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The Blood Brain Barrier is commonly known as BBB. It is a type of membrane and it is very selective in nature. It is a semi-permeable membrane. The blood-brain barrier 1is a physical type of barrier.
There are multiple cell types and cell lines which are needed to make the blood-brain barrier. It is specially formed by brain microvascular endothelial cells (BMVEC)2.
It is present at the border of the endothelial cells. The blood-brain barrier is particularly present between the cerebral capillary blood and the interstitial fluid of the brain. They will stop all the harmful substances from reaching the blood.
The brain endothelial cells act as the backbone of the blood-brain barrier. There are some peripheral tissues of endothelial cells present in the blood-brain barrier. Other than brain endothelial cells, it also contains immune cells, pericytes, basement membranes, and astrocytes.
1. Advantages of Blood-Brain Barrier
Blood-brain barrier acts as a shield that protects the brain (blood vessels, brain tissue) and the central nervous system from exposure to toxic particles. The BBB permeability decides which substance will cross the blood-brain barrier.
- Its function is to stop some particular solutes from entering the extracellular fluid of the central nervous system (CNS)3. It also stops the white blood cells from crossing the blood-brain barrier. Neither B cells nor the T cells are allowed to cross the membrane.
- Substances like hydron, bicarbonates, and fat-soluble molecules are not allowed to cross the blood-brain barrier.
- Blood-brain barrier allows some substances that are required by the brain and the central nervous system to reach the brain like oxygen, water, carbon dioxide, and some general anesthetics to reach the brain. It is known as BBB permeability4.
- It allows small molecules to enter the brain. The toxic substances that reach the blood-brain barriers are sent back into the circulating blood.
There is some disease that causes the improper functioning of the blood-brain barrier like Alzheimer’s disease, and Parkinson’s disease.
2. Exceptions of the Blood-Brain Barrier
There are some vessels in the human brain that do not follow the blood-brain barrier. The brain endothelial cells are not present in these areas other than this they have multiple cell types which will work here.
It includes the circumventricular organs, blood capillaries, or blood vessels present in the pineal gland, on the ceiling of the diencephalon, and at the ceiling of the two ventricles (third and fourth).
The hormone melatonin is secreted by the pineal gland which is released into the systemic circulation of the body and the melatonin does not cause any effect on the blood-brain barrier.
2.1. Circumventricular Organs
The circumventricular organs are also known as CVO. These are those organs that allow the polypeptide hypothalamic hormone to go out of the brain without causing any changes to the blood-brain barrier. It also allows the substance that is not able to cross the blood-brain barrier to cause changes in brain function.
2.2. Pineal Gland
The pineal gland and the posterior pituitary are the regions that are not surrounded by the blood-brain barrier. There are various cell types present in this gland and their function is to secrete hormones and release them into blood vessels.
The main function of the pineal gland is to secrete the serotonin-derived hormone and the melatonin which is necessary for sleep patterns.
3. Requirements of Blood-Brain Barrier
The central nervous system of the body is a very important part of the body that governs the body. It has a very unique structure as well as functions. It needs a specific and stable environment to work to act as a physical barrier.
So, the blood-brain barrier is required by the body to stop the unwanted particles from reaching the central nervous system and to maintain a homeostatic environment5 there. It maintains BBB permeability. So that the central nervous system can perform its function without any disturbance.
4. Components of the Blood-Brain Barrier
The blood-brain barrier is a type of membrane that is made from the brain endothelial cells but it has many other components in it. The components of the blood-brain barrier are listed below along with their functions:
4.1. Pericytes
Pericytes are the brain capillary and the microvessels and they are found near the neurons and the astrocytes. These cells are fibroblast-like cells.
These are multi-functional. They are required for the formation of blood vessels. It plays an important role in the proper maintenance of the blood-brain barrier. It also regulates the proper blood-brain flow.
4.2. Basement Membrane
This membrane is made up of different cell types and cell lines. The function of this membrane is to maintain the integrity of the blood-brain barrier. It is made up of the brain’s capillary endothelial cells.
It will get support from the pericytes present in the vascular basement membrane and from the astrocyte cell projections.
4.3. Microglial Cells
The microglial cells are the immune cells that are present in the central nervous system. These cells play an important role in brain development.
