Share on Facebook Share on Twitter Email
Answers.com

blood-brain barrier

 
Dictionary: blood-brain barrier   (blŭd'brān')
n.

A physiological mechanism that alters the permeability of brain capillaries, so that some substances, such as certain drugs, are prevented from entering brain tissue, while other substances are allowed to enter freely.


Search unanswered questions...
Enter a question here...
Search: All sources Community Q&A Reference topics
World of the Body: blood-brain barrier
Top

The main function of the blood-brain barrier (BBB) is to protect the brain from changes in the levels in the blood of ions, amino acids, peptides, and other substances. The barrier is located at the brain blood capillaries, which are unusual in two ways. Firstly, the cells which make up the walls of these vessels (the endothelium) are sealed together at their edges by tight junctions that form a key component of the barrier. These junctions prevent water-soluble substances in the blood from passing between the cells and therefore from freely entering the fluid environment of the brain cells. Secondly, these capillaries are enclosed by the flattened ‘end-feet’ of astrocytic cells (one type of glia), which also act as a partial, active, barrier. Thus the only way for water-soluble substances to cross the BBB is by passing directly through the walls of the cerebral capillaries, and because their cell membranes are made up of a lipid/protein bilayer, they also act as a major part of the BBB.

In contrast, fat-soluble molecules, including those of oxygen and carbon dioxide, anaesthetics, and alcohol can pass straight through the lipids in the capillary walls and so gain access to all parts of the brain.

Apart from these passive elements of the BBB there are also enzymes on the lining of the cerebral capillaries that destroy unwanted peptides and other small molecules in the blood as it flows through the brain.

Finally, there is another barrier process that acts against lipid-soluble molecules, which may be toxic and can diffuse straight through capillary walls into the brain. In the capillary wall there are three classes of specialized ‘efflux pumps’ which bind to three broad classes of molecules and transport them back into the blood out of the brain.

Diagram of a cerebral capillary enclosed in astrocyte end-feet. Characteristics of the blood-brain barrier are indicated: (1) tight junctions that seal the pathway between the capillary (endothelial) cells; (2) the lipid nature of the cell membranes of the capillary wall which makes it a barrier towater-soluble molecules; (3), (4), and (5) represent some of the carriers and ion channels; (6) the 'enzymatic barrier'that removes molecules from the blood; (7) the efflux pumps which extrude fat-soluble molecules that have crossed into the cells
Diagram of a cerebral capillary enclosed in astrocyte end-feet. Characteristics of the blood-brain barrier are indicated: (1) tight junctions that seal the pathway between the capillary (endothelial) cells; (2) the lipid nature of the cell membranes of the capillary wall which makes it a barrier towater-soluble molecules; (3), (4), and (5) represent some of the carriers and ion channels; (6) the 'enzymatic barrier'that removes molecules from the blood; (7) the efflux pumps which extrude fat-soluble molecules that have crossed into the cells



However, in order for nourishment to reach the brain, water-soluble compounds must cross the BBB, including the vital glucose for energy production and amino acids for protein synthesis. To achieve this transfer, brain vessels have evolved special carriers on both sides of the cells forming the capillary walls, which transport these substances from blood to brain, and also move waste products and other unwanted molecules in the opposite direction.

The successful evolution of a complex brain depends on the development of the BBB. It exists in all vertebrates, and also in insects and the highly intelligent squid and octopus. In man the BBB is fully formed by the third month of gestation, and errors in this process can lead to defects such as spina bifida.

Although the BBB is an obvious advantage in protecting the brain, it also restricts the entry from the blood of water-soluble drugs which are used to treat brain tumours or infections, such as the AIDS virus, which uses the brain as a sanctuary and ‘hides’ behind the BBB from body defence mechanisms. To overcome these problems drugs are designed to cross the BBB, by making them more fat soluble. But this also means that they might enter most cells in the body and be too toxic. Alternative approaches are to make drug molecules that can ‘ride on’ the natural transporter proteins in the cerebral capillaries, and so be more focused on the brain, or to use drugs that open the BBB.

