When Do We Need To Get Through It
The bloodbrain barrier is generally very effective at preventing unwanted substances from accessing the brain, which has a downside. The vast majority of potential drug treatments do not readily cross the barrier, posing a huge impediment to treating mental and neurological disorders.
One possible way around the problem is to trick the bloodbrain barrier into allowing passage of the drug. This is the so-called Trojan horse approach, in which the drug is fused to a molecule that can pass the bloodbrain barrier via a transporter protein.
A different approach is to temporarily open the bloodbrain barrier using ultrasound.
In a mouse with Alzheimers disease, we showed that using ultrasound to open the bloodbrain barrier can improve cognition and decrease the amount of toxic plaque that accumulates in the brain. We think this may be due to the ability of ultrasound, in combination with injected gas microbubbles, to temporarily and safely open up the bloodbrain barrier to let protective blood-borne factors in. Importantly, this approach didnt damage the brain.
In a new study, we have shown that by temporarily opening the bloodbrain barrier, ultrasound allows more of a therapeutic antibody into the brain, improving Alzheimers-like pathology and cognition more than when using ultrasound or the antibody drug in isolation.
Regulation Of The Bbb In Ad
Dysfunction of cerebral vascular ECs and leukocyte transmigration across the BBB probably participate in the development of AD, Parkinsons disease , and other neurodegenerative diseases. As multidrug resistance function at the level of the BBB decreases with age, decreased clearance of neurotoxic compounds and increased oxidative stress in the brain increases the risk of neurodegenerative pathology.
Insulin Transport At The Bbb
Investigators have been examining the transport of insulin into the brain since 1954 when it was observed that minimal amounts of radioactively labeled insulin appeared in brain tissue following intravenous or subcutaneous injection . It was later more definitively shown that serum insulin appeared in CSF in dogs following insulin infusion . Intravenously administered insulin is detected in brain within 1 min . Transport of insulin across the BBB has been validated many times using various techniques including perfusions , species-specific immunoassays , and state-of-the art kinetic analyses . The transporter for insulin at the BBB is not static but rather a dynamic protein regulated by the current physiological state of the body. In fact, during a time in which the brain is developing the greatest, the neonatal period, insulin transport across the BBB and binding to the brain endothelial cells is increased compared to weanling and adult periods . CSF and brain insulin levels are also significantly greater in the neonatal period. Insulin binding to brain capillaries is highest in the newborn rabbits compared to adults suggesting the presence of higher levels of insulin binding sites . These discrepancies between neonates and adults is likely due to the mitogenic nature of insulin action in the CNS rather than the metabolic role. Other physiological regulators of insulin transport that relate to insulin resistance are discussed in the next section.
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What Is The Blood
The brain is precious, and evolution has gone to great lengths to protect it from damage. The most obvious is our 7mm thick skull, but the brain is also surrounded by protective fluid and a protective membrane called the meninges. Both provide further defence against physical injury.
Another protective element is the bloodbrain barrier. As the name suggests, this is a barrier between the brains blood vessels and the cells and other components that make up brain tissue. Whereas the skull, meninges and cerebrospinal fluid protect against physical damage, the bloodbrain barrier provides a defence against disease-causing pathogens and toxins that may be present in our blood.
The bloodbrain barrier was discovered in the late 19th century, when the German physician Paul Ehrlich injected a dye into the bloodstream of a mouse. To his surprise, the dye infiltrated all tissues except the brain and spinal cord. While this showed that a barrier existed between brain and blood, it wasnt until the 1960s researchers could use microscopes powerful enough to determine the physical layer of the bloodbrain barrier.
We now know the key structure of the bloodbrain barrier that offers a barrier is the endothelial tight junction. Endothelial cells line the interior of all blood vessels. In the capillaries that form the bloodbrain barrier, endothelial cells are wedged extremely close to each other, forming so-called tight junctions.