They play a significant role in reducing brain infections and inflammation. They also perform phagocytosis in the brain to kill the unwanted cells present in the brain. Some examples of microglial cells are MeSH, TH, and FMA.
5. Structure of Blood-Brain Barrier
The blood-brain barrier is the result of the selection procedure of the tight junctions between the endothelial cells present in the brain capillary. It is formed with the help of various cell types. It is formed for the restriction of some solutes. This blood-brain barrier will act as an interface between the blood and the brain.
5.1. Tight Junctions
The tight junctions are present to adjoin the endothelial cells continuously. We can call them cellular junctions as well. The tight junctions will also adjoin the adjacent endothelial cells.
These tight junctions are made up of the small subunits of the transmembrane proteins6. The transmembrane proteins include claudins like claudin 5, occluding, and junction adhesion molecules like JAM-A. The tight junctions will provide structural support to the endothelial cells.
The endothelial cells of the blood-brain barrier have tight junctions, and the luminal and abluminal membranes polarize these endothelial cells. The luminal stands for the blood-facing plasma membrane domain and the abluminal is for the brain-facing plasma membrane domain.
5.2. Tight Junction Proteins
Another protein that is present is tight junction proteins and the associated protein. They will provide support to the adjacent cells.
These tight junction proteins stabilize the endothelial cell membrane and it will also use some other protein complex that is like tight junction proteins.
5.3. Astrocytic Feet
Astrocytic feet are the astrocyte cell projections which are also known as glia limitans. It contains glial cells. These cell projections surround the endothelial cells to provide biochemical support to these cells.
6. Difference between Blood Cerebrospinal Fluid Barrier and the Blood Brain Barrier
The blood-brain barrier is quite different from the cerebrospinal fluid barrier.
The cerebrospinal fluid barrier is considered the component of the realm of such types of barriers. This barrier is made up of various cell types that are epithelial cells which makes a huge difference as the blood-brain barrier is made up of endothelial cells.
It functions on the choroidal cells present in the choroid plexus. It will also form a blood-retinal barrier. It maintains the proper cerebral blood flow.
Whereas the blood-brain barrier function is to regulate blood flow. It will stop the toxic substances from reaching the brain and the spinal cord. There are abundant cells present in the brain tissue known as brain cells. The major difference occurs in the cell types as the cerebrospinal fluid barriers are made up of epithelial cells.
7. Development of the Blood-Brain Barrier
The blood-brain barrier starts to perform its work from the time of birth. It is formed by the different cell types and cell lines present in the brain. In the embryonal endothelial cells, there are transporter and the P-glycoprotein which are already present there.
When these are newly born brain uptake is measured. In that brain uptake measurement, the blood-borne solutes are measured and the results are observed as whether the newly born cells are working as those of the adult cells or not.
8. Physiological Variants
There are some areas in which the blood-brain barrier is weakened, so these areas are easily changed due to the changing levels in the metabolites of the blood. It will change the brain’s metabolism.
These are some areas that cause changes in brain cells, and brain capillary endothelium:
8.1. Subfornical Organ
It is an organ of CVO that is formed by different cell types. Its function is to sense things and maintain the balance signals of hydromineral and the hormonal circulating fluid.
8.2. Area Postrema
It is also known as the emetic center. It is the region of the medulla and is a highly vascular paired structure. This is provoked by the toxins present in the blood which will cause vomiting.
8.3. Supraoptic Crest
It is the organ of the CVO. It is not in the range of the blood-brain barrier, so the neurons present in its region can show the responses to the factors that are in the systemic circulation.
8.4. Neurohypophysis
The neurohypophysis is the part of the posterior lobe of the pituitary gland. It is classified into two parts: one is infundibular stalk and the other is pars nervosa.
It is a neuro-humoral system7. Its function is to release the reproductive hormone and the fluid balance with the help of the hormones like oxytocin and vasopressin which are produced in the hypothalamus.
8.5. Commissural Organ
It is also an organ of the CVO which is made up of different cell types. It is like a small glandular structure. It is present near the entrance of the cerebral aqueduct. Its function is to focus on the areas of communication between the brain parenchyma and the blood and also the CSF.
