blood-brain barrier

The blood-brain barrier (BBB) is a membranic structure that acts primarily to protect the brain from chemicals in the blood, while still allowing essential metabolic function. It is composed of endothelial cells, which are packed very tightly in brain capillaries. This higher density restricts 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 "glial 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.

History

The existence of such a barrier was first noticed in experiments by Paul Ehrlich in the late-19th century. Ehrlich was a bacteriologist who was studying staining, used for many studies to make fine structures visible. When injected, some of these dyes (notably the aniline dyes that were then popular) 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 barrier 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.[1] 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 epithelial cells were the basis of the blood-brain barrier because of the densely packed astrocyte processes that surround the epithelial cells of the BBB.

Physiology

In the rest of the body outside the brain, the walls of the capillaries (the smallest of the blood vessels) are made up of endothelial cells which are fenestrated, meaning they have small gaps called fenestrations. Soluble chemicals can pass through these gaps, from blood to tissues or from tissues into blood. However in the brain endothelial cells are packed together more tightly with what are called tight junctions. This makes the blood-brain barrier block the movement of all molecules except those that cross cell membranes by means of lipid solubility (such as oxygen, carbon dioxide, ethanol, and steroid hormones) and those that are allowed in by specific transport systems (such as sugars and some amino acids). Substances with a molecular weight higher than 500 daltons (500 u) generally cannot cross the blood-brain barrier, while smaller molecules often can. In addition, the endothelial cells metabolize certain molecules to prevent their entry into the central nervous system. For example, L-DOPA, the precursor to dopamine, can cross the BBB, whereas dopamine itself cannot. (As a result, L-DOPA is administered for dopamine deficiences (e.g., Parkinson's disease) rather than dopamine).

In addition to tight junctions acting to prevent transport in between endothelial cells, there are two mechanisms to prevent passive diffusion through the cell membranes. Glial cells surrounding capillaries in the brain pose a secondary hindrance to hydrophilic molecules, and the low concentration of interstitial proteins in the brain prevent access by hydrophilic molecules.[2]

The blood-brain barrier protects the brain from the many chemicals flowing within the blood. However, many bodily functions are controlled by hormones in the blood, and while the secretion of many hormones is controlled by the brain, these hormones generally do not penetrate the brain from the blood. This would prevent the brain from directly monitoring hormone levels. In order to control the rate of hormone secretion effectively, there exist specialised sites where neurons can "sample" the composition of the circulating blood. At these sites, the blood-brain barrier is 'leaky'; these sites include three important 'circumventricular organs', the subfornical organ, the area postrema and the organum vasculosum of the lamina terminalis (OVLT).

The blood-brain barrier acts very effectively to protect the brain from many common 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 which do occur are often very serious and difficult to treat.

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.

Nanotechnology may also help in the transfer of drugs across the BBB. Recently, researchers have been trying to build nanoparticles loaded with liposomes 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.

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.[3][4]

Diseases

Meningitis

Meningitis is inflammation of the membranes which surround the brain and spinal cord (these membranes are also known as meninges). Meningitis is most commonly caused by infections with various pathogens. 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.[5] Treatment with third generation or fourth generation cephalosporin is usually preferred.

Multiple sclerosis (MS)

Multiple sclerosis (MS) is considered an auto-immune disorder in which the immune system attacks the myelin protecting the nerves 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 his/her 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. 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[6].

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)[7].hjo

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.[8][9]

Alzheimer's Disease

New evidence indicates that disrupton 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 hypothesize 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]

References

1. ^ Lina Stern: Science and fate by A.A. Vein. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
2. ^ Amdur, Doull, Klaassen (1991) Casarett and Doull's Toxicology; The Basic Science of Poisons 4th ed
3. ^ 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. 
4. ^ 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. PMID 14730455. 
5. ^ 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. 
6. ^ Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity [2]
7. ^ The NMO-IgG autoantibody links to the aquaporin 4 channel [3]
8. ^ 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. PMID 15132717. 
9. ^ 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. PMID 12029447. 
endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary.
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The choroid plexus is the area on the ventricles of the brain where cerebrospinal fluid (CSF) is produced by modified ependymal cells.