Maintain Ionic Homeostasis And Brain Nutrition
The BBB provides a controlled microenvironment via a combination of specific ion channels and transporters, which keep the ionic composition optimal for neural and synaptic signaling functions. For instance, the levels of potassium in CSF and ISF is maintained at ~2.52.9 mM. In comparison, plasma concentration is approximately 4.5 mM, despite fluctuations that can occur in potassium plasma levels following exercise or a meal, imposed experimentally, or resulting from pathology . Other ions such as calcium and magnesium and pH are also actively regulated at the BBB and BCSFB . Calcium and potassium homeostasis controls neuronal excitability but is also essential for the transmigration of macrophage across the BBB . Furthermore, Ca2+ is involved in the modulation of BBB integrity and endothelial morphology .
Specific ion channels and transporters at BBB provides the optimal preservation environment for synaptic and neural activity. As an example, the abluminal sodium pump maintains a high concentration of Na+ and low levels of K+ in brain ISF via transporting Na+into the brain and K+out of the brain. Or the luminal Na+, K+, Cl cotransporter facilitate the transfer of Na+, K+, 2Cl from blood to the endothelium. Calcium transporters and voltage-gated K+ channel also regulate the ion transport across the BBB .
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General Characteristics Of The Blood
Three major modifications to the capillary bed of the brain prevent the formation of a plasma ultrafiltrate in the CNS : tight junctions that cement together brain endothelial cells that are in apposition, a greatly reduced rate of pinocytosis, and a lack of intracellular fenestrations . These modifications prevent the unregulated leakage of serum proteins into the CNS under normal conditions. Substances are still able to cross the vascular BBB by a variety of mechanisms. These mechanisms include transmembrane diffusion, saturable transport, adsorptive endocytosis, and the extracellular pathways. Below, we discuss transmembrane diffusion and saturable transporters. Reviews on adsorptive endocytosis and the extracellular pathways can be found elsewhere .
Postnatal Bbb Permeability Assay
P9 pups were deeply anaesthetized and 10 Âµl of Dextran, Alexa Fluor647 anionic fixable or EZ-Link Sulfo-NHS-Biotin , were injected into the left ventricle with a Hamilton syringe. After 5 min of circulation, brains were dissected and fixed by immersion in 4% PFA at 4 Â°C overnight, cryopreserved in 30% sucrose and frozen in TissueTek OCT .
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Dysfunction Of The Bbb In Cns Disorders
Disruption of the BBB is observed in many different neurological disorders including MS, stroke, Alzheimer’s disease , epilepsy, and traumatic brain injuries. Functional imaging of human patients and analysis of postmortem brain samples has identified the pathological breakdown of the barrier in different neurological diseases. In addition, work with animal models of disease and with cell culture BBB models has enabled the identification of some of the molecular mechanisms that cause changes to the BBB. This dysfunction can include alterations in many different properties of the BBB including TJs, transporters, transcytosis, and LAM expression. This breakdown can lead to edema, disruption of ionic homeostasis, altered signaling, and immune infiltration that can lead to neuronal dysregulation and, ultimately, degeneration. Although BBB dysfunction is often secondary to the primary insult in these diseases, in some cases, it has been a suggested cause, including MS, epilepsy, and AD .
Schematic representation of signaling regulating the bloodbrain barrier in health and disease. ICAM, intercellular adhesion molecule MMP, matrix metalloproteinase ROS, reactive oxygen species.
Regulation Of The Bbb Formation And Homeostasis
Although key properties of the BBB are manifested within the ECs, important transplantation studies have shown that they are regulated by interactions with the microenvironment of the CNS . The BBB is not one physiology, but a series of physiological properties that either need to be induced or inhibited in CNS ECs. Recent work has dissected the cellular and molecular mechanisms that regulate this process, and have identified that it is a complex process of induction and maintenance signaling interactions among CNS ECs and PCs, astrocytes, and immune cells.
