What is the Blood-Brain Barrier?

The blood-brain barrier refers to the barrier between plasma and brain cells formed by the walls of brain capillaries and glial cells and the barrier between plasma and cerebrospinal fluid formed by the choroid plexus. These barriers can block certain substances (mostly harmful) ) From the blood into the brain tissue. Many solutes in the blood enter the brain tissue from the capillaries of the brain. It is difficult or easy; some pass quickly, some are slow, and some cannot pass at all. This selective permeability phenomenon makes people imagine that there may be limited solute permeability. A certain structure exists, which can protect the brain tissue from harmful substances in the circulating blood or even from it, thereby maintaining the basic stability of the environment in the brain tissue and having important biological functions for maintaining the normal physiological state of the central nervous system. significance.

Chinese name: Blood-brain barrier
Foreign name: blood brain barrier

Department: brain
Features: Prevent diseases from invading the brain

Blood brain barrier

Capillary endothelium (continuous type with tight junctions between endothelial cells)

Structural base film (complete)

Glial membrane (foot board of astrocytes)

Function: Prevent harmful substances from entering the brain and maintain a relatively constant internal environment.

Blood-brain barrier measurement model

Flocel three-dimensional dynamic blood-brain barrier

Blood-Brain Barrier Model)

External blood-brain barrier measurement models generally include:

1) Trans-membrane resistance measurement (TEER detection) system

2) Computer controlled pulsation pump

3) Flocel control software

BBB characteristics

Compared with the traditional blood-brain barrier system, the characteristics of Flocel's in vitro dynamic blood-brain barrier system model are as follows:

Can do more accurate pharmacokinetics and toxicology studies
More clearly and accurately reflects the characteristics of the blood-brain barrier in the body
Simulate the role of important endothelial cells and astrocytes
Electrical method was used to test the integrity of the blood-brain barrier
Experiments with real cells
Forms tighter connections than existing static models
Reduce the cost of drug development

1.DIV-BBB Lumen

characteristic

advantage

Controllable intra-cavity / non-cavity volume ratio

Small size, only 175px long

Integrated electrode and lumen

low cost

Consistent with body volume ratio

Reduced number of cells required for the test

TEER detection system is easy to operate

Single use, cannot be reused

Dynamic blood-brain barrier parameters

2. Trans-Cell Membrane Resistance Measurement (TEER Detection) System

The TEER detection system provides developers with a quick and easy way to assess the integrity of the blood-brain barrier. In addition, the electrical impedance value (> 1000 -cm ) is very close to the in vivo value. The TEER inspection system is also equipped with the required inspection software, wires and liners, which can be used for 4 DIV-BBB lumen at the same time. The testing software can customize the pump's flow rate, frequency, waveform and other parameters. Other characteristics and advantages are shown in the table below:

characteristic	advantage
Detection of electrical impedance at multiple frequencies	Describe the resistance and capacitance of the electrode
Low voltage, Max = 60mV	Limit potential damaging effects on barriers
Automatic detection of multiple lumens	Can connect 4 boxes at the same time
Testing software can customize parameters such as pump flow rate, frequency and waveform	Detect electrical impedance and record data
USB connection	Desktop or laptop computer can be connected

Dynamic blood-brain barrier dynamic partial meter, perfusion pulse pump

Blood-brain barrier structure

A dynamic interface between blood and brain tissue that selectively inhibits the passage of matter. The continuous capillary endothelium of the brain and the tight connection between its cells, a complete basement membrane, pericytes, and astrocytes. The surrounding glial membrane is composed of the endothelium as the main structure of the blood-brain barrier.

The brain barrier is a general term for the three barriers of blood-brain, blood-cerebrospinal fluid and cerebrospinal fluid-brain.

Compared with the capillaries of other tissues and organs, the brain capillaries and their adjacent areas do have some obvious characteristics in structure (under normal conditions):

Blood-brain barrier Cerebral capillaries lack pores that are common to capillaries, or these pores are few and small. Endothelial cells overlap and cover each other, and are tightly connected, which can effectively prevent macromolecular substances from passing through the junction of endothelial cells.