Choroid plexus is present in all components of the ventricular system except for the cerebral aqueduct and the occipital and frontal horns
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Paul Ehrlich (March 14, 1854 – August 20, 1915) was a German scientist who won the 1908 Nobel Prize in Physiology or Medicine. He is noted for his work in hematology, immunology, and chemotherapy. Ehrlich predicted autoimmunity calling it "horror autotoxicus".
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The 19th Century (also written XIX century) lasted from 1801 through 1900 in the Gregorian calendar. It is often referred to as the "1800s.
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Microbiology is the study of microorganisms, which are unicellular or cell-cluster microscopic organisms.[1] This includes eukaryotes such as fungi and protists, and prokaryotes such as bacteria and certain algae.
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Staining is a biochemical technique of adding a class-specific (DNA, proteins, lipids, carbohydrates) dye to a substrate to qualify or quantify the presence of a specific compound. It is similar to fluorescent tagging.
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Aniline, phenylamine or aminobenzene is an organic compound with the formula C6H5NH2. It is the simplest and one of the most imporant aromatic amines, being used as a precursor to more complex chemicals.
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organ (Latin: organum, "instrument, tool") is a group of tissues that perform a specific function or group of functions. Usually there is a main tissue and sporadic tissues. The main tissue is the one that is unique for the specific organ.
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In animals, the brain or encephalon (Greek for "in the skull"), is the control center of the central nervous system, responsible for behavior. The brain is located in the head, protected by the skull and close to the primary sensory apparatus of vision, hearing,
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19th century - 20th century - 21st century
1880s  1890s  1900s  - 1910s -  1920s  1930s  1940s
1910 1911 1912 - 1913 - 1914 1915 1916

Year 1913 (MCMXIII
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Cerebrospinal fluid (CSF), Liquor cerebrospinalis, is a clear bodily fluid that occupies the subarachnoid space and the ventricular system around and inside the brain.
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The blood vessels are part of the cardiovascular system and function to transport blood throughout the body. The most important types, arteries and veins, carry blood away from or towards the heart, respectively.
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Lina Stern

Born August 26, 1878
Liepaja, Russian Empire
Died March 7, 1968
USSR
Citizenship USSR
Field blood-brain barrier, biochemistry, neuroscience
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scanning electron microscope (SEM) is a type of electron microscope capable of producing high-resolution images of a sample surface. Due to the manner in which the image is created, SEM images have a characteristic three-dimensional appearance and are useful for judging the
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Centuries: 19th century - 20th century - 21st century

1930s 1940s 1950s - 1960s - 1970s 1980s 1990s
1960 1961 1962 1963 1964
1965 1966 1967 1968 1969

- -
-

Their 1960s decade refers to the years from 1960 to 1969, inclusive.
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capillary is used to describe any very narrow tube or channel through which a fluid can pass. See capillary action for details.


Capillaries are the smallest of a body's blood vessels, measuring 5-10 μm, which connect arterioles and venules, and are
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The blood vessels are part of the cardiovascular system and function to transport blood throughout the body. The most important types, arteries and veins, carry blood away from or towards the heart, respectively.
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endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary.
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Fenestrae (singular: fenestra) are small pores in epithelial cells to allow for rapid exchange of molecules between blood vessels and surrounding tissue. These pores can enlarge and contract at the action of various stimuli such as noradrenaline.
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Tight junctions, or zonula occludens, are the closely associated areas of two cells whose membranes join together forming a virtual impermeable barrier to fluid. It is a type of junctional complex only present in vertebrates.
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Lipids can be broadly defined as any fat-soluble (hydrophobic), naturally-occurring molecules. The term is more-specifically used to refer to fatty-acids and their derivatives (including tri-, di-, and monoglycerides and phospholipids) as well as other fat-soluble sterol-containing
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2, −1
(neutral oxide)
Electronegativity 3.44 (Pauling scale)
Ionization energies
(more) 1st: 1313.9 kJmol−1
2nd: 3388.3 kJmol−1
3rd: 5300.5 kJmol−1

Atomic radius 60 pm
Atomic radius (calc.
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Carbon dioxide is a chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom. It is a gas at standard temperature and pressure and exists in Earth's atmosphere in this state.
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Ethanol, also known as ethyl alcohol, drinking alcohol or grain alcohol, is a flammable, colorless, slightly toxic chemical compound, and is best known as the alcohol found in alcoholic beverages.
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Sugars, brown
Nutritional value per 100 g (3.5 oz)

Energy 0 kcal   0 kJ

Carbohydrates     97.33 g
- Sugars  96.21 g
- Dietary fiber  0 g  
Fat 0 g
Protein 0 g
Water 1.77 g
Thiamin (Vit. B1)  0.
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The unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic and molecular masses. It is defined to be one twelfth of the mass of an unbound atom of the carbon-12 nuclide, at rest and in its ground state.
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The unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic and molecular masses. It is defined to be one twelfth of the mass of an unbound atom of the carbon-12 nuclide, at rest and in its ground state.
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Levodopa (INN) or L -DOPA (3,4-dihydroxy- L -phenylalanine) is an intermediate in dopamine biosynthesis. In clinical use, levodopa is administered in the management of Parkinson's disease.
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Dopamine is a hormone and neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In chemical structure, it is a phenethylamine.
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