Since the brain is contained in a rigid, bony skull, its volume has to be kept constant. The BBB plays a key role in this process, by limiting the freedom of movement of water and salts from the blood into the extracellular fluid of the brain. Whereas in other body tissues extracellular fluid is formed by leakage from capillaries, the BBB in fact secretes brain extracellular fluid at a controlled rate and is thus critical in the maintenance of normal brain volume. If the barrier is made leaky by trauma or infection, water and salts cross into the brain, causing it to swell (cerebral oedema), which leads to raised intracranial pressure; this can be fatal.

The blood-brain barrier is thus a key element in the normal functioning of the brain, and isolates it from disturbances in the composition of the fluids in the rest of the body.

— Malcolm Segal

See also acid-base homeostasis; body fluids; cell membrane; cerebrospinal fluid; meninges.

Sports Science and Medicine: blood-brain barrier
Top

The layer of fatty cells covering the capillaries of the brain, which acts as a barrier to the passage of some chemicals (including some drugs) from the blood to brain tissue.

Science Dictionary: blood-brain barrier
Top

The separation of the brain, which is bathed in a clear cerebrospinal fluid, from the bloodstream. The cells near the capillary beds external to the brain selectively filter the molecules that are allowed to enter the brain, creating a more stable, nearly pathogen-free environment.

  • Oxygen, glucose, and white blood cells are molecules that are able to pass through this barrier. Red blood cells cannot.
  • Wikipedia: Blood-brain barrier
    Top
    Part of a network of capillaries supplying brain cells

    The blood-brain barrier (BBB) is a separation of circulating blood and cerebrospinal fluid (CSF) maintained by the choroid plexus in the central nervous system (CNS). Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria) and large or hydrophilic molecules into the CSF, while allowing the diffusion of small hydrophobic molecules (O2, hormones, CO2). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins.

    Contents

    Physiology

    This "barrier" results from the selectivity of the tight junctions between endothelial cells in CNS vessels that restricts the passage of solutes. At the interface between blood and brain, endothelial cells and associated astrocytes are stitched together by these tight junctions, which are composed of smaller subunits, frequently dimers, that are transmembrane proteins such as occludin, claudins, junctional adhesion molecule (JAM), ESAM and others. Each of these transmembrane proteins is anchored into the endothelial cells by another protein complex that includes zo-1 and associated proteins.

    The blood-brain barrier is composed of high density cells restricting passage of substances from the bloodstream much more than endothelial cells in 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. The BBB is distinct from the similar blood-cerebrospinal fluid barrier, 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.[1]

    Several areas of the brain are not "behind" the BBB. One example is the pineal gland, which secretes the hormone melatonin "directly into the systemic circulation."[2]

    History

    Paul Ehrlich was a bacteriologist studying staining, used for many studies to make fine structures visible. When he injected some of these dyes (notably the aniline dyes that were then popular), the dye would stain all of the organs of an animal except the brain. At the time, Ehrlich attributed this 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 into the spinal fluid of the brain directly. He found that in this case the brain would become dyed, but the rest of the body would not. This clearly demonstrated the existence of some sort of compartmentalization between the two. At the time, it was thought that the blood vessels themselves were responsible for the barrier, as no obvious membrane could be found. The concept of the blood-brain barrier (then termed hematoencephalic barrier) was proposed by Lina Stern in 1921.[3] It was not until the introduction of the scanning electron microscope to the medical research fields in the 1960s that the actual membrane could be demonstrated.

    It was once believed that astrocytes rather than endothelial cells were the basis of the blood-brain barrier because of the densely packed astrocyte foot processes that surround the endothelial cells of the BBB.

    Pathophysiology

    The blood-brain barrier acts very effectively to protect the brain from many common bacterial infections. Thus, infections of the brain are very rare. However, since antibodies are too large to cross the blood-brain barrier, infections of the brain that do occur are often very serious and difficult to treat. The blood brain barrier becomes more permeable during inflammation however, meaning some antibiotics can get across. Viruses easily bypass the blood-brain barrier by attaching themselves to circulating immune cells.