Endothelial cells are also surrounded by a continuous basement membrane.

There are many astrocytes around the basement membrane that surround the brain capillaries by about 85% of their surface. This forms a multilayer membrane structure of brain capillaries, which constitutes a protective barrier for brain tissue. In pathological conditions, such as vascular cerebral edema, the tightly bonded areas of endothelial cells are opened. As the swollen and overlapping parts of endothelial cells disappear, many macromolecular substances can leak out of capillaries with the plasma filtrate, which will damage the internal environment of brain tissue Has serious consequences.

Blood-brain barrier discovery

In the early 20th century, it was discovered that after intravenous injection of amphetamine in animals, the drug can be distributed to tissues and organs throughout the body, except that brain tissue has no trace of it. After injection of trypan blue (trypan blue), the whole body tissue was stained, but the brain and spinal cord were not stained. In the future, it was discovered that many drugs and dyes had similar distribution after being injected into animals. These facts suggest that people think of a "barrier" to protect brain tissue. After injecting glutamic acid into chicken embryos, it was found that glutamic acid can quickly enter the brain tissue of chicken embryos, but it is difficult to enter into the adult chicken brain. The permeability of brain capillaries in newborns is much higher than that of adults. After severe jaundice, bile pigments quickly penetrate the central nervous system and destroy the basal ganglia to form nuclear jaundice. The central nervous system in adult patients with jaundice is not contaminated by bile pigments. The above facts show that the perfection of the structure and function of the blood-brain barrier is formed with the development of the individual animal.

Normal blood-brain barrier function

The microstructure of the blood-brain barrier has been described above, including non-porous or less porous endothelial cells, a continuous basement membrane, and a discontinuous membrane composed of loosely connected astrocytes and blood vessels. They constitute the blood-brain barrier control. Various solutes in the blood plasma are selectively permeated. Some scholars call it closed doors or safety flaps, and exclude harmful substances from the brain tissue so that it cannot escape from the brain capillaries, which vividly illustrates the normal function of the blood-brain barrier. . But there are different opinions on which of the three components play a major role in performing normal functions. According to Japanese pharmacologist Kenichi Nakai, "Astrocytes play a major role in the barrier, and endothelial cells also play an important role to a certain extent." According to the microstructure, the area surrounding the blood vessels of the brain capillaries is only about 85%, and there is still a large exposed part for the exudation of harmful substances. Obviously, this statement is flawed.

Blood-brain barrier barrier site

According to the results of electron microscopy and enzyme labeling, brain capillary endothelial cells may be the key part of the barrier. The basis is as follows:

Use a small molecular weight horseradish peroxidase (a protein with a molecular weight of about 40,000 and a molecular diameter of about 500-600 nanometers) or a fragment thereof as a marker that penetrates the capillary wall and a small molecular weight horseradish peroxidase It can quickly enter muscle tissue through muscle capillaries, but this enzyme fragment in brain capillaries is blocked in the blood vessels and cannot enter the brain tissue. In this barrier role, the basement membrane and the perivascular discontinuous membrane only play an auxiliary role.

The drinking effect of cerebral capillary endothelial cells is weak. Therefore, there is less material exchange between vascular endothelial cells and brain tissue. After the animals were exposed to ionizing radiation, their cytotoxicity increased, and the permeability of the blood-brain barrier also improved.

