Is This A Cure For Als
No. This research is in its early stages and the primary goal is to demonstrate safety and feasibility. If successful, the ultimate goal is to use this novel technique to open the blood-brain-barrier and then test the most promising ALS therapeutics. ALS stands for Amyotrophic Lateral Sclerosis and is also known as Lou Gehrig’s disease.
Therapies To Increase Bbb Insulin Transport And Cns Insulin Levels
In this review, we have summarized the detrimental effects of altered insulin signaling within specific cell types at the BBB. However, many of these detrimental effects are due to decreased exposure to insulin and hence insulin BBB transport. Therefore, if CNS insulin can be increased, some of these detrimental effects could be overcome. Alternative routes to increase CNS insulin has recently been reviewed by our group in detail . We have highlighted here a couple of therapies that are the most translational to increase CNS insulin levels.
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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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 .
Where Is The Blood
The blood-brain barrier surrounds most of the blood vessels in the brain. It is a structure that is formed primarily due to the establishment of tight junctions between endothelial cells . There are also several other cells and proteins contributing to the blood-brain barrier complex for example, processes called astrocytic end-feet extend from astrocytes to surround blood vessels and provide support to the endothelial cells of the blood-brain barrier.
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The Bbb Can Be Broken Down By:
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.
What Is The Bloodbrain Barrier
Clinical and experimental findings indicate that BBB damage and dysfunction is a common and prominent pathological feature in stroke and TBI. Several underlying events are involved, such as disruption of the tight junction seals, alterations in endothelial transport properties and extracellular matrix degradation. Understanding the time course and events involved in BBB disruption is important to determine the rate and extent to which it leads to secondary injury events, the extent and the level of barrier disruption that allows free mobility of toxic substances and identify the window of opportunity to deliver therapeutics. In the next section, we review the spatial and temporal changes in BBB breakdown.
Why Would Anyone Want To Break It
The BBB has been a persistent obstacle to delivering valuable medication therapies to treat diseases of the brain such as tumours and various types of neurological disorders because of its plastic wrap layer around the blood vessels.
Some medications can get through this BBB but it can vary from zero percent to a small amount. For example, some chemotherapy has up to a 20 per cent chance of reaching these parts of the brain because of the BBB.
Researchers are hoping that by temporarily and safely opening this barrier in a patient to deliver medication directly to the brain tumour, it may potentially mean providing more targeted treatment in the future, which they think will require less medication, leave fewer side effects and improve quality of life.
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Biology And Models Of The Bloodbrain Barrier
Annual Review of Biomedical Engineering
Cynthia Hajal,1,* Baptiste Le Roi,2,* Roger D. Kamm,1,3 and Ben M. Maoz2,4,5
1Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
2Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, Israel
3Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
4Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel email:
5Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel
Bloodbrain Barrierrelated Diseases: Current Models And Improvements
Multiple neurological or brain diseases are known to affect the BBB through the secretion of inflammatory cytokines that degrade TJs . Because of the limited spatiotemporal resolution of in vivo models and the challenge of translating results from animal to human studies, several groups have shifted their efforts to the development of in vitro human BBB disease systems. These platforms also enable the generation of high-throughput identical models that can be used for studies pertaining to drug delivery across the BBB.
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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.
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.
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Other Components Of The Bbb
Large-scale genomic and proteomic approaches have identified signaling cascades that are turned on in CNS ECs. In particular, Wnt/-catenin signaling through Lef1, as well as Sonic hedgehog signaling through Gli have been shown to be important for regulating the formation and function of the BBB . In addition, vascular metabolism has been implicated in regulating barrier properties of CNS vasculature by metabolizing potential toxins or altering the properties of molecules . Specific enzymes, including carbonic anhydrase IV and -glutamyl transpeptidase, have been identified as enriched in CNS vessels compared with vessels from non-neural tissues .
Large-scale genomic and proteomic approaches have provided invaluable resources in understanding the gene expression of the BBB, but work still needs to be done to identify which of these BBB-enriched genes are important for each aspect of the BBB, whether there is heterogeneity of these genes at different segments of the vascular tree and in different brain regions, and whether the expression and function of each protein is dynamically regulated by neuronal function, stress, or diet. In addition, work expanding beyond genomics is aimed at identifying the proteomics, miRNAs, noncoding RNAs, lipids, metabolomics, epigenetics, and other regulatory steps that are important for BBB formation and function.
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.
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.
Regulate Levels Of Neurotransmitters
The central and peripheral nervous systems share many of the same neurotransmitters, so the BBB helps to keep the central and peripheral transmitter pools separate, minimizing crosstalk and protecting the brain from unexpected changes in their plasma levels. For example, blood plasma contains high levels of the neuroexcitatory amino acid glutamate, which fluctuate significantly after the ingestion of food. High levels of glutamate in the brain ISF will have harmful effects on neuronal tissues. An example is a case of glutamate secretion from hypoxic neurons during ischemic stroke, which results in considerable and permanent neurotoxic/neuroexcitatory damage to neural tissue .
The transfer of neurotransmitters from the brain to blood primarily dependent on Na+-coupled and Na+-independent amino acid transporters. The BBB limits the influx of some amino acids including the neurotransmitters glutamate and glycine, while it effluxes many other essential amino acids. Hladky and Barrand reviewed comprehensively the transport of amino acids across the BBB with different transport systems based on the type of amino acids .
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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:
Endothelial Cells And Blood
Endothelial cells that make up the BBB include capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane transporters that regulate the passage of molecules, such as nutrients and drugs, into and out of the brain. The main function of these cells is to regulate the movement of water and solutes between the blood and the brain. They also help to protect the brain from infection and keep harmful substances out.
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The Blood Brain Barrier
More than 100 years ago it was discovered that if blue dye was injectedinto the bloodstream of an animal, that tissues of the whole body EXCEPTthe brain and spinal cord would turn blue. To explain this, scientiststhought that a “Blood-Brain-Barrier” which prevents materials fromthe blood from entering the brain existed. More recently, scientists havediscovered much more about the structure and function of theBBB.
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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Bbb Disruption In Different Pathological Conditions
BBB dysfunction is reported in many CNS pathological conditions including multiple sclerosis hypoxic and ischemic insult Parkinsons and Alzheimers disease epilepsy brain tumors glaucoma , and lysosomal storage diseases . The observed barrier dysfunction can range from mild and transient changes in BBB permeability, resulting from tight junction opening, to chronic barrier breakdown, and changes in transport systems and enzymes can also occur. This process can also be associated with the degradation of the basement membrane . Microglial activation and infiltration of different plasma components and immune cells into the brain parenchyma result in disturbance of CNS homeostasis and variable damage to the surrounding brain. In most cases, it is not possible to determine whether barrier compromise is causal in disease onset or a result of neurological disease progression. Still, barrier disturbance can often be seen to contribute to and exacerbate developing pathology .
Table 1 Different CNS pathological conditions involving BBB disruption