Blood–brain barrier

Source: Wikipedia, the free encyclopedia.
Blood–brain barrier
Solute permeability at the BBB
vs. choroid plexus
Details
SystemNeuroimmune system
Identifiers
Acronym(s)BBB
MeSHD001812
Anatomical terminology

The blood–brain barrier (BBB) is a highly selective

pericytes embedded in the capillary basement membrane.[2] This system allows the passage of some small molecules by passive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial to neural function.[3]

The blood–brain barrier restricts the passage 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 non-polar molecules.[4][5] Cells of the barrier actively transport metabolic products such as glucose across the barrier using specific transport proteins.[6] The barrier also restricts the passage of peripheral immune factors, like signaling molecules, antibodies, and immune cells, into the CNS, thus insulating the brain from damage due to peripheral immune events.[7]

Specialized brain structures participating in sensory and secretory integration within brain

circumventricular organs and choroid plexus—have in contrast highly permeable capillaries.[8]

Structure

Part of a network of capillaries supplying brain cells
The astrocytes type 1 surrounding capillaries in the brain
Sketch showing constitution of blood vessels inside the brain

The BBB results from the selectivity of the

claudins (such as Claudin-5), junctional adhesion molecule (such as JAM-A).[6] Each of these tight junction proteins is stabilized to the endothelial cell membrane by another protein complex that includes scaffolding proteins such as tight junction protein 1 (ZO1) and associated proteins.[6]

The BBB is composed of endothelial cells restricting passage of substances from the blood more selectively than endothelial cells of capillaries elsewhere in the body.

blood-retinal barrier, which can be considered a part of the whole realm of such barriers.[11]

Not all vessels in the human brain exhibit BBB properties. 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",[12] thus melatonin is not affected by the blood–brain barrier.[13]

Development

The BBB appears to be functional by the time of birth.

transporter, exists already in the embryonal endothelium.[14]

Measurement of brain uptake of various blood-borne solutes showed that newborn endothelial cells were functionally similar to those in adults,[15] indicating that a selective BBB is operative at birth.

In mice, Claudin-5 loss during development is lethal and results in size-selective loosening of the BBB.[16]

Function

See also: Neuroimmune system

The blood–brain barrier acts effectively to protect brain tissue from circulating

blood-cerebrospinal fluid barrier.[19][20]

Circumventricular organs

Main article: Circumventricular organs

vascular organ of the lamina terminalis, median eminence, pineal gland, and three lobes of the pituitary gland.[21][23]

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.

neuroendocrine function.[21][23][24]

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),[25] and median eminence—hypothalamic arcuate nucleus.[24][26] 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.[24][25] 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.[24][26]

Therapeutic research

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.[1] Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders.[27][28] 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 to be clinically effective.[27] The BBB represents an obstacle to some drugs reaching the brain, thus to overcome this barrier some peptides able to naturally cross the BBB have been widely investigated as a drug delivery system.[29]

Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for

high-intensity focused ultrasound (HIFU).[31]

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

active efflux transporters such as p-glycoprotein.[27] Some studies have shown that 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.[27][32]

Nanoparticles

Main article: Nanoparticles for drug delivery to the brain

astrocytes, may contribute to the resistance of brain tumors to therapy using nanoparticles.[35] Fat soluble molecules less than 400 daltons in mass can freely diffuse past the BBB through lipid mediated passive diffusion.[36]

Damage in injury and disease

The blood–brain barrier may become damaged in select

phagocytes to move across the BBB.[1][27]

Prediction

There have been many attempts to correlate the experimental blood–brain barrier permeability with

physicochemical properties. In 1988, the first QSAR study of brain–blood distribution conducted reported the in vivo values in rats for a large number of H2 receptor histamine agonists.[40]

The first papers modelling blood-brain barrier permeability identified three properties, i.e., molecular volume, lipophilicity, and hydrogen bonding potential, as contributing to solute transport through the blood-brain barrier.[41] A 2022 dataset selected different classification models[42] based on molecular fingerprints,[43] MACCS166 keys[44] and molecular descriptors.[45]

History

A 1898 study observed that low-concentration "

bile salts" failed to affect behavior when injected into the blood of animals. Thus, in theory, the salts failed to enter the brain.[46]

Two years later, Max Lewandowsky may have been the first to coin the term "blood–brain barrier" in 1900, referring to the hypothesized semipermeable membrane.[47] There is some debate over the creation of the term blood–brain barrier as it is often attributed to Lewandowsky, but it does not appear in his papers. The creator of the term may have been Lina Stern.[48] Stern was a Russian scientist who published her work in Russian and French. Due to the language barrier between her publications and English-speaking scientists, this could have made her work a lesser-known origin of the term.

All the while,

organs of some kinds of animals except for their brains.[49] At that time, Ehrlich attributed this lack of staining to the brain simply not picking up as much of the dye.[47]

However, in a later experiment in 1913, Edwin Goldmann (one of Ehrlich's students) injected the dye directly into the cerebrospinal fluid 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.

See also

References

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