Blood-brain barrier determinants

Material fat solubility

Solutes in the blood must pass through the endothelial cells of the brain capillaries to reach the brain tissues. The membrane of the endothelial cells is based on a bilayer structure of lipids, which is lipophilic and easy to pass fat-soluble substances. Therefore, the level of fat solubility of the solute in the blood determines its ease and speed. The more fat-soluble the solute is, the faster it can enter the brain tissue through the barrier. According to this rule, certain central nervous system drugs can be modified to make it easier to enter the brain tissue in order to exert the effect of the drug faster. For example, barbiturate is a central anesthetic, but its lipophilicity is weak, so it enters the brain tissue slowly. However, if it is transformed into phenobarbital, it has a stronger lipophilicity, so it can be easily entered through the blood-brain barrier The brain tissue quickly exerts its hypnotic anesthetic effect. Another example is the transformation of morphine into diacetylmorphine, which makes it easier to reach the brain tissue through the lipophilic endothelial cell membrane to exert its analgesic effect. Carotenoids are a fat-soluble pigment, but only astaxanthin in the carotenoid family is the only substance that can cross the blood-brain barrier.

Hydrophilicity of the substance

Regardless of positively or negatively charged solutes, when dissolved in water, they form hydrogen bonds with the oxygen atoms of water molecules. The more charges the solute has, the stronger the ability to form hydrogen bonds, and the stronger the water solubility. The worse it is. However, water itself and solutes such as glucose have a small molecular weight and can enter the brain through the junction of endothelial cells and astrocytes. Epinephrine and norepinephrine are difficult to enter the brain through the barrier due to their strong water solubility and high hydroxyl groups. Amino acids can cross the blood-brain barrier, but amines are difficult.

Degree of binding to plasma proteins

Many compounds in plasma are bound to plasma proteins. Small molecule compounds such as hormones do not easily penetrate the blood-brain barrier after binding to plasma proteins, so they cannot exert their physiological effects; they must be released before they can exert their effects through the barrier. For example, thyroxine binds to more than 99% of plasma proteins in plasma and is less than 1% free; thyroxine content in cerebrospinal fluid is low, but similar to free thyroxine in plasma, so it can still meet physiological needs. Free thyroxine can easily enter the interstitial fluid of the brain. Any drug that prevents thyroxine from binding to plasma proteins can increase free thyroxine in the plasma and increase the dose across the barrier.

Carrier operating system

Brain capillary endothelial cells have a variety of carrier proteins that transport blood from the endothelial cells. Carrier proteins have high selectivity. One carrier protein can only transport one substance. The specific carrier protein of cerebrovascular endothelial cells can make it difficult for substances that are difficult to cross the blood-brain barrier to enter the brain quickly. The main energy source of brain tissue metabolism originally passed through the blood-brain barrier slowly, but the glucose carrier can quickly pass through the blood-brain barrier to meet the needs of brain metabolism in time. The carriers that have been confirmed are: hexose carrier, neutral amino acid carrier, basic amino acid carrier, and short-chain monocarboxylic acid carrier, which are all conducive to the proper transport of substances through the blood-brain barrier.

Central transmitters can hardly cross the blood-brain barrier under normal circumstances, which is beneficial to maintaining the stability of central transmitter levels in the brain and eliminating interference from extra-brain stimuli. So it may be related to the enzyme system in brain capillary endothelial cells. It has been found that it contains monoamine oxidase, and many central transmitters are monoamine compounds, such as catecholamine, serotonin, histamine, etc., can be destroyed by monoamine oxidase This kind of biochemical transformation in endothelial cells strengthens the function of the blood-brain barrier, thereby keeping the environment in the brain tissue stable and less disturbed by drastic changes in the content of substances with strong physiological effects in general circulating blood.

Blood brain barrier pathological changes

Diseases of the central nervous system often cause dramatic changes in the structure and function of the blood-brain barrier. As mentioned previously, neonatal jaundice and vascular cerebral edema open tight connections between endothelial cells of brain capillaries, and the permeability of the barrier is significantly improved, so that macromolecular substances such as plasma albumin (molecular weight 69000) are acceptable. Through the barrier. Severe brain injury causes severe damage to the blood-brain barrier, allowing serum proteins to enter the brain tissue through the barrier. With the repair of the damage, the entry of macromolecules into the brain stops first. After the complete recovery, the phenomenon of accelerated exchange of small molecules will disappear, and the blood-brain barrier function is normal at this time. Ionizing radiation, laser, and ultrasound can increase the permeability of the blood-brain barrier.