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Tightjunction BBB
Freeze-fracture morphology of the blood-brain barrier of a rat
Dr Joe KiffAdded by Dr Joe Kiff
The blood-brain barrier (abbreviated BBB) is composed of endothelial cells packed tightly in brain capillaries that more greatly restrict passage of substances from the bloodstream than do endothelial cells in capillaries elsewhere in the body. Processes from astrocytes surround the epithelial cells of the BBB providing biochemical support to the epithelial cells. The BBB should not be confused with the 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. Some of these dyes, notably the aniline dyes that were then popular, would stain all of the organs of an animal except the brain when injected. 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 remained dye-free. This clearly demonstrated the existence of some sort of barrier between the two sections of the body. At the time, it was thought that the blood vessels themselves were responsible for the barrier, as there was no obvious membrane that could be found. It was not until the introduction of the scanning electron microscope to the medical research fields in the 1960s that this could be demonstrated. The concept of the blood-brain (then termed hematoencephalic) barrier was proposed by Lina Stern in 1921 [3].

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

Throughout the body, the walls of the capillaries (the smallest of the blood vessels) are made up of endothelial cells separated by small gaps. These gaps allow soluble chemicals within tissues to pass into the blood stream, where they can be carried throughout the body, and subsequently pass out of the blood into different tissues. In the brain, these endothelial cells are packed more tightly together, due to the existence of zonulae occludentes (tight junctions) between them, blocking the passage of most molecules. The blood-brain barrier blocks 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 atomic mass unit) 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 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 epithelial cells, there are two mechanisms to prevent passive diffusion through the cell membranes. Glial cells surrounding capilaries 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.[1]

The blood-brain barrier protects the brain from the many chemicals flowing around the body. Many bodily functions are controlled by hormones, which are detected by receptors on the plasma membranes of targeted cells throughout the body. The secretion of many hormones are controlled by the brain, but these hormones generally do not penetrate the brain from the blood, so in order to control the rate of hormone secretion effectively, there are 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 is an effective way to protect the brain from common infections. Thus infections of the brain are very rare; however, as antibodies are too large to cross the blood-brain barrier, when infections of the brain do occur they can be very serious and difficult to treat.

Drugs targeting the brain

A major challenge for treatment of most brain disorders is overcoming the difficulty of delivering therapeutic agents to specific regions of the brain. 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 disruption of the BBB by osmotic means, biochemically by the use of vasoactive substances such as bradykinin, or even by localized exposure to high intensity focused ultrasound (HIFU). The potential for using BBB opening to target specific agents to brain tumors has just begun to be explored. 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 could 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 are most effective and how they can be improved for patients with brain tumors.

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.[2]

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.

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[3].

Neuromyelitis optica

Neuromyelitis optica, also known as Devic's disease, is similar 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)[4].

Late-stage neurological trypanosomiasis (Sleeping sickness)

Late-stage neurological trypanosomiasis, or sleeping sickness, is a condition in which trypanosoma protozoa have crossed the blood-brain barrier.

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.[5][6]

Alzheimer's Disease

New evidence indicates that disrupton of the blood brain barrier in AD patients allows beta amyloid containing blood plasma to enter the brain where the A beta 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 by (or more likely, aggravated) by a breakdown in the blood brain barrier. [4]

See also

References

  1. Amdur, Doull, Klaassen (1991) Casarett and Doull's Toxicology; The Basic Science of Poisons 4th ed
  2. Beam, TR Jr., Allen, JC (December 1977). Blood, brain, and cerebrospinal fluid concentrations of several antibiotics in rabbits with intact and inflamed meninges. Antimicrobial agents and chemotherapy 12 (6): 710-6. PMID 931369.
  3. Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity [1]
  4. The NMO-IgG autoantibody links to the aquaporin 4 channel [2]
  5. Pascual, JM, Wang D, Lecumberri B, Yang H, Mao X, Yang R, De Vivo DC (May 2004). GLUT1 deficiency and other glucose transporter diseases. European journal of endocrinology 150 (5): 627-33. PMID 15132717.
  6. Klepper, J, Voit T (June 2002). Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain-- a review. European journal of pediatrics 161 (6): 295-304. PMID 12029447.
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