The
blood-brain barrier (BBB) is a separation of circulating
bloodBlood is a specialized bodily fluid that delivers necessary substances to the body's cells — such as nutrients and oxygen — and transports waste products away from those same cells....
and
cerebrospinal fluidCerebrospinal fluid , Liquor cerebrospinalis, is a clear bodily fluid that occupies the subarachnoid space and the ventricular system around and inside the brain. In essence, the brain "floats" in it....
(CSF) maintained by the
choroid plexusThe choroid plexus is the area on the ventricles of the brain where cerebrospinal fluid is produced by modified ependymal cells.-Locations:...
in the
central nervous systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
(CNS). Endothelial cells restrict the diffusion of microscopic objects (e.g.
bacteriaThe bacteria are a large group of unicellular microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
) and large or hydrophillic molecules into the CSF, while allowing the diffusion of small hydrophobic molecules (O
2, hormones, CO
2). Cells of the barrier actively transport
metabolicMetabolism is the set of chemical reactions that occur in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter,...
products such as glucose across the barrier with specific proteins.
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
occludinOccludin is a protein that in humans is encoded by the OCLN gene.Occludin is a 65-kDa integral plasma-membrane protein located specifically at tight junctions described for the first time in 1993 by S Tsukita....
, claudins, junctional adhesion molecule (JAM), ESAM and others. Each of these
transmembrane proteinA transmembrane protein is a protein that spans the entire biological membrane. Transmembrane proteins aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them can be also extracted using denaturing agents.-Types:There are two basic...
s 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.
AstrocyteAstrocytes are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a...
cell projections called astrocytic feet (also known as "
glia limitansThe Glia limitans, or glial limiting membrane, is the outermost layer of proper nervous tissue of the brain and spinal cord, lying directly under the pia mater.-Structure:...
") 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 plexusThe choroid plexus is the area on the ventricles of the brain where cerebrospinal fluid is produced by modified ependymal cells.-Locations:...
, and from the
blood-retinal barrierThe blood-retinal barrier, or the BRB, is part of the blood-ocular barrier that consists of cells that are joined tightly together in order to prevent certain substances from entering the tissue of the retina...
, which can be considered a part of the whole.
Several areas of the brain are not "behind" the BBB. One example is the
pineal glandThe pineal gland is a small endocrine gland in the vertebrate brain. It produces melatonin, a hormone that affects the modulation of wake/sleep patterns and photoperiodic functions...
which secretes the hormone
melatoninMelatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring hormone found in animals and in some other living organisms, including algae. Circulating levels vary in a daily cycle, and melatonin is important in the regulation of the circadian rhythms of several...
"directly into the systemic circulation."
History
Paul EhrlichPaul Ehrlich was a German scientist in the fields of hematology, immunology, and chemotherapy, and Nobel laureate. He is noted for curing syphilis and for his research in autoimmunity, calling it "horror autotoxicus"...
was a bacteriologist studying staining, used for many studies to make fine structures visible. When he interjected some of these dyes (notably the aniline dyes that were then popular), the dye would stain all of the
organsIn biology and anatomy, an organ is a collection of tissues joined in structural unit to serve a common function ....
of an animal except the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
. 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 vesselThe blood vessels are the part of the circulatory system that transport blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart, the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s 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 SternLina Solomonovna Stern was a notable Soviet biochemist, physiologist and humanist whose medical discoveries saved thousands of lives at the fronts of World War II...
in 1921. It was not until the introduction of the
scanning electron microscopeThe scanning electron microscope is a type of electron microscope that images the sample surface by scanning it with a high-energy beam of electrons in a raster scan pattern...
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
infectionAn infection is the detrimental colonization of a host organism by a foreign species. In an infection, the infecting organism seeks to utilize the host's resources to multiply, usually at the expense of the host. The infecting organism, or pathogen, interferes with the normal functioning of the...
s. 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. 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.
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
bradykininBradykinin is a peptide that causes blood vessels to enlarge , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
, 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
transcytosisTranscytosis is the process by which various macromolecules are transported across the interior of a cell. Vesicles are employed to intake the macromolecules on one side of the cell, draw them across the cell, and eject them on the other side. While transcytosis is most commonly observed in cells...
for
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
or
transferrinTransferrin is a blood plasma protein for iron ion delivery that, in humans, is encoded by the TF gene. Transferrin is a glycoprotein that binds iron very tightly but reversibly. Although iron bound to transferrin is less than 0.1% of the total body iron, it is the most important iron pool, with...
; 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. 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 tumorA brain tumor is an abnormal growth of cells within the brain or inside the skull, which can be cancerous or non-cancerous .It is defined as any intracranial tumor created by abnormal and uncontrolled cell division, normally either in the brain itself , in the cranial nerves...
s. 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
antineoplasticAntineoplastics are drugs that inhibit and combat the development of neoplasms.In the Anatomical Therapeutic Chemical Classification System, they are classified under L01D.- Health effects/occupational exposure :...
drugs to tumors in the central nervous system. For example, radiolabeled polyethylene glycol coated hexadecylcyanoacrylate nanospheres targeted and accumulated in a rat gliosarcoma. 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 membraneThe basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
is sometimes incomplete. Other factors, such as astrocytes, may contribute to the resistance of brain tumors to therapy.
Meningitis
MeningitisMeningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
is inflammation of the membranes which surround the brain and spinal cord (these membranes are also known as
meningesThe meninges is the system of membranes which envelops the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater...
