamic arcuate nucleus.{{cite journal | vauthors = Shaver SW, Pang JJ, Wainman DS, Wall KM, Gross PM | s2cid = 27789146 | title = Morphology and function of capillary networks in subregions of the rat tuber cinereum | journal = Cell and Tissue Research | volume = 267 | issue = 3 | pages = 437–48 | date = March 1992 | pmid = 1571958 | doi = 10.1007/BF00319366 }} These zones appear to function as rapid transit regions for brain structures involved in diverse neural circuits—like the NTS and arcuate nucleus—to receive blood signals which are then transmitted into neural output. The permeable capillary zone shared between the median eminence and hypothalamic arcuate nucleus is augmented by wide pericapillary spaces, facilitating bidirectional flow of solutes between the two structures, and indicating that the median eminence is not only a secretory organ, but may also be a sensory organ.

The blood–brain barrier is formed by the brain capillary endothelium and excludes from the brain 100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs.{{cite journal|display-authors=3 |vauthors=Hersh DS, Wadajkar AS, Roberts N, Perez JG, Connolly NP, Frenkel V, Winkles JA, Woodworth GF, Kim AJ |title=Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier |journal=Current Pharmaceutical Design |volume=22 |issue=9 |pages=1177–1193 |date=2016 |pmid=26685681 |pmc=4900538 |doi=10.2174/1381612822666151221150733}} Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders.{{cite journal | vauthors = Sweeney MD, Sagare AP, Zlokovic BV | title = Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders | journal = Nature Reviews. Neurology | volume = 14 | issue = 3 | pages = 133–150 | date = March 2018 | pmid = 29377008 | pmc = 5829048 | doi = 10.1038/nrneurol.2017.188 }}{{cite journal | vauthors = Harilal S, Jose J, Parambi DG, Kumar R, Unnikrishnan MK, Uddin MS, Mathew GE, Pratap R, Marathakam A, Mathew B | display-authors = 6 | title = Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules | journal = Brain Research Bulletin | volume = 160 | pages = 121–140 | date = July 2020 | pmid = 32315731 | doi = 10.1016/j.brainresbull.2020.03.018 | s2cid = 215807970 }} In its neuroprotective role, the blood–brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and antibodies that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts to be clinically effective. To overcome this problem some peptides able to naturally cross the BBB have been widely investigated as a drug delivery system.{{cite journal | vauthors = de Oliveira EC, da Costa KS, Taube PS, Lima AH, Junior CS | title = Biological Membrane-Penetrating Peptides: Computational Prediction and Applications | journal = Frontiers in Cellular and Infection Microbiology | volume = 12 | pages = 838259 | date = 2022-03-25 | pmid = 35402305 | pmc = 8992797 | doi = 10.3389/fcimb.2022.838259 | doi-access = free }}

Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for drug delivery to the brain in unit doses through the BBB entail its disruption by osmotic means, or biochemically by the use of vasoactive substances, such as bradykinin,{{cite journal | vauthors = Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J, Vivien D, Gauberti M | display-authors = 6 | title = Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism | journal = Blood | volume = 128 | issue = 20 | pages = 2423–2434 | date = November 2016 | pmid = 27531677 | doi = 10.1182/blood-2016-03-705384 | doi-access = free }} or even by localized exposure to high-intensity focused ultrasound (HIFU).{{cite journal | vauthors = McDannold N, Vykhodtseva N, Hynynen K | title = Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index | journal = Ultrasound in Medicine & Biology | volume = 34 | issue = 5 | pages = 834–40 | date = May 2008 | pmid = 18207311 | pmc = 2442477 | doi = 10.1016/j.ultrasmedbio.2007.10.016 }}

Other methods used to get through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters, such as glucose and amino acid carriers, receptor-mediated transcytosis for insulin or transferrin, and the blocking of active efflux transporters such as p-glycoprotein. Some studies have shown that vectors targeting BBB transporters, such as the transferrin receptor, have been found to remain entrapped in brain endothelial cells of capillaries, instead of being ferried across the BBB into the targeted area.{{cite journal | vauthors = Wiley DT, Webster P, Gale A, Davis ME | title = Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 21 | pages = 8662–7 | date = May 2013 | pmid = 23650374 | pmc = 3666717 | doi = 10.1073/pnas.1307152110 | bibcode = 2013PNAS..110.8662W | doi-access = free }}