    An exception to the bacterial exclusion are the diseases caused by spirochetes, such as Borrelia, which causes Lyme disease, and treponema pallidum, which causes syphilis. The bacteria seem to breach the barrier by physically tunneling through the blood vessel walls.

    Drugs targeting the brain

    Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. 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 genes that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts.

    Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for drug delivery through the BBB entail its disruption by osmotic means, biochemically by the use of vasoactive substances such as bradykinin, or even by localized exposure to high-intensity focused ultrasound (HIFU). Other strategies to go 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 blocking of active efflux transporters such as p-glycoprotein. Strategies for drug delivery behind the BBB include intracerebral implantation and convection-enhanced distribution.

    Nanoparticles

    Nanotechnology may also help in the transfer of drugs across the BBB.[4] Recently, researchers have been trying to build liposomes loaded with nanoparticles to gain access through the BBB. More research is needed to determine which strategies will be most effective and how they can be improved for patients with brain tumors. The potential for using BBB opening to target specific agents to brain tumors has just begun to be explored.

    Delivering drugs across the blood brain barrier is one of the most promising applications of nanotechnology in clinical neuroscience. Nanoparticles could potentially carry out multiple tasks in a predefined sequence, which is very important in the delivery of drugs across the blood brain barrier.

    A significant amount of research in this area has been spent exploring methods of nanoparticle-mediated delivery of antineoplastic drugs to tumors in the central nervous system. For example, radiolabeled polyethylene glycol coated hexadecylcyanoacrylate nanospheres targeted and accumulated in a rat gliosarcoma. [5] However, this method is not yet ready for clinical trials due to the accumulation of the nanospheres in surrounding healthy tissue.

    It should be noted that vascular endothelial cells and associated pericytes are often abnormal in tumors and that the blood-brain barrier may not always be intact in brain tumors. Also, the basement membrane is sometimes incomplete. Other factors, such as astrocytes, may contribute to the resistance of brain tumors to therapy.[6][7]

    Diseases

    Meningitis

    Meningitis is inflammation of the membranes that surround the brain and spinal cord (these membranes are also known as meninges). Meningitis is most commonly caused by infections with various pathogens, examples of which are Streptococcus pneumoniae and Haemophilus influenzae. When the meninges are inflamed, the blood-brain barrier may be disrupted. This disruption may increase the penetration of various substances (including antibiotics) into the brain. Antibiotics used to treat meningitis may aggravate the inflammatory response of the central nervous system by releasing neurotoxins from the cell walls of bacteria like lipopolysaccharide (LPS) [8] Treatment with third-generation or fourth-generation cephalosporin is usually preferred.

    Epilepsy

    Epilepsy is a common neurological disease characterized by frequent and often untreatable seizures. Several clinical and experimental data have implicated failure of blood-brain barrier function in triggering chronic or acute seizures [9][10], some studies implicate the interactions between a common blood protein - albumin and astrocytes[11]. These findings have shown that acute seizures are a predictable consequence of disruption of the BBB by either artificial or inflammatory mechanisms. In addition, expression of drug resistance molecules and transporters at the BBB are a significant mechanism of resistance to commonly used anti-epileptic drugs [12].

    Multiple sclerosis (MS)

    Multiple sclerosis (MS) is considered an auto-immune and neurodegenerative disorder in which the immune system attacks the myelin protecting the neurons in the central nervous system. Normally, a person's nervous system would be inaccessible for the white blood cells due to the blood-brain barrier. However, it has been shown using Magnetic Resonance Imaging that, when a person is undergoing an MS "attack," the blood-brain barrier has broken down in a section of the brain or spinal cord, allowing white blood cells called T lymphocytes to cross over and destroy the myelin. It has been suggested that, rather than being a disease of the immune system, MS is a disease of the blood-brain barrier[13]. However, current scientific evidence is inconclusive.

    There are currently active investigations into treatments for a compromised blood-brain barrier. It is believed that oxidative stress plays an important role into the breakdown of the barrier; anti-oxidants such as lipoic acid may be able to stabilize a weakening blood-brain barrier[14].

