| Blood–brain barrier | |
|---|---|
 Solute permeability at the BBB vs. choroid plexus | |
| Details | |
| System | Neuroimmune system |
| Identifiers | |
| Acronym(s) | BBB |
| MeSH | D001812 |
| Anatomical terminology | |
Theblood–brain barrier (BBB) is a highly selectivesemipermeable border ofendothelial cells that regulates the transfer of solutes and chemicals between thecirculatory system and thecentral nervous system, thus protecting thebrain from harmful or unwanted substances in theblood.[1] The blood–brain barrier is formed by endothelial cells of thecapillary wall,astrocyte end-feet ensheathing the capillary, andpericytes embedded in the capillarybasement membrane.[2] This system allows the passage of some small molecules bypassive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose andamino acids that are crucial to neural function.[3]
The blood–brain barrier restricts the passage ofpathogens, the diffusion ofsolutes in the blood, andlarge orhydrophilic molecules into thecerebrospinal fluid, while allowing the diffusion ofhydrophobic molecules (O2, CO2, hormones) and small non-polar molecules.[4][5] Cells of the barrier actively transportmetabolic products such as glucose across the barrier using specifictransport proteins.[6] The barrier also restricts the passage of peripheral immune factors, like signaling molecules, antibodies, and immune cells, into the central nervous system, thus insulating the brain from damage due to peripheral immune events.[7]
Specialized brain structures participating in sensory and secretory integration within brainneural circuits—thecircumventricular organs andchoroid plexus—have in contrast highly permeable capillaries.[8]
The BBB results from the selectivity of thetight junctions between the endothelial cells of brain capillaries, restricting the passage of solutes.[1] At the interface between blood and the brain, endothelial cells are adjoined continuously by these tight junctions, which are composed of smaller subunits oftransmembrane proteins, such asoccludin,claudins (such asClaudin-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 astight 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.Astrocyte cell projections called astrocytic feet (also known as "glia limitans") surround the endothelial cells of the BBB, providing biochemical support to those cells.[9] The BBB is distinct from the quite similarblood-cerebrospinal fluid barrier, which is a function of the choroidal cells of thechoroid plexus, and from theblood-retinal barrier, which can be considered a part of the whole realm of such barriers.[10]
Not all vessels in the human brain exhibit BBB properties. Some examples of this include thecircumventricular organs, the roof of the third and fourthventricles, capillaries in the pineal gland on the roof of thediencephalon and thepineal gland.[11][12]
The BBB appears to be functional by the time of birth.P-glycoprotein, atransporter, exists already in the embryonal endothelium.[13]
Measurement of brain uptake of various blood-borne solutes showed that newborn endothelial cells were functionally similar to those in adults,[14] indicating that a selective BBB is operative at birth.
The blood–brain barrier acts effectively to protect brain tissue from circulatingpathogens and other potentially toxic substances.[15] Accordingly,blood-borne infections of the brain are rare.[1]Infections of the brain that do occur are often difficult to treat.Antibodies are too large to cross the blood–brain barrier, and only certainantibiotics are able to pass.[16] In some cases, a drug has to be administered directly into the cerebrospinal fluid where it can enter the brain by crossing theblood-cerebrospinal fluid barrier.[17][18]
Circumventricular organs (CVOs) are individual structures located adjacent to thefourth ventricle orthird ventricle in the brain, and are characterized by dense capillary beds withpermeable endothelial cells unlike those of the blood–brain barrier.[11][12] Included among CVOs having highly permeable capillaries are thearea postrema,subfornical organ,vascular organ of the lamina terminalis,median eminence,pineal gland, and three lobes of thepituitary gland.[11][19]
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.[11][12] Consequently, the CVO permeable capillaries are the point of bidirectional blood–brain communication forneuroendocrine function.[11][19][20]
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),[21] and median eminence—hypothalamicarcuate nucleus.[20][22] 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.[20][21] 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.[20][22]
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.[23] Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders.[24][25] 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.[24] To overcome this problem some peptides able to naturally cross the BBB have been widely investigated as a drug delivery system.[26]
Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities fordrug delivery to the brain inunit doses through the BBB entail its disruption byosmotic means, or biochemically by the use of vasoactive substances, such asbradykinin,[27] or even by localized exposure tohigh-intensity focused ultrasound (HIFU).[28]
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-mediatedtranscytosis forinsulin ortransferrin, and the blocking ofactive efflux transporters such asp-glycoprotein.[24] Some studies have shown thatvectors targeting BBB transporters, such as thetransferrin receptor, have been found to remain entrapped in brain endothelial cells of capillaries, instead of being ferried across the BBB into the targeted area.[24][29]
The brain can be targeted non-invasively via the nasal passage. The drugs that remain in the passage after mucociliary clearance, enter the brain via three pathways: (1) Olfactory nerve-olfactory bulb-brain; (2) Trigeminal nerve-brain; and (3) Lungs/ Gastrointestinal tract-blood–brain[30] The first and second methods involve the nerves, so they use the neuronal pathway and the third is via systemic circulation. However, these methods are less efficient to deliver drugs as they are indirect methods.
Nanotechnology is under preliminary research for its potential to facilitate the transfer of drugs across the BBB.[24][31][32] Capillary endothelial cells and associatedpericytes may be abnormal in tumors and the blood–brain barrier may not always be intact in brain tumors.[32] Other factors, such asastrocytes, may contribute to the resistance of brain tumors to therapy using nanoparticles.[33] Fat soluble molecules less than 400daltons in mass can freely diffuse past the BBB throughlipid mediated passive diffusion.[34]
The blood–brain barrier may become damaged in certainneurological diseases, as indicated byneuroimaging studies ofAlzheimer's disease,amyotrophic lateral sclerosis,epilepsy, ischemic stroke,[15][35][36][37] andbrain trauma,[24] and insystemic diseases, such asliver failure.[1] Effects such as impaired glucose transport and endothelial degeneration may lead to metabolic dysfunction within the brain, and an increased permeability of the BBB toproinflammatory factors, potentially allowing antibiotics andphagocytes to move across the BBB.[1][24] However, in many neurodegenerative diseases, the exact cause and pathology remains unknown. It is still unclear whether the BBB dysfunction in the disease is a causative agent, a result of the disease, or somewhere in the middle.
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.[38]
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.[39] There is some debate over the creation of the termblood–brain barrier as it is often attributed to Lewandowsky, but it does not appear in his papers. The creator of the term may have beenLina Stern.[40] 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,bacteriologistPaul Ehrlich was studyingstaining, a procedure that is used in manymicroscopy studies to make fine biological structures visible using chemical dyes.[41] As Ehrlich injected some of these dyes (notably theaniline dyes that were then widely used), the dye stained all of theorgans of some kinds of animals except for their brains.[41] At that time, Ehrlich attributed this lack of staining to the brain simply not picking up as much of the dye.[39]
However, in a later experiment in 1913,Edwin Goldmann (one of Ehrlich's students) injected the dye directly into thecerebrospinal 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.
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