The brain can be targeted non-invasively via the nasal passage. The drugs that remain in the passage after mucociliary clearance, enter the brain via three pathways: (1) Olfactory nerve-olfactory bulb-brain; (2) Trigeminal nerve-brain; and (3) Lungs/ Gastrointestinal tract-blood–brain {{Cite journal |last1=Agrawal |first1=Mukta |last2=Saraf |first2=Swarnlata |last3=Saraf |first3=Shailendra |last4=Antimisiaris |first4=Sophia G. |last5=Chougule |first5=Mahavir Bhupal |last6=Shoyele |first6=Sunday A. |last7=Alexander |first7=Amit |date=2018-07-10 |title=Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs |url=https://pubmed.ncbi.nlm.nih.gov/29772289/ |journal=Journal of Controlled Release|volume=281 |pages=139–177 |doi=10.1016/j.jconrel.2018.05.011 |issn=1873-4995 |pmid=29772289}} The first and second methods involve the nerves, so they use the neuronal pathway and the third is via systemic circulation. However, these methods are less efficient to deliver drugs as they are indirect methods.

{{main|Nanoparticles for drug delivery to the brain}}

Nanotechnology is under preliminary research for its potential to facilitate the transfer of drugs across the BBB.{{cite journal | vauthors = Krol S, Macrez R, Docagne F, Defer G, Laurent S, Rahman M, Hajipour MJ, Kehoe PG, Mahmoudi M | display-authors = 6 | title = Therapeutic benefits from nanoparticles: the potential significance of nanoscience in diseases with compromise to the blood brain barrier | journal = Chemical Reviews | volume = 113 | issue = 3 | pages = 1877–903 | date = March 2013 | pmid = 23157552 | doi = 10.1021/cr200472g }}{{cite journal | vauthors = Silva GA | title = Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS | journal = BMC Neuroscience | volume = 9 | issue = Suppl 3 | pages = S4 | date = December 2008 | pmid = 19091001 | pmc = 2604882 | doi = 10.1186/1471-2202-9-S3-S4 | doi-access = free }} Capillary endothelial cells and associated pericytes may be abnormal in tumors and the blood–brain barrier may not always be intact in brain tumors. Other factors, such as astrocytes, may contribute to the resistance of brain tumors to therapy using nanoparticles.{{cite journal | vauthors = Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM | display-authors = 6 | title = Openings between defective endothelial cells explain tumor vessel leakiness | journal = The American Journal of Pathology | volume = 156 | issue = 4 | pages = 1363–80 | date = April 2000 | pmid = 10751361 | pmc = 1876882 | doi = 10.1016/S0002-9440(10)65006-7 }} Fat soluble molecules less than 400 daltons in mass can freely diffuse past the BBB through lipid mediated passive diffusion.{{cite journal | vauthors = Souza RM, da Silva IC, Delgado AB, da Silva PH, Costa VR | title = Focused ultrasound and Alzheimer's disease A systematic review | journal = Dementia & Neuropsychologia | volume = 12 | issue = 4 | pages = 353–359 | date = 2018 | pmid = 30546844 | pmc = 6289486 | doi = 10.1590/1980-57642018dn12-040003 }}

