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The blood-brain barrier (BBB) is a membranic structure that acts primarily to protect the brain from chemicals in the blood, while still allowing essential metabolic function. It is composed of endothelial cells, which are packed very tightly in brain capillaries. This higher density restricts 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 "glial 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.

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. 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 barrier 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.[1] 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 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

In the rest of the body outside the brain, the walls of the capillaries (the smallest of the blood vessels) are made up of endothelial cells which are fenestrated, meaning they have small gaps called fenestrations. Soluble chemicals can pass through these gaps, from blood to tissues or from tissues into blood. However in the brain endothelial cells are packed together more tightly with what are called tight junctions. This makes the blood-brain barrier block the movement of 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 u) 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 itself 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 endothelial cells, there are two mechanisms to prevent passive diffusion through the cell membranes. Glial cells surrounding capillaries 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.[2]

The blood-brain barrier protects the brain from the many chemicals flowing within the blood. However, many bodily functions are controlled by hormones in the blood, and while the secretion of many hormones is controlled by the brain, these hormones generally do not penetrate the brain from the blood. This would prevent the brain from directly monitoring hormone levels. In order to control the rate of hormone secretion effectively, there exist 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 acts very effectively to protect the brain from many common 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.

Blood-Retinal Barrier

Eyes' retinas are extensions to CNS[3], and as such, they are covered by the BBB. Usually this part of the BBB is called Blood retinal barrier[4]

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.

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. [5] However, this method is not yet ready for clinical trials due to the accumulation of the nanospheres in surrounding healthy tissue. Another, recent effort with the nanoparticle mediated delivery of doxorubicin to a rat glioblastoma has shown significant remission as well as low toxicity. Not only is this result very encouraging, but it could lead to clinical trials.

Not only are nanoparticles being utilized for drug delivery to central nervous system ailments, but they are also being investigated as possible agents in imaging. The use of solid lipid nanoparticles consisting of microemulsions of solidified oil nanodrops loaded with iron oxide could increase in MRI imaging because of the ability of these nanoparticles to effectively cross the blood brain barrier.

While it is known that the above methods do indeed allow the passage of nanoparticles across the blood brain barrier, little is known about how this crossing occurs. Not only that, but not much is known about the potential side effects of nanoparticle use. Therefore, before this technology may be widely utilized, more research must be done on the potentially harmful effects of nanoparticle use as well as proper handling protocols. Should such steps be taken, nanoparticle mediated drug delivery across the blood brain barrier could be one of the highest impact contributions of nanotechnology to clinical neuroscience. [6]


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.[7][8]

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 Staph 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 CNS by releasing neurotoxins from the cell walls of bacteria like lipopolysaccharide (LPS) [9] Treatment with third generation or fourth generation cephalosporin is usually preferred.

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. 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[10].

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)[11].

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.[12][13]

Alzheimer's Disease

New evidence indicates that disrupton 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. [3]

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 sentinal 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

  1. Lina Stern: Science and fate by A.A. Vein. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
  2. Amdur, Doull, Klaassen (1991) Casarett and Doull's Toxicology; The Basic Science of Poisons 4th ed
  3. Vugler A, Lawrence J, Walsh J, et al (2007). Embryonic stem cells and retinal repair.
  4. Hamilton RD, Foss AJ, Leach L (2007). Establishment of a human in vitro model of the outer blood-retinal barrier.
  5. Brigger I, Morizet J, Aubert G, Chacun H, Terrier-Lacombe MJ, Couvreur P, Vassal G. Poly(ethylene glycol)-coated hexadecylcyanoacrylate nanospheres display a combined effect for brain tumor targeting. J Pharmacol Exp Ther 2002;303:928-36
  6. Silva, Gabriel. "Nanotechnology approaches for drug and small molecule delivery across the blood brain barrier." Surgical Neurology 67(2007): 113-116.
  7. Hashizume, H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (April 2000). Openings between defective endothelial cells explain tumor vessel leakiness. American Journal of Pathology 156 (4): 1363-1380. PMID 10751361.
  8. Schneider, SW, Ludwig T, Tatenhorst L, Braune S, Oberleithner H, Senner V, Paulus W (March 2004). Glioblastoma cells release factors that disrupt blood-brain barrier features. Acta Neuropathologica 107 (3): 272-276. PMID 14730455.
  9. 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.
  10. Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity [1]
  11. The NMO-IgG autoantibody links to the aquaporin 4 channel [2]
  12. 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.
  13. 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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