). Meningitis is most commonly caused by infections with various
pathogenA pathogen , infectious agent, or germ, is a biological agent that causes disease or illness to its host....
s, 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)
Treatment with
third generation or fourth generation cephalosporinThe cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium"....
is usually preferred.
Epilepsy
EpilepsyEpilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures...
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 , some studies implicate the interactions between a common blood protein -
albuminAlbumin refers generally to any protein with water solubility, which is moderately soluble in concentrated salt solutions, and experiences heat coagulation...
and
astrocytesAstrocytes are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a...
. 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 .
Multiple sclerosis (MS)
Multiple sclerosisMultiple sclerosis is an idiopathic disease of suspected autoimmune cause, in which the body's immune response attacks a person's central nervous system , leading to demyelination. Disease onset usually occurs in young adults, and it is more common in females...
(MS) is considered an auto-immune and neurodegenerative disorder in which the
immune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumour cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
attacks the
myelinMyelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system...
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 ImagingMagnetic Resonance Imaging , or nuclear magnetic resonance imaging , is primarily a medical imaging technique most commonly used in radiology to visualize the internal structure and function of the body...
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 cellWhite blood cells , or leukocytes , are cells of the immune system defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s called T lymphocytes to cross over and destroy the
myelinMyelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system...
. 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 stressOxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. All forms of life maintain a reducing environment within their cells...
plays an important role into the breakdown of the barrier; anti-oxidants such as
lipoic acidLipoic acid is an organosulfur compound, one enantiomer of which is an essential cofactor for many enzyme complexes. This yellow solid is a carboxylic acid and features a cyclic disulfide, or ditholane ring, functional group. The R-enantiomer is biosynthesized and used as a cofactor. It is...
may be able to stabilize a weakening blood-brain barrier.
Neuromyelitis optica
Neuromyelitis optica, also known as
Devic's diseaseDevic's disease, also known as Devic's syndrome or neuromyelitis optica , is an autoimmune, inflammatory disorder in which a person's own immune system attacks the optic nerves and spinal cord. This produces an inflammation of the optic nerve and the spinal cord...
, is similar to and often confused with
multiple sclerosisMultiple sclerosis is an idiopathic disease of suspected autoimmune cause, in which the body's immune response attacks a person's central nervous system , leading to demyelination. Disease onset usually occurs in young adults, and it is more common in females...
. 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
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
called
aquaporin 4Aquaporin 4 also known as AQP4 is protein which in humans is encoded by the AQP4 gene. AQP4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane.- Function :...
(a component of the astrocytic foot processes in the blood-brain barrier).
Late-stage neurological trypanosomiasis (Sleeping sickness)
Late-stage neurological
trypanosomiasisTrypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. More than 66 million women, men, and children in 36 countries of sub-Saharan Africa suffer from human African trypanosomiasis which is caused by...
, or sleeping sickness, is a condition in which trypanosoma
protozoaProtozoa or Cornelius protozoans Protozoa or Cornelius protozoans Protozoa or Cornelius protozoans (from Greek πρῶτον proton "first" and ζῷα zoa "animals"; singular protozoon; (the word "protozoan" is originally an adjective, used as a noun) are microorganisms classified as unicellular eukaryotes....
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 plexusThe choroid plexus is the area on the ventricles of the brain where cerebrospinal fluid is produced by modified ependymal cells.-Locations:...
, a circumventricular organ.
Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations...
(PML) is a demyelinating disease of the central nervous system caused by reactivation of a latent
papovavirusA Papovavirus is a member of the Papovaviridae family of viruses. Papovaviridae includes two genera: Papillomavirus and Polyomavirus....
(the JC polyomavirus) infection, that can cross the BBB. It affects immune-compromised patients and is usually seen with patients having
AIDSAcquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus ....
.
De Vivo disease
De Vivo diseaseDe Vivo disease is an autosomal dominant developmental disorder associated with a deficiency of GLUT1 also know as Glucose transporter type 1 deficiency syndrome - Presentation :...
(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 transporterGlucose transporters are a family of membrane proteins found in most mammalian cells.-Function:Glucose is an essential substrate for the metabolism of most cells...
type 1 (GLUT1) appears to be the main cause of De Vivo disease.
Alzheimer's Disease
New evidence indicates that disruption of the blood-brain barrier in AD patients allows blood plasma containing
amyloid betaAmyloid beta is a peptide of 39–43 amino acids that appear to be the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease. Aβ also forms aggregates coating...
(Aβ) to enter the brain where the Aβ adheres preferentially to the surface of
astrocyteAstrocytes are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a...
s. 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
endocytosisEndocytosis is the process by which cells absorb molecules from outside the cell by engulfing it with their cell membrane. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma membrane or cell membrane...
. 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.
http://www.umdnj.edu/research/publications/fall06/4.htm
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.
http://www.manchester.ac.uk/aboutus/news/archive/list/item/?id=4230&year=2008&month=12
HIV Encephalitis
It is believed that latent
HIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid,...
can cross the blood-brain barrier inside circulating monocytes in the bloodstream ("
Trojan horseThe Trojan Horse was a tale from the Trojan War, as told in Virgil's Latin epic poem The Aeneid. The events in this story from the Bronze Age took place after Homer's Iliad, and before Homer's Odyssey. It was the stratagem that allowed the Greeks finally to enter the city of Troy and end the...
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.