8.6. Median Eminence of the Hypothalamus
It is the area where the hormones or the secretions are stored until they are released into the portal capillary bed for further release in the anterior pituitary.
After this, it will send signals to the endocrine system. It acts as an interface between the peripheral and the neural endocrine system.
8.7. Choroid Plexus
The Choroid Plexus8 is a special brain tissue. It is the network of the blood vessels and is present in every ventricle of the brain. The main function of the choroid plexus is to produce a sufficient amount of cerebrospinal fluid. It consists of the filtration system which will separate the blood from the cerebrospinal fluid.
8.8. Pineal Gland
It will produce melatonin. This melatonin helps in the sleep pattern of the body. They will receive the information regarding the light and dark cycle and then the process of melatonin secretion starts.
9. Functions of the Blood-Brain Barrier
The major function of the blood-brain barrier is to maintain homeostasis. This function is completed with the help of the transport of the tightly regulated ions and the solute in between the CNS and the intravascular plasma with the help of the molecular exchange pathways. There is an interstitial fluid filled in it.
This molecular exchange pathway helps to transport or transfer the molecules from the brain to blood and vice versa i.e. blood to the brain.
Whereas, there is no requirement for a transport system for all molecules to cross the blood-brain barrier. Some molecules can easily cross the blood-brain barrier by diffusion like gases (oxygen, carbon dioxide) and lipophilic molecules which have a molecular weight of around 400 Dalton.
The integrity of the blood-brain barrier is maintained and stabilized by the astrocytes. The most critical transport pathway and the mechanism of the blood-brain barrier are contained by the pericytes and the endothelial cells.
10. Mechanism of Transport across the Blood Brain Barrier
There are two different types of capillary endothelial cells that are cerebral capillary endothelial cells and peripheral capillary endothelial cells. They are different from each other in the number of tight junctions present in each.
They have less number of cytoplasmic vesicles. and contains a high concentration of mitochondria. Due to the presence of tight junctions, the paracellular movement is reduced.
So, the membrane of endothelial cells is divided into two different sides having different membrane compositions.
Due to this limitation in movement, various mechanisms are introduced through which the molecules cross the blood-brain barrier. Amino acids are also able to cross the blood-brain barrier with the help of transport systems.
The BBB permeability is discussed by this mechanism. These are as follows:
10.1. Diffusion
There are some substances that will reach the brain by a diffusion process. It can be done by either transcellular or paracellular pathways.
In some cases, some water-soluble molecules will cross the blood-brain barrier by the simple diffusion method. Whereas, lipid-soluble molecules like steroid hormone and alcohol will cross the blood-brain barrier by transcellular penetration through the plasma membrane.
10.2. Transport Proteins
The molecules which are not able to cross the blood-brain barrier with the simple diffusion process will take the help of the transport proteins like amino acids, and glucose. They act as amino acid transporters
These substances will bind to the protein transporter at one side of the membrane and then some conformational changes take place in the protein so that it will move from the higher concentration to the lower concentration. ATP is utilized during this process.
10.3. Efflux Pumps
The efflux pump method is used for the exogenous and the endogenous compound which is needed to transfer to the brain like drugs.
ATP binding cassette is the most important and active drug efflux transporter. It plays an important role in the distribution and elimination of the drug in the CNS. It sometimes acts as a metabolic barrier.
10.4. Receptor-Mediated Transcytosis (RMT)
This mechanism is used for the selective macro-molecule uptake in the brain. There are some receptors that are present on the cerebral endothelial cells which will select the specific molecules needed by the brain.
The receptors include the following receptors:
Transferrin Receptor: The transferrin receptor is used for the transfer of iron to the brain parenchyma to complete the need for iron in the brain and to maintain iron homeostasis.
It plays a significant role in neural conductivity and proper metabolism. So, it will help the brain tissue to function properly.
Insulin Receptor: Insulin plays an important role in the brain or brain tissue. With the help of the insulin receptors, the insulin is transferred to the brain. The insulin receptor will read the signals and help in the transfer of insulin to the brain.
Lipoprotein Transport Receptor: The lipoprotein transport receptor will help to transfer the lipid-soluble compounds to the brain but only whenever they are needed by the brain or brain tissue.
