What Can Cross The Bbb And Enter The Brain
The BBB is very restrictive, limiting what can access the brain. Glucose and other nutrients necessary to keep the brain healthy and functioning properly are allowed to cross the BBB and enter the brain.
Typically, cells of the immune system are not able to cross the BBB. This helps prevent brain inflammation. Unfortunately, sometimes, pathogens damage the BBB, enabling them to leave the blood and enter the brain. As a result of the damage, immune cells also enter the brain in an attempt to kill the invading organisms. When this happens, the person may experience:
- Meningitis Inflammation of the meninges, the outer membrane of the brain and spinal cord
- Encephalitis – Inflammation of the brain
Meningitis and encephalitis are serious conditions that typically require hospitalization and may lead to permanent brain damage or death.
Different types of germs can cross the BBB and lead to serious infections:
The Bbb Can Be Broken Down By:
Not Many Have Heard Of The Blood
As one of the most abused substances in the United States, numerous studies have been conducted on the effects of alcohol and the long-term issues that can result from alcohol abuse. These studies have produced research that displays the connection between the blood brain barrier and alcohol. As the rates of alcoholism continue to rise, the relationship between the two is further analyzed.
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Cell Lines For Research
A major challenge for the development of in vitro models of the BBB is the availability of appropriate cell lines, particularly BMECs. An in vitro model of the human BBB should exhibit restricted paracellular transport , BMECs with the morphology and characteristics typical of the BBB, expression of BBB-specific markers and transporters, and be readily available, convenient to use, and reproducible . While primary human BMECs are often considered preferable for in vitro models, the difficulties in harvesting and purification of these cells can significantly limit accessibility and reliability . In general, primary cells are used only at very low passage numbers to avoid down-regulation of BBB characteristics . In contrast, currently available cell lines can overcome limitations associated with accessibility and convenience, but do not exhibit all of the required features of the human BBB . Nevertheless, specific cell lines may recapitulate properties that are necessary for some physiological, pathological, or pharmacological applications. Common sources for animal BMECs include rodent, bovine, and porcine brain cortices. Primary astrocytes and pericytes can also be extracted from the brain cortex . Advances in stem cell engineering suggest that differentiation of stem cells to BMECs and astrocytes may ultimately solve the problem of limited cell lines.
Why Does The Blood
It is thought that there are a series of events that lead to multiple sclerosis. A breakdown in the blood-brain barrier is thought to be an early stage in this process. If the BBB is damaged or weakened in some way, immune cells are able to cross. These cells then attack the myelin around your nerves, which leads to nerve damage and MS symptoms.
The BBB can be damaged or disrupted by many things including stress, inflammation, or chemical processes thought to be triggered by disease, drugs, air pollution or smoking. Possible links between gut health and the strength of the BBB have been explored through work on the microbiome.
Several of the disease modifying drugs currently available or in development act on the blood-brain barrier itself, or aim to stop immune cells from passing through the BBB. These include;Tysabri , which binds to immune cells so they can’t get through the barrier.;Gilenya targets receptors on the BBB to strengthen the barrier, and also traps immune cells in the lymph glands so they don’t cross into the central nervous system. Siponimod, Ponesimod and Ozanimod, currently under development, target the same receptors as Gilenya .;
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Expression Of Glut1 In Brain Is Localized To The Bloodbrain Barrier
Predicted secondary structure of the bovine bloodbrain barrier GLUT1 glucose transporter is shown, which is formed by 12 transmembrane domains, a glycosylated extracellular loop between transmembrane domains 1 and 2, and intracellular amino and carboxyl termini. Northern blot of mRNA derived from either total rabbit brain or capillary-depleted rabbit brain for either the GLUT1 glucose transporter or actin. Electron microscopic immunogold study of human brain with a primary antiserum against the purified human erythrocyte glucose transporter, and a secondary antibody conjugated with 10nm gold particles, shows abundant expression of immunoreactive GLUT1 glucose transporter on the luminal and abluminal membranes of the capillary endothelium in human brain.