    Neuromyelitis optica

    Neuromyelitis optica, also known as Devic's disease, is similar to and often confused with multiple sclerosis. Among other differences from MS, the target of the autoimmune response has been identified. Patients with neuromyelitis optica have high levels of antibodies against a protein called aquaporin 4 (a component of the astrocytic foot processes in the blood-brain barrier)[15].

    Late-stage neurological trypanosomiasis (Sleeping sickness)

    Late-stage neurological trypanosomiasis, or sleeping sickness, is a condition in which trypanosoma protozoa are found in brain tissue. It is not yet known how the parasites infect the brain from the blood, but it is suspected that they cross through the choroid plexus, a circumventricular organ.

    Progressive multifocal leukoencephalopathy (PML)

    Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of a latent papovavirus (the JC polyomavirus) infection, that can cross the BBB. It affects immune-compromised patients and is usually seen with patients having AIDS.

    De Vivo disease

    De Vivo disease (also known as GLUT1 deficiency syndrome) is a rare condition caused by inadequate transport of glucose across the barrier, resulting in mental retardation and other neurological problems. Genetic defects in glucose transporter type 1 (GLUT1) appears to be the main cause of De Vivo disease.[16][17]

    Alzheimer's Disease

    New evidence indicates that disruption of the blood-brain barrier in AD patients allows blood plasma containing amyloid beta (Aβ) to enter the brain where the Aβ adheres preferentially to the surface of astrocytes. These findings have led to the hypotheses that (1) breakdown of the blood-brain barrier allows access of neuron-binding autoantibodies and soluble exogenous Aβ42 to brain neurons and (2) binding of these autoantibodies to neurons triggers and/or facilitates the internalization and accumulation of cell surface-bound Aβ42 in vulnerable neurons through their natural tendency to clear surface-bound autoantibodies via endocytosis. Eventually the astrocyte is overwhelmed, dies, ruptures, and disintegrates, leaving behind the insoluble Aβ42 plaque. Thus, in some patients, Alzheimer’s disease may be caused (or more likely, aggravated) by a breakdown in the blood brain barrier. [1]

    The herpes virus produces the amyloid beta (Aβ) and has been found to be the pathogen responsible for being a major cause of the disease. [2]

    HIV Encephalitis

    It is believed[citation needed] that latent HIV can cross the blood-brain barrier inside circulating monocytes in the bloodstream ("Trojan horse theory") within the first 14 days of infection. Once inside, these monocytes become activated and are transformed into macrophages. Activated macrophages release virions into the brain tissue proximate to brain microvessels. These viral particles likely attract the attention of sentinel brain microglia and perivascular macrophages initiating an inflammatory cascade that may cause a series of intracellular signaling in brain microvascular endothelial cells and damage the functional and structural integrity of the BBB. This inflammation is HIV encephalitis (HIVE). Instances of HIVE probably occur throughout the course of AIDS and are a precursor for HIV-associated dementia (HAD). The premier model for studying HIV and HIVE is the simian model.

