Blood-brain barrier

The blood-brain barrier (BBB) is a membrane that controls the passage of substances from the blood into the central nervous system. It is a physical barrier between the blood vessels in the central nervous system and most parts of the central nervous system itself that stops many substances from travelling across it.

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 spine 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.

Physiology
Throughout the body, the capillaries (the smallest of the blood vessels) are made up of endothelial cells separated by small gaps. This allows chemicals in solution to pass into the blood stream, where they can be carried about the body, and subsequently pass out of the blood stream. In the brain, these endothelial cells are packed much tighter together, due to the existence of zonula 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, and ethanol) and those that are allowed in by specific transport systems (such as sugars and some amino acids). It is generally accepted that substances with a molecular weight higher than 500 daltons cannot cross the blood-brain barrier, while the lighter ones can. Many drugs are unable to pass the barrier, since 98 percent of them are heavier than 500 daltons. In addition, the endothelial cells metabolize certain molecules to prevent their entry into the central nervous system; the most-studied example of this is L-DOPA.

The blood-brain barrier appears to exist primarily to protect the brain from the chemical messenger systems flowing around the body. Many bodily functions are controlled via the use of hormones, which are detected by receptors on the plasma membranes of targeted cells throughout the body. The hormones are released on cue from the brain, so, if they acted on the brain itself, a feedback loop could result. Thus, in areas of the brain that are involved in feedback control of hormone levels (such as the hypothalamus), the blood-brain barrier is not present. In addition, the blood-brain barrier is an excellent way to protect the brain from common infection. Due to this, an infection of the brain is very rare.

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, either by osmotic means or biochemically by the use of vasoactive substances such as bradykinin. 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 active efflux transporters such as p-glycoprotein. Strategies for drug delivery behind the BBB include intracerebral implantation and convection-enhanced distribution. More research is needed to determine which strategies are most effective and how they can be improved for patients with e.g., brain tumors.

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 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. The yellow ingredient turmeric, found in curry, has been shown to strengthen the blood brain barrier to resist attacks.

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 virus) infection. It affects immune-compromised patients and is usually seen with patients having AIDS.

Other diseases
There is also a rare condition caused by inadequate transport of glucose across the barrier, resulting in mental retardation and other neurological problems.

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