Effects Of Wheatgerm Agglutinin And Heparin
We co-injected WGA with I-S1 to determine the role of glycoproteins containing sialic acid and N-acetylglucosamine in the uptake of S1 by the BBB and other tissues. Mice were anesthetized, after which the jugular vein and right carotid artery were exposed. Mice then received a jugular vein injection of 0.1ml of BSA-LR containing 3×105c.p.m. of I-S1 and 6×105c.p.m. of T-Alb and, in a subset of mice, 10g of the plant lectin WGA . Brain, tissues and serum samples were collected 5min later and tissue/serum ratios calculated as above in units of l per gram. Heparan sulfate is used as a receptor by some viruses and heparin by binding to viral proteins can block viral entry into brain,. Therefore, separate groups of mice had heparin included in the injection.
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An Immune Response: Using And Delivering Antibodies
Monoclonal antibodies are ideal drugs because of their specific targeting but they have a hard time getting into the brain. Typically, antibody concentrations are 1,000 times lower in the brain than in the bloodstream. But, Banks says, this isnt dampening interest within the pharmaceutical industry. They are enamoured with getting antibodies into the brain, says Banks. I can understand that because they have had so much success in treating peripheral diseases with antibodies, he adds.
In some cases, antibodies can be used as Trojan horses, currently an approach being developed by California biotech company, ArmaGen. Since 2004, the company has developed a pipeline of CNS drugs that fuse a therapeutic protein to an antibody, selected to bind to insulin or transferrin receptors on the BBB. Acting as a shuttle, the antibody therefore enables the fused protein to travel through the BBB. The company has several drugs in clinical trials for treating lysosomal storage disorders.
Kim Andersen, Lundbecks head of research, says the company is investigating the use of shark antibodies as transporters for antibody central nervous system drugs
Blood Pressure Medications That Cross Blood
A meta-analysis of 14 studies suggests use of antihypertensive agents known to cross the blood-brain barrier was associated with improved memory recall over time compared to nonpenetrant agents in older adults with hypertension.
Data from a large meta-analysis suggests some blood pressure medications were linked to better memory recall in aging adults than others.
Results of the meta-analysis, which included data from more than a dozen studies, indicates use of blood pressure medications known to cross the blood-brain barrier were associated with better memory recall over up to 3 years of follow-up compared to those taking nonpenetrant medications, despite being at a higher vascular risk burden.
Research has been mixed on which medicines have the most benefit to cognition, said study investigator Daniel Nation, PhD,;an associate professor of psychological science in the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, in a statement from the American Heart Association. Studies of angiotensin II receptor blockers and angiotensin-converting-enzyme inhibitors have suggested these medicines may confer the greatest benefit to long-term cognition, while other studies have shown the benefits of calcium channel blockers and diuretics on reducing dementia risk.
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Hitching A Lift: The Trojan Horse Approach
What about larger molecules such as the biologics that make up an increasing number of todays therapeutics? Can they get through the brick wall? Banks says many natural peptides and molecules such as insulin, transferrin and lipoproteins do pass through via regulated entry mechanisms a second aspect of the BBBs function. Regulated entry mechanisms use influx transporter proteins in the barrier. Macromolecules are then transported across cells in several ways, including transcytosis, where molecules are transported in vesicles.
Taking advantage of these mechanisms is the cornerstone of the Trojan horse approach. By attaching a therapeutic molecule to something that is transported across the BBB, the drug cargo can be smuggled through. However, it has not always been successful, says Banks. One of the first attempts was to use the glucose transport system. People were putting really big molecules on and it didnt work. He jokes: It was like having a Volkswagen pull the space shuttle.
Approaches today often use short amino acid chains called peptides as Trojan horses. In 2007, the first peptide was proven to transport drugs into the brain. The 29-amino-acid peptide RVG29 was derived from rabies virus glycoprotein and was able to deliver a gene-silencing RNA molecule to the brain. Intravenous injection delivered the antiviral siRNA to neuronal cells in mice and, once inside, the payload provided protection against fatal viral encephalitis.
