November 30, 2020

Blood-brain barrier; structure, functions, and what could go wrong.

In 1882, Paul Ehrlich injected a dye into the bloodstream of a mouse. After later examining the mouse, the dye had stained all of the organs except the brain and the spinal cord. This protection was named the blood-brain barrier and it was later discovered that this protection extended to peripheral nerves. The blood-brain barrier is an extremely useful concept to understand – it can even help doctors make diagnoses about cancer. Today, we will explore the blood-brain barrier – what causes it, what molecules can and can not pass, and what happens when it goes wrong.

Functions

The blood-brain barrier has numerous important functions. It allows for neuronal homeostasis and stabilizes the nervous system which prevents fluctuation due to hormone changes or changes in the levels of glucose and insulin. The barrier also protects the nervous system from toxins and other dangerous chemicals. This is often a problem for the pharmaceutical industry because many of the drugs developed to help with various diseases and illnesses are not permitted to pass through the nervous system. Finally, the barrier also preserves the concentration of neurotransmitters. If there was no barrier, the neurotransmitters would flow from areas of high concentration (in the brain) to areas of low concentration (the rest of the body). As neurotransmitters are essential for brain function, this would create numerous problems.

Structure

The brain has continuous capillaries which are also found in other parts of the body. However, the capillaries that provide blood supply to the brain have noticeable features that allow them to create such a strong barrier. Although the capillaries are continuous, they have small gaps between the endothelial cell lining. In the brain, these gaps are filled by proteins such as occludins and claudins which create tight junctions. This prevents substances from freely moving in between these junctions. This blocks the paracellular route.

Furthermore, this paracellular block is strengthened by astrocytes (a type of glial cell) on the other side of the barrier. Behind the basement membrane which is adjacent to the endothelial layer, there is a layer of astrocytes with foot processes that cover 80-90% of the basement membrane. These foot processes ensure that the tight functions remain tight by inducing the formation of proteins (like occludins).

In addition, in some capillaries, there is transport through the endothelial cells. This transcellular route involves transporting molecules through vesicles. This transcytotic vesicular transport method is also blocked in the blood-brain barrier, further preventing toxic molecules from passing through.

Similarly to how there is a second layer of defense to the paracellular route, there is also another mechanism to prevent toxins and other hazardous molecules from entering through the transcellular route. If a molecule is able to get past the preventions against transcellular transport, special transporters called p-glycoprotein multidrug nonspecific prevent them from entering the nervous system. These transporters are made to “throw” out lipid-soluble neurotoxins which are able to move through the endothelial cells. Most of the pharmaceutical efforts are focused on disabling these transporters in order to allow therapeutic drugs to pass.

What can go through?

The blood-brain barrier has a myriad of restrictions on molecules. It prevents large proteins such as plasma proteins or anything bound to them from passing. Highly charged or polar particles are also not allowed to pass as the more charge a molecule has the less lipid-soluble it is. Finally, toxic molecules are also not allowed to pass.

However, the brain does require some molecules to function. So, how does the blood-brain barrier ensure that the right molecules are able to get through? Small lipid-soluble molecules are allowed to pass including water, oxygen, and carbon dioxide. Freeform proteins and hormones are also allowed into the nervous system. Yet, there are other molecules such as glucose that are large and not lipid-soluble but are required for the nervous system to function. In order to get around this problem, there are built-in transporters on the surface of the endothelial cells that allow the transport of glucose and amino acids. The transporter (Glut-1) for glucose is not dependent on insulin – a notable feature as the brain receives 90% of its energy from glucose.

The Blood-CSF Barrier

Unlike the rest of the brain, the ventricles (which contain cerebrospinal fluid) have a barrier that serves a similar purpose albeit with a different structure. The capillaries that supply blood to this part of the brain are fenestrated capillaries which means that there are gaps in between the endothelial cells. Furthermore, there are no tight junctions which allow for transcellular and paracellular transportation of molecules. However, the ventricles are protected by specialized ependymal cells, choroidal cells. Ependymal cells line the ventricles and are derived from the neuroectoderm. These choroidal cells have tight junctions between them and are able to provide protection against toxins.

When it goes wrong …

The blood-brain barrier can be broken due to trauma, infection, inflammation, radiation, neoplasms, or even hypertension. When it is broken, it causes the swelling of the brain (vasogenic edema). It can also be a sign of some brain cancers that cause ruptures in the BBB. This is especially problematic in babies who have a weak blood-brain barrier. If there are high bilirubin (which is a neurotoxin) levels in the blood, it could pass into the nervous system and cause kernicterus.

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