Blood-brain barrier

The blood-brain barrier (BBB) is a metabolic or cellular structure in the central nervous system (CNS) that restricts the passage of various chemical substances and microscopic objects (e.g. bacteria) between the bloodstream and the neural tissue itself, while still allowing the passage of substances essential to metabolic function (e.g. oxygen).

This "barrier" results from the selectivity of the tight junctions between endothelial cells in CNS vessels that restricts the passage of solutes. At the interface between blood and brain, endothelial cells and associated astrocytes are stitched together by structures called tight junctions. The tight junction is composed of smaller subunits, frequently dimers, that are transmembrane proteins such as occludin, claudins, junctional adhesion molecule (JAM), ESAM and others. Each of these transmembrane proteins is anchored into the endothelial cells by another protein complex that includes zo-1 and associated proteins.

The blood-brain barrier is composed of high density cells restricting passage of substances from the bloodstream much more than endothelial cells in 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 similar blood-cerebrospinal fluid barrier, 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 [cite journal |author=Hamilton RD, Foss AJ, Leach L |title=Establishment of a human in vitro model of the outer blood-retinal barrier |journal= Journal of Anatomy|volume= 211|issue= | pages = 707|year=2007 |pmid=17922819 |doi=10.1111/j.1469-7580.2007.00812.x] (the retina of the eye is an extension 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 compartmentalization 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 barrier (then termed hematoencephalic barrier) was proposed by Lina Stern in 1921. [ [http://www.bri.ucla.edu/nha/ishn/ab44-2006.htm Lina Stern: Science and fate] by A.A. Vein. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands] 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 endothelial cells were the basis of the blood-brain barrier because of the densely packed astrocyte foot processes that surround the endothelial cells of the BBB.

Physiology

The blood-brain barrier acts very effectively to protect the brain from many common bacterial 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. Viruses easily bypass the blood-brain barrier, however, attaching themselves to circulating immune cells.

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.

Nanoparticles

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.

Delivering drugs across the blood brain barrier is one of the most promising applications of nanotechnology in clinical neuroscience. Nanoparticles could potentially carry out multiple tasks in a predefined sequence, which is very important in the delivery of drugs across the blood brain barrier.

A significant amount of research in this area has been spent exploring methods of nanoparticle mediated delivery of antineoplastic drugs to tumors in the central nervous system. For example, radiolabeled polyethylene glycol coated hexadecylcyanoacrylate nanospheres targeted and accumulated in a rat gliosarcoma. [cite journal |author=Brigger I, Morizet J, Aubert G, "et al" |title=Poly(ethylene glycol)-coated hexadecylcyanoacrylate nanospheres display a combined effect for brain tumor targeting |journal=J. Pharmacol. Exp. Ther. |volume=303 |issue=3 |pages=928–36 |year=2002 |month=December |pmid=12438511 |doi=10.1124/jpet.102.039669 |url=] However, this method is not yet ready for clinical trials due to the accumulation of the nanospheres in surrounding healthy tissue.

It should be noted that vascular endothelial cells and associated pericytes are often abnormal in tumors and that the blood-brain barrier may not always be intact in brain tumors. Also, the basement membrane is sometimes incomplete. Other factors, such as astrocytes, may contribute to the resistance of brain tumors to therapy. [cite journal
first = H
last = Hashizume
coauthors = Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM
year = 2000
month = April
title = Openings between defective endothelial cells explain tumor vessel leakiness
journal = American Journal of Pathology
volume = 156
issue = 4
pages = 1363–1380
pmid = 10751361
pmc = 1876882 ] [cite journal
first = SW
last = Schneider
coauthors = Ludwig T, Tatenhorst L, Braune S, Oberleithner H, Senner V, Paulus W
year = 2004
month = March
title = Glioblastoma cells release factors that disrupt blood-brain barrier features
journal = Acta Neuropathologica
volume = 107
issue = 3
pages = 272–276
pmid = 14730455
doi = 10.1007/s00401-003-0810-2 ]

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, examples of which are "Staphylococcus aureus" 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 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) [cite journal
first = TR Jr.
last = Beam
coauthors = Allen, JC
year = 1977
month = December
title = Blood, brain, and cerebrospinal fluid concentrations of several antibiotics in rabbits with intact and inflamed meninges
journal = Antimicrobial agents and chemotherapy
volume = 12
issue = 6
pages = 710–6
pmid = 931369 ] Treatment with third generation or fourth generation cephalosporin is usually preferred.

Epilepsy

Epilepsy is a common neurological disease characterized by frequent and often untreatable seizures. Several clinical and experimental data have implicated failure of blood-brain barrier function in triggering chronic or acute seizures [E. Oby and D. Janigro, The Blood-brain barrier and epilepsy. Epilepsia. 2006 Nov;47(11):1761-74] [ Marchi,N. et al. Seizure-Promoting Effect of Blood-Brain Barrier Disruption. Epilepsia 48(4), 732-742 (2007). Seiffert,E. et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J. Neurosci. 24, 7829-7836 (2004). Uva,L. et al. Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood-brain barrier permeability. Neuroscience (2007). van Vliet,E.A. et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130, 521-534 (2007).

] . These findings have shown that acute seizures are a predictable consequence of disruption of the BBB by either artificial or inflammatory mechanisms. In addition, expression of drug resistance molecules and transporters at the BBB are a significant mechanism of resistance to commonly used anti-epileptic drugs [ Awasthi,S. et al. RLIP76, a non-ABC transporter, and drug resistance in epilepsy. BMC. Neurosci. 6, 61 (2005). Loscher,W. & Potschka,H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat. Rev. Neurosci. 6, 591-602 (2005).] .

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 the 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.fact|date=March 2008 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 [cite journal |author=Schreibelt G, Musters RJ, Reijerkerk A, "et al" |title=Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity |journal=J. Immunol. |volume=177 |issue=4 |pages=2630–7 |year=2006 |month=August |pmid=16888025 |doi= |url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=16888025] .

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) [cite journal |author=Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR |title=IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel |journal=J. Exp. Med. |volume=202 |issue=4 |pages=473–7 |year=2005 |month=August |pmid=16087714 |pmc=2212860 |doi=10.1084/jem.20050304 |url=] .

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. [cite journal
first = JM
last = Pascual
coauthors = Wang D, Lecumberri B, Yang H, Mao X, Yang R, De Vivo DC
year = 2004
month = May
title = GLUT1 deficiency and other glucose transporter diseases
journal = European journal of endocrinology
volume = 150
issue = 5
pages = 627–33
pmid = 15132717
doi = 10.1530/eje.0.1500627 ] [cite journal
first = J
last = Klepper
coauthors = Voit T
year = 2002
month = June
title = Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain-- a review
journal = European journal of pediatrics
volume = 161
issue = 6
pages = 295–304
pmid = 12029447
doi = 10.1007/s00431-002-0939-3 ]

Alzheimer's Disease

New evidence indicates that disruption 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 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 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. [http://www.umdnj.edu/research/publications/fall06/4.htm]

HIV Encephalitis

It is believed that HIV can cross the blood-brain barrier inside circulating monocytes in the bloodstream ("Trojan horse theory"). Once inside, these monocytes become activated and are transformed into macrophages. Activated monocytes release virions into the brain tissue proximate to brain microvessels. These viral particles likely attract the attention of sentinel brain microglia and initiate an inflammatory cascade that may cause tissue damage to the BBB. This inflammation is HIV encephalitis (HIVE). Instances of HIVE probably occur throughout the course of AIDS and is a precursor for HIV-associated dementia (HAD). The premier model for studying HIV and HIV encephalitis is the simian model.

References