| Blood-brain Barrier |
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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 Dye s that were then popular) would stain all of the Organ s 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 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 Cell s 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 Sugar s and some amino acids). Substances with a molecular weight higher than 500 Dalton s (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.Amdur, Doull, Klaassen (1991) Casarett and Doull's Toxicology; The Basic Science of Poisons 4th ed The blood-brain barrier protects the brain from the many chemicals flowing within the blood. However, many bodily functions are controlled by Hormone s 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 Infection s. 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. 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 Tumor s. The potential for using BBB opening to target specific agents to brain tumors has just begun to be explored. DISEASES Meningitis 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 his/her brain or spinal cord, allowing White Blood Cell s 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 barrierLipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity {Link without Title} . 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)The NMO-IgG autoantibody links to the aquaporin 4 channel {Link without Title} . 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 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 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 (or more likely, aggravated) by a breakdown in the blood brain barrier. {Link without Title} REFERENCES |
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