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Conditions With Altered Insulin Bbb Transport
While the molecular mediators regulating insulin transport across the BBB are not exactly clear, there are specific conditions and factors that are known to alter the transport rate, total amount, and level of endothelial binding of insulin at the BBB . However, since the year of that review , the impact of other factors on BBB insulin transport have been investigated. Estrogen does not impact the transport of insulin into the CSF , while the gastrointestinal hormone cholecystokinin increases transport . Other conditions and factors including starvation , triglycerides , and nitric oxide have also been investigated and will be discussed below with the conditions related to insulin resistance .
Figure 3. Conditions and factors that regulate insulin transport across the BBB. Brain endothelial cells separate the blood from the brain and make up the BBB. Insulin is transported across the BBB by a carrier-mediated system. Diabetes, triglycerides, and inflammation are known enhancers of insulin transport. Obesity, fasting, and aging/Alzheimers disease attenuate this transport.
Examples And Special Cases
The various strategies used to develop drugs towards the CNS are meeting with varied levels of success. Those that consider the special features of the BBB rather than ‘black boxing’ it, attempt to understand the underlying mechanisms of promising leads, and consider the peripheral pharmacokinetics of the candidate drug should have advantages. However, there is a great deal that is unknown about the BBB that would be of great use to CNS drug development. For example, there are likely a great many BBB transporters yet to be discovered. Below, we consider two newly discovered transporters and their early applications to drug development.
Mucopolysaccharidoses consist of a number of diseases in which missing enzymes lead to the accumulation of glycosaminoglycans in brain and peripheral tissues. Enzyme replacement clears the glycosaminoglycans from the peripheral tissues, but not from the CNS as the enzymes do not cross the BBB. However, it was recently discovered that the mannose-6 phosphate receptor acts as a saturable transporter at the neonatal BBB . As a result, enzyme given to the neonate is effective in clearance of glycosaminoglycans from the CNS . Unfortunately, this transport function is lost with development. Recent work has shown that transporter function can be re-induced in the adult with epinephrine . How epinephrine invokes this re-induction of activity is unclear, but it may be a useful strategy for delivery of enzyme to the CNS.
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Ms And Related Disorders
Besides its primary neuroprotective function, the BBB has also been shown to actively promote neuroinflammation by orchestrating immune responses during CNS-targeted autoimmune aggression. BBB ECs are an important source of proinflammatory chemokines CCL2 , CCL5, and CXCL10, which are required for lymphocyte and monocyte recruitment to the CNS . Immune cell infiltration into the CNS correlates with production of proinflammatory mediators, such as interleukin -17, IL-22, granulocyte macrophage colonystimulating factor , interferon -, and tumor necrosis factor . These cytokines have been implicated in the modulation of EC function by up-regulating the expression of proinflammatory mediators and by affecting the expression of junctional proteins and, thus, compromising BBB permeability. Last, BBB ECs express intercellular adhesion molecule -1, ICAM-2, vascular CAM -1, activated leukocyte CAM , melanoma CAM , and Ninjurin-1, which mediate, at least in part, the adhesion process and transmigration of leukocytes and leukocyte subtypes to the CNS . Thus, although the BBB protects against CNS-directed inflammation by restricting immune cell access to the brain, it can also regulate the local inflammatory response by expressing proinflammatory molecules that promote the recruitment of peripheral immune cells into the CNS.
What Happened At Sunnybrook
Sunnybrook scientists made history as they used focused ultrasound to non-invasively breach the blood-brain barrier in an attempt to more effectively deliver chemotherapy into the brain tumour of a patient.
They essentially poked holes in the plastic wrap and allowed the various chemicals that they want delivered to the brain to get into the brain.
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Core Concept: Circumventing The Bloodbrain Barrier
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If the brain is the bodys central processing unit, then the bloodbrain barrier is its firewall. A specialized network of cells that lines the brains vascular system, the bloodbrain barrier selectively ushers in nutrients and other essential biomolecules while denying entry to most everything else. But the same system that protects the brain also stymies many therapeutics that could potentially treat disease.
