Thursday, June 16, 2022

What Is The Function Of The Blood Brain Barrier

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Hemodynamic Modulatory Functions In Bbb Physiology: Role Of Shear Stress

what is the blood-brain barrier? what are the components and functions of the blood-brain barrier?

Mammalian endothelial cells are known to undergo dynamic changes under different stimuli. Cellular, molecular, and physical stimuli are the essential players that help ECs to acquire specialized functions. For most cell types, chemical signaling seems to play a pivotal role in cell physiology. Physical stimulation, such as shear stress, is one of the most important but underestimated physiological stimuli, which contributes to vascular ECs differentiation and maturation besides other cellular and molecular signaling. Akin to responses to inflammatory cytokines, shear stress has been shown to cause dramatic changes in ECs morphology , gene expression , and function . Shear stress showed to induce the production of reactive oxygen species and nitric oxide . NO is known to cause vasodilation, autocrine signaling, and also increase the production of free radicals. A study showed that ECs might scavenge free radicals by increasing levels of GAPDH and other intracellular enzymes . Another study showed that NO might have a protective role in BBB during reperfusion after the transient loss of flow in a condition mimicking ischemic stroke .

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.

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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Blood Brain Barrier Cells

Blood brain barrier is made up of capillary endothelial cells and basement membrane, neuroglial membrane, and glial podocytes, i.e., projections of astrocytes. These 3 components work in synchronicity with one another to limit entry of various substances into the cerebral blood flow and subsequently the brain parenchyma.

Figure 2. Blood brain barrier cells

Footnote: Cellular constituents of the blood-brain barrier . The blood-brain barrier is formed by brain microvascular endothelial cells, which are connected by tight junctions. The endothelium, together with the basal lamina, pericytes, and astrocytic end-feet forms the neurovascular unit. Some substances diffuse freely into and out of the brain parenchyma, others such as nutrients need specific transporters, while molecules such as insulin, leptin and transferrin are transported by receptor- mediated transcytosis.

Issues Surrounding The Bbb

(A) The illustration of the blood

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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

Development And Function Of The Blood

  • Laboratory of Cell Signaling and Obesity and Comorbidities Research Center, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil

Under physiological conditions, the brain consumes over 20% of the whole body energy supply. The blood-brain barrier allows dynamic interactions between blood capillaries and the neuronal network in order to provide an adequate control of molecules that are transported in and out of the brain. Alterations in the BBB structure and function affecting brain accessibility to nutrients and exit of toxins are found in a number of diseases, which in turn may disturb brain function and nutrient signaling. In this review we explore the major advances obtained in the understanding of the BBB development and how its structure impacts on function. Furthermore, we focus on the particularities of the barrier permeability in the hypothalamus, its role in metabolic control and the potential impact of hypothalamic BBB abnormities in metabolic related diseases.

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Bbb Structure And Function

In the last decade, there has been exponential progress in the understanding of how BBB structure and function work both in health and pathological conditions . The first evidence for the existence of a barrier controlling the passage of substances from the circulating blood to and from the CNS dates back to 1885 when the German researcher Paul Ehrlich carried out experiments injecting Trypan Blue dye into the bloodstream of mice. Surprisingly, he noted that the dye could penetrate several tissues but not the brain and spinal cord . Years later, further studies performed by Goldmann , Ehrlich’s student, indicated that injection of the same dye directly into the brain showed the opposite as observed previously: the brains turned blue, whereas the peripheral tissues did not . The term blood-brain-barrier was introduced by Lewandowsky , based on experiments demonstrating that neurotoxic substances, e.g., cholic acids or sodium ferrocyanide, exhibited neurological symptoms only after intraventricular applications but not when injected into the bloodstream. Only in the late 1960s, with the development of electron microscopy, Reese and Karnovsky were able to visualize for the first time, at ultrastructural level, that the brain endothelial cells present unique cell-to-cell junctions, constituting a structural barrier that creates an almost impermeable frontier between the blood and CNS .

Next, we present the main features of the cellular components of the BBB:

Regulate Levels Of Neurotransmitters

Blood Brain Barrier – Structure & Function

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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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.

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.

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What Is The Difference Between The Blood Brain Barrier And The Blood Csf Barrier

Bloodbrain barrierbloodCSF barrier

. Regarding this, what is the blood CSF barrier?