10.5. Adsorptive Mediated Transcytosis (AMT)
It is also known as pinocytosis. Pinocytosis is initiated when the positively charged protein interacts with the negatively charged surface of the cell membrane.
The molecules which are cationic in nature will bind to the luminal surface and then the exocytosis starts at the surface of the abluminal membrane.
10.6. Cell-Mediated Transcytosis
It is a mechanism by which the pathogens will reach the brain and brain tissue or a brain cell. They use immune cells like monocytes or macrophages to cross the blood-brain barrier. This method is also used by drugs to reach the brain.
11. Pathophysiology of Blood-Brain Barrier
Blood-brain barrier performs various functions. Mainly it provides security to the brain so that unwanted things will not reach the brain.
But sometimes the blood-brain barrier is not able to function properly due to some reasons. Sometimes it is due to the BBB breakdown which has its reasons.
The reason is that the body is suffering from some chronic neurological disorders like Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, brain tumors, improper gene expression, and amyotrophic lateral sclerosis. The blood-brain barrier is also not able to function properly when there are brain tumors or brain strokes.
11.1. Alzheimer’s Disease
In Alzheimer’s disease, the blood-brain barrier will not function properly due to damage to blood vessels. This blood vessel damage can cause vascular risks like hypertension or diabetes.
Alzheimer’s disease will kill the brain cells and the connections of the brain cells. Due to this the person suffering from Alzheimer’s disease will lose his memory and retarded in mental functioning. Alzheimer’s disease will cause damage to the neural tissue or the nervous tissue
11.2. Parkinson’s Disease
Parkinson’s disease is a neuronal disease that causes improper neuronal function in which the nerve cells of the brain are damaged due to which the blood-brain barrier will function improperly and sometimes it will lead to the BBB breakdown. The decreased expression of dopamine is observed in this disorder.
11.3. Traumatic Brain Injury
Traumatic Brain Injury is generally caused due to a head injury which will be the result of an accident or injury while playing any sport. It causes problems in the human brain. or animal brains. It generally leads to the BBB breakdown.
Sometimes the blood-brain barrier breaks breakdown due to the reactive oxygen species.
12. Clinical Implications
The blood-brain barrier plays an important role but sometimes it will start improper functioning due to some neurological disease. The reactive oxygen species also degrade the blood-brain barrier.
There is a very small number of drugs introduced that are used to solve these clinical implications of the blood-brain barrier. Due to this the immune responses are not easily triggered.
There are some issues due to which the drugs are so little in number. The first one is the effective transportation of the drug so that the drug will reach the target site.
The second one is due to the breakdown of the blood-brain barrier the perivascular accumulation of the toxic products which are derived from blood is started. It will invade vascular regression and inflammatory responses.
All these changes will reduce the distribution of neurotherapeutic drugs in the central nervous system. It will block the interstitial fluid flow dynamics. It also stops the transport of substances across the brain and the endothelial cells. Also, it affects cerebral blood flow.
13. Final Note
The blood-brain barrier is present in the human brain and the animal brain. It protects the brain tissue, blood vessels, cell surface, different cell types, and brain capillaries. The blood-brain barrier acts as the physical barrier.
The blood-brain barrier is made up of endothelial cells also known as the brain endothelial cells and different cell lines have cellular junctions in them which provide them with structural support. There are some adhesion molecules present in the endothelial cells which help them to join with each other.
These cellular junctions are present in the adjacent endothelial cells. Also, there are some brain capillary endothelium present. There is a vascular endothelial growth factor that helps in the formation of blood vessels.
Vascular smooth muscle cells found in the vascular organs are present in the middle of the blood vessels of the blood-brain barrier. They play an important role in vascular permeability. The white blood cells neither B cells nor T cells can cross the blood-brain barrier.
The blood-brain barrier allows the small molecules to cross and reach the human brain. Blood-brain barrier allows some immune cells to cross and reach the brain tissue, brain vessels, and brain capillaries. It maintains proper cerebral blood flow.
Sometimes due to some neuronal diseases like Alzheimer’s disease, brain tumors, Parkinson’s disease, improper gene expression, and tumor necrosis factor the blood-brain barrier is not able to function properly.
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