Blood–brain barrier

The **blood–brain barrier** (**BBB**) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from *non-selectively* crossing into the extracellular fluid of the central nervous system where neurons reside. The blood-brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some molecules by passive diffusion, as well as the selective transport of various nutrients, ions, organic anions, and macromolecules such as glucose, water and amino acids that are crucial to neural function.

The blood-brain barrier restricts the passage of pathogens, the diffusion of solutes in the blood, and large or hydrophilic molecules into the cerebrospinal fluid, while allowing the diffusion of hydrophobic molecules (O2, CO2, hormones) and small polar molecules. Cells of the barrier actively transport metabolic products such as glucose across the barrier using specific transport proteins.

Specialized brain structures participating in sensory and secretory integration within brain neural circuits — the circumventricular organs and choroid plexus — have highly permeable capillaries.

## Structure

The blood-brain barrier 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, junctional adhesion molecule. Each of these transmembrane proteins is anchored into the endothelial cells by another protein complex that includes tight junction protein 1 and associated proteins.

The blood-brain barrier 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. 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.

Several areas of the human brain are not on the brain side of the BBB. 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 pineal gland secretes the hormone melatonin "directly into the systemic circulation", thus melatonin is not affected by the blood-brain barrier.

### Development

The blood-brain barrier appears to be functional by the time of birth. P-glycoprotein, a transporter, exists already in the embryonal endothelium.

Measurement of brain uptake of various blood-borne solutes showed that newborn endothelial cells were functionally similar to those in adults, indicating that a selective BBB is operative at birth.

## Function

See also: Neuroimmune system
The blood-brain barrier acts effectively to protect the brain from circulating pathogens. 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. 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.

The blood-brain barrier may become leaky in select neurological diseases, such as amyotrophic lateral sclerosis, epilepsy, brain trauma and edema, and in systemic diseases, such as liver failure. The blood-brain barrier becomes more permeable during inflammation, allowing antibiotics and phagocytes to move across the BBB. However, this also allows bacteria and viruses to infiltrate the blood-brain barrier. Examples of pathogens that can traverse the blood-brain barrier include *Toxoplasma gondii* which causes toxoplasmosis, spirochetes like *Borrelia* (Lyme disease), Group B streptococci which causes meningitis in newborns, and *Treponema pallidum* which causes syphilis. Some of these harmful bacteria gain access by releasing cytotoxins like pneumolysin which have a direct toxic effect on brain microvascular endothelium and tight junctions.

### Circumventricular organs

Main articles: 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. 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.

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.

### Specialized permeable zones

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), and median eminence—hypothalamic arcuate nucleus. 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.

## Clinical significance

### As a drug target

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. 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 antibodies 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 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, or even by localized exposure to high-intensity focused ultrasound (HIFU). 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. However, 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.

#### Nanoparticles

Main articles: Nanoparticles for drug delivery to the brain
Nanotechnology is under preliminary research for its potential to facilitate the transfer of drugs across the BBB. 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.

## Disease

### Meningitis

Meningitis is an inflammation of the membranes that surround the brain and spinal cord (these membranes are 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 either toxins or 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). Depending on the causative pathogen, whether it is bacterial, fungal, or protozoan, treatment with third-generation or fourth-generation cephalosporin or amphotericin B is usually prescribed.

### Brain abscess

A brain or cerebral abscess, like other abscesses, is caused by inflammation and collection of lymphatic cells and infected material originating from a local or remote infection. A brain abscess is a rare, life-threatening condition. Local sources may include infections of the ear, the oral cavity and teeth, the paranasal sinuses, or an epidural abscess. Remote sources may include infections in the lung, heart or kidney. A brain abscess may also be caused by head trauma or as a complication of surgery. In children cerebral abscesses are usually linked to congenital heart disease. In most cases, 8–12 weeks of antibacterial therapy is required.

### Multiple sclerosis

Multiple sclerosis is considered to be an autoimmune and neurodegenerative disorder in which the immune system attacks the myelin that protects and electrically insulates the neurons of the central and peripheral nervous systems. Normally, a nervous system would be inaccessible to the white blood cells due to the blood–brain barrier. However, magnetic resonance imaging has shown that when a person is undergoing an MS "attack," the blood–brain barrier has become more permeable in a section of the brain or spinal cord, allowing white blood cells called T lymphocytes to cross over and attack the myelin. One consideration is multiple sclerosis may be a disease of the blood–brain barrier.

### Neuromyelitis optica

Neuromyelitis optica, also known as Devic's disease, is similar to and is often confused with multiple sclerosis. People 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).

### De Vivo disease

De Vivo disease (also known as GLUT1 deficiency syndrome) is a rare condition caused by inadequate transportation of the sugar glucose across the blood–brain barrier, resulting in developmental delays and other neurological problems. Genetic defects in glucose transporter type 1 (GLUT1) appears to be the primary cause of De Vivo disease.

### Alzheimer's disease

Some evidence indicates that disruption of the blood–brain barrier in Alzheimer's disease allows 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 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. Alzheimer's disease may be caused (or more likely, aggravated) by a breakdown in the blood–brain barrier.

### HIV encephalitis

A 2002 review indicated 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.

### Systemic inflammation

During systemic inflammation, whether in the form of infection or sterile inflammation, the BBB may become leaky to blood-borne compounds. Such changes may be part of a productive host response to systemic inflammation, or may lead to deleterious consequences within the central nervous system. These changes may also affect the course of multiple sclerosis or Alzheimer's disease.

## History

Paul Ehrlich was a bacteriologist studying staining, a procedure that is used in many microscopy studies to make fine biological structures visible using chemical dyes. 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 fluids 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. The concept of the blood–brain barrier (then termed **hematoencephalic barrier**) was proposed by a Berlin physician, Lewandowsky, in 1900.