The blood–brain barrier may become damaged in certain neurological diseases, as indicated by neuroimaging studies of Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy, ischemic stroke,{{cite journal | vauthors = Turner RJ, Sharp FR | title = Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke | journal = Frontiers in Cellular Neuroscience | volume = 10 | pages = 56 | date = 2016-03-04 | pmid = 26973468 | doi = 10.3389/fncel.2016.00056 | pmc = 4777722 | doi-access = free }}{{cite journal | vauthors = Mracsko E, Veltkamp R | title = Neuroinflammation after intracerebral hemorrhage | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 388 | date = 2014-11-20 | pmid = 25477782 | doi = 10.3389/fncel.2014.00388 | pmc = 4238323 | doi-access = free }}{{cite journal | vauthors = Alluri H, Wiggins-Dohlvik K, Davis ML, Huang JH, Tharakan B | title = Blood-brain barrier dysfunction following traumatic brain injury | journal = Metabolic Brain Disease | volume = 30 | issue = 5 | pages = 1093–1104 | date = October 2015 | pmid = 25624154 | doi = 10.1007/s11011-015-9651-7 | s2cid = 17688028 }} and brain trauma, and in systemic diseases, such as liver failure. Effects such as impaired glucose transport and endothelial degeneration may lead to metabolic dysfunction within the brain, and an increased permeability of the BBB to proinflammatory factors, potentially allowing antibiotics and phagocytes to move across the BBB. However, in many neurodegenerative diseases, the exact cause and pathology remains unknown. It is still unclear whether the BBB dysfunction in the disease is a causative agent, a result of the disease, or somewhere in the middle.

A 1898 study observed that low-concentration "bile salts" failed to affect behavior when injected into the blood of animals. Thus, in theory, the salts failed to enter the brain.{{cite journal |last1=Biedl |first1=A |last2=Kraus |first2=R |date=1898 |title=Über eine bisher unbekannte toxische Wirkung der Gallensäuren auf das Zentralnervensystem |trans-title=A previously unknown toxic effect of bile acids on the central nervous system |journal=Zentralblatt Inn Med |volume=19 |pages=1185–1200}} Google Scholar: [https://scholar.google.com/scholar?cluster=4353654721035571173 4353654721035571173]

Two years later, Max Lewandowsky may have been the first to coin the term "blood–brain barrier" in 1900, referring to the hypothesized semipermeable membrane.{{cite web |title=History of Blood-Brain Barrier |url=https://davislab.med.arizona.edu/history-blood-brain-barrier |access-date=2023-11-02 |website=Davis Lab |publisher=The University of Arizona}} There is some debate over the creation of the term blood–brain barrier as it is often attributed to Lewandowsky, but it does not appear in his papers. The creator of the term may have been Lina Stern.{{cite journal |last1=Saunders |first1=Norman R. |last2=Dreifuss |first2=Jean-Jacques |last3=Dziegielewska |first3=Katarzyna M. |last4=Johansson |first4=Pia A. |last5=Habgood |first5=Mark D. |last6=Møllgård |first6=Kjeld |last7=Bauer |first7=Hans-Christian |date=2014 |title=The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history |journal=Frontiers in Neuroscience |volume=8 |page=404 |doi=10.3389/fnins.2014.00404 |pmid=25565938 |pmc=4267212 |issn=1662-453X |doi-access=free }} Stern was a Russian scientist who published her work in Russian and French. Due to the language barrier between her publications and English-speaking scientists, this could have made her work a lesser-known origin of the term.

All the while, bacteriologist Paul Ehrlich was studying staining, a procedure that is used in many microscopy studies to make fine biological structures visible using chemical dyes.{{cite journal | vauthors = Saunders NR, Dziegielewska KM, Møllgård K, Habgood MD | title = Markers for blood-brain barrier integrity: how appropriate is Evans blue in the twenty-first century and what are the alternatives? | journal = Frontiers in Neuroscience | volume = 9 | pages = 385 | year = 2015 | pmid = 26578854 | pmc = 4624851 | doi = 10.3389/fnins.2015.00385 | doi-access = free }} As Ehrlich injected some of these dyes (notably the aniline dyes that were then widely used), the dye stained all of the organs of some kinds of animals except for their brains. At that time, Ehrlich attributed this lack of staining to the brain simply not picking up as much of the dye.

However, in a later experiment in 1913, Edwin Goldmann (one of Ehrlich's students) injected the dye directly into the cerebrospinal fluid of animal brains. He found then the brains did become dyed, but the rest of the body did not, demonstrating the existence of a compartmentalization between the two. At that time, it was thought that the blood vessels themselves were responsible for the barrier, since no obvious membrane could be found.

• {{annotated link|Blood–ocular barrier}}
• {{annotated link|Blood–retinal barrier}}
• {{annotated link|Blood–saliva barrier}}
• {{annotated link|Blood–spinal cord barrier}}
• {{annotated link|Blood–testis barrier}}

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