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 cells called astrocytic feet 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
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 (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.
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.
[3]
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
[4].
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)
[5].
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.
[6][7]
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.
[3]
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. Blood, brain, and cerebrospinal fluid concentrations of several antibiotics in rabbits with intact and inflamed meninges, , TR Jr., Beam, Antimicrobial agents and chemotherapy, 1977
4. Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity [1]
5. The NMO-IgG autoantibody links to the aquaporin 4 channel [2]
6. GLUT1 deficiency and other glucose transporter diseases, , JM, Pascual, European journal of endocrinology, 2004
7. Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain-- a review, , J, Klepper, European journal of pediatrics, 2002
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