    References

    1. ^ Hamilton RD, Foss AJ, Leach L (2007). "Establishment of a human in vitro model of the outer blood-retinal barrier". Journal of Anatomy 211: 707. doi:10.1111/j.1469-7580.2007.00812.x. PMID 17922819. 
    2. ^ Pritchard, Thomas C.; Alloway, Kevin Douglas (1999) (Google books preview). Medical Neuroscience. Hayes Barton Press. pp. 76–77. ISBN 1889325295. http://books.google.com/books?id=m7Y80PcFHtsC&printsec=frontcover#PPA76,M1. Retrieved 2009-02-08. 
    3. ^ Lina Stern: Science and fate by A.A. Vein. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
    4. ^ Silva, GA (December 2008). "Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS". BMC Neuroscience 9 (Suppl. 3): S4. doi:10.1186/1471-2202-9-S3-S4. PMID 19091001. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19091001. 
    5. ^ Brigger I, Morizet J, Aubert G, et al. (December 2002). "Poly(ethylene glycol)-coated hexadecylcyanoacrylate nanospheres display a combined effect for brain tumor targeting". J. Pharmacol. Exp. Ther. 303 (3): 928–36. doi:10.1124/jpet.102.039669. PMID 12438511. 
    6. ^ Hashizume, H; Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (April 2000). "Openings between defective endothelial cells explain tumor vessel leakiness". American Journal of Pathology 156 (4): 1363–1380. PMID 10751361. 
    7. ^ Schneider, SW; Ludwig T, Tatenhorst L, Braune S, Oberleithner H, Senner V, Paulus W (March 2004). "Glioblastoma cells release factors that disrupt blood-brain barrier features". Acta Neuropathologica 107 (3): 272–276. doi:10.1007/s00401-003-0810-2. PMID 14730455. 
    8. ^ Beam, TR Jr.; Allen, JC (December 1977). "Blood, brain, and cerebrospinal fluid concentrations of several antibiotics in rabbits with intact and inflamed meninges". Antimicrobial agents and chemotherapy 12 (6): 710–6. PMID 931369. 
    9. ^ E. Oby and D. Janigro, The Blood-brain barrier and epilepsy. Epilepsia. 2006 Nov;47(11):1761-74
    10. ^ Marchi,N. et al. Seizure-Promoting Effect of Blood-Brain Barrier Disruption. Epilepsia 48(4), 732-742 (2007). Seiffert,E. et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J. Neurosci. 24, 7829-7836 (2004). Uva,L. et al. Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood-brain barrier permeability. Neuroscience (2007). van Vliet,E.A. et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130, 521-534 (2007).
    11. ^ Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O et al. (2007). "TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis.". Brain 130 (Pt 2): 535-47. doi:10.1093/brain/awl317. PMID 17121744. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17121744. 
    12. ^ Awasthi,S. et al. RLIP76, a non-ABC transporter, and drug resistance in epilepsy. BMC. Neurosci. 6, 61 (2005). Loscher,W. & Potschka,H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat. Rev. Neurosci. 6, 591-602 (2005).
    13. ^ Waubant E (2006). "Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis". Disease Markers 22 (4): 235–44. PMID 17124345. http://iospress.metapress.com/openurl.asp?genre=article&issn=0278-0240&volume=22&issue=4&spage=235. 
    14. ^ Schreibelt G, Musters RJ, Reijerkerk A, et al. (August 2006). "Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity". J. Immunol. 177 (4): 2630–7. PMID 16888025. http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=16888025. 
    15. ^ Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (August 2005). "IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel". J. Exp. Med. 202 (4): 473–7. doi:10.1084/jem.20050304. PMID 16087714. 
    16. ^ Pascual, JM; Wang D, Lecumberri B, Yang H, Mao X, Yang R, De Vivo DC (May 2004). "GLUT1 deficiency and other glucose transporter diseases". European journal of endocrinology 150 (5): 627–33. doi:10.1530/eje.0.1500627. PMID 15132717. 
    17. ^ Klepper, J; Voit T (June 2002). "Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain-- a review". European journal of pediatrics 161 (6): 295–304. doi:10.1007/s00431-002-0939-3. PMID 12029447. 


     
     

     

    Copyrights:

    Dictionary. The American Heritage® Dictionary of the English Language, Fourth Edition Copyright © 2007, 2000 by Houghton Mifflin Company. Updated in 2009. Published by Houghton Mifflin Company. All rights reserved.  Read more
    World of the Body. The Oxford Companion to the Body. Copyright © 2001, 2003 by Oxford University Press. All rights reserved.  Read more
    Sports Science and Medicine. The Oxford Dictionary of Sports Science & Medicine. Copyright © Michael Kent 1998, 2006, 2007. All rights reserved.  Read more
    Science Dictionary. The New Dictionary of Cultural Literacy, Third Edition Edited by E.D. Hirsch, Jr., Joseph F. Kett, and James Trefil. Copyright © 2002 by Houghton Mifflin Company. Published by Houghton Mifflin. All rights reserved.  Read more
    Wikipedia. This article is licensed under the Creative Commons Attribution/Share-Alike License. It uses material from the Wikipedia article "Blood-brain barrier" Read more