Radioiodination And Purification Of Peptides And Bsa
SynB3, Tat 4757, dermorphin and albumin were radiolabeled using the Iodo-Gen method. A previously established procedure was used , but in case of Tat 4757 and dermorphin, a 1 mol/ml sodium iodide carrier solution was used. The peptides were iodinated by transfer of the iodonium solution to 50 l of a 1 mol/ml peptide solution. TP10, TP10-2 and pVEC were radiolabeled using the chloramine-T method . Briefly, to 50 l of a 1 mol/ml peptide solution or 110 l of a 1 mg/ml pVEC solution, dissolved in 0.1% formic acid in 95:5 water:acetonitrile, 20 l of a 3.75 mol/ml sodium iodide in aqueous 0.1% formic acid solution or 20 l of a 2.5 mol/ml sodium iodide in 25 mM phosphate buffer pH 8.5 was added. Then, a volume containing 1 mCi of Na125I was transferred to this solution, followed by 30 l of a 0.5 mg/ml chloramine-T solution in 25 mM phosphate buffer or pH 8.5 ). The iodination reaction proceeded during 40 s, followed by the addition of 30 l of a 1 mg/ml sodium metabisulfite in 25 mM phosphate buffer or pH 8.5 ) to stop the iodination reaction. For evaluation of the used influx mechanism, pVEC, SynB3 and TP10 were radiolabeled using a no-carrier added protocol, in which the sodium iodide solution was replaced by its solvent.
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Microvasculature Of The Human Brain
The average adult human brain weighs about 1500 g and occupies about 1200 cm3. The surface area of microvessels is 100200 cm2 g1 tissue , corresponding to a total surface area of 1525 m2. In comparison, the surface area of the gut is 300400 m2, the lung is about 100 m2, and the skin is about 2 m2. The microvessel density is about 500 m cm3 , corresponding to a total microvessel length of about 600 km in the adult human brain .
The human brain is comprised of about 100 billion neurons and a similar number of glial cells. Neurons, astrocytes, microglia, and pericytes account for almost 80% of the brain volume. The extracellular space occupies 1530% of the brain volume and the brain vasculature about 3% of the brain volume. Capillaries in the brain may be as small as 710 m in diameter and the average intercapillary distance is about 40 m . Consequently, the cell body of a neuron is typically about 1020 m from the nearest capillary .
The microvasculature in the brain differs from other capillary networks in the human body, for example those in the lung, in two significant ways. First, the brain microvasculature tightly regulates transport into the brain. Second, the capillaries can exhibit significant plasticity in response to abnormal physiological conditions. For example, during ischemia capillaries can dilate to increase oxygen influx .
Regional Variation In Brain Influx Between Different Brain Regions
After measuring the whole brain radioactivity, the brains collected during the MTR experiment of pVEC, SynB3 and TP10, as well as of the controls dermorphin and radioiodinated BSA, were dissected into eight brain regions in order to evaluate regional variations in brain influx: cerebellum, medulla oblongata, frontal cortex, striatum, hippocampus, thalamus + hypothalamus, midbrain and occipital + parietal cortex, including rest of brain. Different dissected brain regions were weighed and measured in the gamma counter. The unidirectional influx and initial distribution volume of the iodinated peptides for the different brain regions are determined using Eq 1.
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How Do We Know Vaccine Components Dont Cross The Bbb
Vaccines contain versions of a pathogen that are different than the ones that cause disease. Many vaccines do not contain live pathogens, but rather pieces of pathogens. As such, they do not replicate and, therefore, cannot cause infections or damage to the BBB. Live, weakened vaccines replicate a very limited number of times, so the tissue damage that can result during an infection does not occur. Therefore, the BBB is not damaged by vaccines; instead, vaccines lead to protective immune responses that prevent infections and, therefore, the damage that can result from these infections.