In November 2015, researchers at Sunnybrook Health Sciences Centre in Toronto began a clinical trial to noninvasively breach the bloodbrain barrier with focused ultrasound in an attempt to deliver chemotherapy to brain tumors. Image courtesy of Doug Nicholson .
A handful of drugs slip into the brain by passive diffusionamong them, antidepressants and medications for schizophrenia and epilepsy, along with caffeine, alcohol, and nicotine. These molecules are exceedingly small. They also can readily dissolve into the lipid membranes that encase bloodbrain barrier cells. But new drug leads of this type are growing more elusive. Most of the small molecule combinations have been explored, says biomedical engineer Peter Searson at Johns Hopkins University in Baltimore, MD.
Protect The Brain Against Neurotoxins
Many potential neurotoxins are circulating in our blood, including those from endogenous sources such as metabolites or proteins, or exogenous ones such as xenobiotics ingested in the diet or otherwise acquired from the environment. The BBB function is to regulate the entry of different circulating substances based on CNS needs. The transport barrier represented by multiple ABC energy-dependent efflux transporters occupies the BBB luminal surface. It actively pumps many of these agents out of the brain . The adult CNS has a limited regenerative capacity if damaged, and fully differentiated neurons have a minimal ability to divide and replace themselves under normal circumstances. There is a continuous steady rate of neuronal cell death from birth throughout life in the healthy human brain, with relatively low levels of neurogenesis . That is why any factor promoting an acceleration of the natural rate of cell death would become prematurely debilitating.
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Why Do We Need It
The purpose of the bloodbrain barrier is to protect against circulating toxins or pathogens that could cause brain infections, while at the same time allowing vital nutrients to reach the brain.
Its other function is to help maintain relatively constant levels of hormones, nutrients and water in the brain fluctuations in which could disrupt the finely tuned environment.
So what happens if the bloodbrain barrier is damaged or somehow compromised?
One common way this occurs is through bacterial infection, as in meningococcal disease. Meningococcal bacteria can bind to the endothelial wall, causing tight junctions to open slightly. As a result, the bloodbrain barrier becomes more porous, allowing bacteria and other toxins to infect the brain tissue, which can lead to inflammation and sometimes death.
Its also thought the bloodbrain barriers function can decrease in other conditions. In multiple sclerosis, for example, a defective bloodbrain barrier allows white blood cells to infiltrate the brain and attack the functions that send messages from one brain cell to another. This causes problems with how neurons signal to each other.
How Did They Do This
On the first day, the patient received a small dose of chemotherapy that was slowly infused into her bloodstream through a drip IV in her arm.
She was then taken to an MRI Suite where she was prepped for the focused ultrasound procedure. A head frame was screwed to her skull and she laid down on the MRI bed where the head frame was connected to a helmet that is part of Insightecs Exablate Neuro System.
A number of standard MRI scans were initially done to help the researchers locate positions and plans of where they needed to go.
The researchers administered microscopic bubbles into the patient’s bloodstream through an IV. The microbubbles are smaller than red blood cells and pass harmlessly through the circulation. Once ready, the researchers used state-of-the-art MRI-guided focused low-intensity ultrasound to target blood vessels in the BBB area near the tumour.
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Associated Conditions And Problems
The blood-brain barrier is usually effective at keeping foreign or toxic substances out of your central nervous system. Most of the time this is a good thing, but it can pose a problem when developing new drugs for the nervous system. For example, one of the major challenges in treating brain tumors is that it can be difficult to make a medication capable of getting across the blood-brain barrier to reach the cancer. Because of this problem, researchers are developing medicine to try to bypass the blood-brain barrier.
The blood-brain barrier can sometimes also be broken down by injuries and infections. Research shows that strokes and traumatic brain injury can damage the endothelial tissue and cause the blood-brain barrier to open. Researchers have also found that those with early signs of cognitive impairment have a breakdown of the blood-brain barrier. The findings could help to lead to early diagnostic tests for Alzheimers disease and other conditions that cause cognitive impairment.