The bloodcerebrospinal fluid barrier is a fluidbrain barrier that is composed of a pair of membranes that separate blood from CSF at the capillary level and CSF from brain tissue. The bloodCSF boundary at the choroid plexus is a membrane composed of epithelial cells and tight junctions that link them.

Secondly, how is cerebrospinal fluid different from blood plasma? CSF is derived from blood plasma and is largely similar to it, except that CSF is nearly protein-free compared with plasma and has some different electrolyte levels. Due to the way it is produced, CSF has a higher chloride level than plasma, and an equivalent sodium level.

Moreover, what can and Cannot pass through the blood brain barrier?

Large molecules do not pass through the BBB easily. Low lipid soluble molecules do not penetrate into the brain. However, lipid soluble molecules, such as barbituate drugs, rapidly cross through into the brain. Molecules that have a high electrical charge are slowed.

Does gentamicin cross the blood brain barrier?

Antibiotics vary widely in their ability to penetrate the bloodbrain barrier. In studies of 70 rats, the permeability of the normal bloodbrain barrier to gentamicin was shown to be poor.

Protect The Brain Against Neurotoxins

Blood brain barrier, blood brain barrier function &  cells

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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Ependymal Cells And Blood

Ependymal cells are a type of cell that lines the ventricles of the brain. These cells have many functions, one of which is to produce cerebrospinal fluid . CSF is a clear, watery fluid that surrounds the brain and spinal cord. It provides cushioning and protection for these delicate tissues and allows the brain to function properly. Ependymal cells also help to circulate CSF throughout the brain and they help to maintain the tight junctions between endothelial cells. Ventricles of the brain are cavities that contain CSF. The choroid plexus is a network of blood vessels located in the ventricles of the brain. These blood vessels produce CSF. The choroid plexus is composed of two types of cells: epithelial cells and stromal cells. Epithelial cells are involved in the production of CSF, while stromal cells provide structural support. The choroid plexus is important for the circulation of CSF and the removal of waste products from the brain.

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.

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Limit Plasma Macromolecules Leak Into The Brain

The production of CSF from plasma, under normal condition, passed through an efficient filtration process in the choroid plexus to remove unneeded plasma proteins. This process helps in controlling the protein content of CSF and results in minimal quantities of proteins in CSF compared to the plasma protein levels .

Under physiologic conditions, the BBB prevents many macromolecules from entering the brain through normal paracellular or diffusion routes. The leakage of these large molecular weight serum proteins into the brain across a damaged BBB can have severe pathological consequences. For example, the leakage of plasma proteins such as albumin, prothrombin, and plasminogen has a detrimental effect on nervous tissue, causing cellular activation, which can lead to apoptosis . There is a wide distribution of different activators for these proteins within the CNS. These include factor Xa, which converts prothrombin to thrombin, or tissue plasminogen activator, which converts plasminogen to plasmin. The resulting proteins, thrombin or plasmin, can bind to their receptors in brain tissue and initiate cascades resulting in seizures, glial activation, glial cell division and scarring, and cell death . Thus, the BBB works as a gatekeeper, allowing the entry of only the beneficial materials.

Intracellular Drug Accumulation Rhodamine123

What is the Blood-Brain Barrier?

Rh123 passively diffuses into hCMEC/D3 cells and is then subject to being expelled from the cells by the efflux transporter P-gp. When hCMEC/D3 cells were treated with the P-gp inhibitor verapamil, Rh123 accumulation within the cell increased significantly . Next, Rh123 accumulation in the cells treated with Tat and/or methamphetamine was studied to assess the effects of treatment of P-gp-mediated efflux activity. Compared to the control, only the Tat-plus-methamphetamine experimental group showed a significant increase in intracellular accumulation of Rh123 . This suggests that Tat and methamphetamine coexposure may influence P-gp expression or function within our BBB model. To further evaluate the influence of Tat and methamphetamine on P-gp, similar experiments were performed with Rh123 but also in the presence of the P-gp inhibitor verapamil . As would be expected in cells with functional P-gp, inhibition of P-gp by verapamil decreased efflux of Rh123 and resulted in significant increases in Rh123 intracellular accumulation in the control group . The increase in Rh123 within the cell upon P-gp inhibition was also observed with the Tat-only group , again consistent with the finding that exposure to Tat alone does not alter P-gp function. Verapamil inhibition did not alter intracellular accumulation of Rh123 in the methamphetamine and Tat-plus-methamphetamine groups, suggesting that P-gp function was already impaired after exposure to these treatments.

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