Some people wonder not about the pathogens in vaccines, but rather other components of vaccines:
Discovery Of Bloodbrain Barrier Carrier
Physiology of bloodbrain barrier carrier-mediated transport
The first evidence of saturable or CMT of a solute across the BBB was demonstrated by Crone for -glucose using the indicator dilution technique, which is a venous sampling-carotid artery injection method. Subsequently, the Brain Uptake Index technique, a tissue sampling-carotid artery injection method developed by Oldendorf, was used to characterize the saturable kinetics of BBB transport of multiple water-soluble metabolic substrates. The MichelisMenten kinetics of BBB CMT for the major metabolic substrates were determined, and this analysis showed a wide range of affinity and maximal transport activity for the BBB nutrient transporters .
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Discovery Of Bloodbrain Barrier Receptor
Light micrograph of freshly isolated bovine brain capillaries stained with trypan blue, which stains nuclei blue and luminal red blood cells yellow. The capillaries are isolated free of adjoining brain tissue. Schematic diagram of different brain endothelial receptors, including the insulin receptor, the transferrin receptor, the scavenger receptor , which mediates only the endocytosis from blood into the endothelial compartment for ligands such as acetylated low density lipoprotein; and the neonatal Fc receptor , which mediates the asymmetric transcytosis of IgG molecules selectively from brain to blood, but not blood to brain. Confocal microscopy of isolated rat brain capillaries showing the expression of the Tf receptor on both luminal and abluminal membranes of the endothelium. Light micrograph of rat brain removed after a 10-minute carotid artery infusion of a conjugate of 5nm gold and the mouse OX26 monoclonal antibody against the rat TfR. The staining of the capillary compartment represents TfRMAb present in the intraendothelial compartment of the brain. Electron microscopy of rat brain after perfusion with the conjugate of gold and TfRMAb shows the MAb concentrated in intraendothelial vesicles , as well as MAb molecules undergoing exocytosis from the endothelial compartment to the brain interstitial space .
Drug That Crosses Blood
The drug vorinostat is able to cross the blood-brain barrier and reduce the development of large metastatic tumors in mice brains by 62 percent when compared to mice that did not receive the drug, according to a new study. In humans, the drug has been approved by the U.S. Food and Drug Administration for the treatment of a cancer called cutaneous T-cell lymphoma but can be used experimentally to study its effectiveness against other cancers. This research, by investigators at the National Cancer Institute , part of the National Institutes of Health, and their collaborators, appears online Sept. 29, 2009, in Clinical Cancer Research.
For people, while various therapies are improving the survival of breast cancer patients, the incidence of breast cancer spreading to the brain is increasing. Brain metastases of breast cancer have proven to be largely untreatable because the blood-brain barrier, which arises from the specialized structure of blood capillaries in the brain, severely limits drug access and many drugs are actively transported out of brain at this barrier. Consequently, the one-year survival estimate for breast cancer patients after a diagnosis of brain metastasis is only about 20 percent.
For more information on Dr. Steeg’s research, please go to
NIHTurning Discovery Into Health®
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The Challenge Of The Blood
The blood-brain barrier consists of a blood vessel lining of endothelial cells that keeps foreign molecules from escaping from the blood vessels and entering the brain fluid where they could affect neurons and other brain cells. The barrier is highly selective about the non-native molecules it allows into the brain, and that includes therapeutic substances.
While small molecule or macromolecule drugshave the potential to treat brain tumors, infections, neurogenerative disorders, and stroke, the presence of the blood-brain barrier makes it difficult for doctors to administer such therapies.
Scientists have attempted various workarounds, and none have proven sufficiently safe or effective. Direct injection of compounds into the brain, as well as efforts to force leaks through the barrier, carry risks, such as neurotoxicity, infection, and tissue damage.
Researchers have looked into the use of carriers, such as monoclonal antibodies and modified viruses, that travel into the brain, taking therapeutic molecules with them.
However, cost and safety concerns accompany this approach. Scientists have also investigated a similar use of polymers, nanocapsules, and nanoparticles with some success. However, adapting these materials for such use is often complicated.