Blood-brain barrier

The blood-brain barrier is extremely important for the maintenance of brain homeostasis, but many questions concerning its formation are still not fully understood. But already now it is absolutely clear that the BBB is the most pronounced on the differentiation, complexity and density of the histohematological barrier. Its main structural and functional unit is the endothelial cells of the capillaries of the brain.

The metabolism of the brain, like no other organ, depends on the substances coming in with the bloodstream. Numerous blood vessels providing the work of the nervous system are distinguished by the fact that the process of penetration of substances through their walls is selective. Endothelial cells of the capillaries of the brain are connected by continuous continuous contacts, so substances can pass only through the cells themselves, but not between them. Glial cells, the second component of the blood-brain barrier, adhere to the outer surface of the capillaries. In the vascular plexuses of the ventricles of the brain, the anatomical basis of the barrier is the epithelial cells, also tightly connected. At present, the blood-brain barrier is considered not as anatomo-morphological, but as a functional entity that can selectively pass, and in some cases, deliver various molecules to the nerve cells via active transport mechanisms. Thus, the barrier performs regulatory and protective functions

In the brain, there are structures in which the blood-brain barrier is weakened. This is, first of all, the hypothalamus, as well as a number of formations on the bottom of the 3rd and 4th ventricles - the posterior field (area postrema), subfunctional and subcommission organs, and the pineal body. The integrity of the BBB is disturbed by ischemic and inflammatory lesions of the brain.

The blood-brain barrier is considered to be finally formed when the properties of these cells satisfy two conditions. First, the rate of liquid-phase endocytosis (pinocytosis) in them should be extremely low. Secondly, specific dense contacts must form between the cells, for which a very high electrical resistance is characteristic. It reaches values of 1000-3000 Ω / cm ² for capillaries of the soft dura mater and from 2000 to 8000 0m / cm2 for intraparenchymal cerebral capillaries. For comparison: the average value of the transendothelial electrical resistance of capillaries of skeletal muscle is only 20 ohm / cm2.

The permeability of the blood-brain barrier for most substances is largely determined by their properties, as well as by the ability of neurons to synthesize these substances on their own. The substances that can overcome this barrier include, first of all, oxygen and carbon dioxide, as well as various metal ions, glucose, essential amino acids and fatty acids necessary for the normal functioning of the brain. Transport of glucose and vitamins is carried out using vectors. At the same time, D- and L-glucose have different rates of penetration through the barrier - in the first it is more than 100 times higher. Glucose plays a major role in both energy metabolism of the brain and in the synthesis of a number of amino acids and proteins.

The leading factor determining the functioning of the blood-brain barrier is the level of metabolism of nerve cells.

Provision of neurons with the necessary substances is carried out not only with the help of suitable blood capillaries, but also due to the processes of the soft and arachnoid shells over which the cerebrospinal fluid circulates. Cerebrospinal fluid is located in the cavity of the skull, in the ventricles of the brain and in the spaces between the membranes of the brain. In humans, its volume is about 100-150 ml. Due to the cerebrospinal fluid, the osmotic balance of the nerve cells is maintained and metabolic products toxic to the nervous tissue are removed.

The ways of mediator exchange and the role of the blood-brain barrier in the metabolism (on: Shepherd, 1987) 

The passage of substances through the blood-brain barrier depends not only on the permeability to them of the vascular wall (molecular weight, charge and lipophilicity of the substance), but also on the presence or absence of an active transport system.

Stereospecific insulin-independent glucose transporter (GLUT-1), which provides the transfer of this substance through the blood-brain barrier, is rich in endothelial cells of the capillaries of the brain. The activity of this transporter can ensure the delivery of glucose in an amount 2-3 times that required by the brain under normal conditions.

Characteristics of the transport systems of the blood-brain barrier (after: Pardridge, Oldendorf, 1977)

Transportable connections	Primary substrate	Km, mM	Vmax nmol / min * g
Hexoses	Glucose	9	1600
Monocarboxylic acids	Lactate	1.9	120
Neutral amino acids	Phenylalanine	0.12	Thirty
Basic amino acids	Lysine	0.10	6th
Amine	Choline	0.22	6th
Purines	Adenine	0.027	1
Nucleosides	Adenosine	0.018	0.7

In children with the disruption of the functioning of this transporter, there is a significant decrease in the level of glucose in the cerebrospinal fluid and a disruption in the development and functioning of the brain.

Monocarboxylic acids (L-lactate, acetate, pyruvate), as well as ketone bodies are transported by separate stereospecific systems. Although the intensity of their transport is lower than the transport of glucose, they are an important metabolic substrate in newborns and in fasting.

Transport of choline to the central nervous system is also mediated by the carrier and can be regulated by the rate of synthesis of acetylcholine in the nervous system.

Vitamins are not synthesized by the brain and are supplied from the blood by means of special transport systems. Despite the fact that these systems have relatively low transport activity, under normal conditions they can provide the transport of the amount of vitamins necessary for the brain, but their deficiency in food can lead to neurological disorders. Some plasma proteins can also penetrate the blood-brain barrier. One of the ways of their penetration is transcytosis, mediated by receptors. This is how insulin, transferrin, vasopressin and insulin-like growth factor penetrate the barrier. Endothelial cells of the capillaries of the brain have specific receptors for these proteins and are capable of carrying out endocytosis of the protein-receptor complex. It is important that as a result of subsequent events the complex disintegrates, intact protein can be released on the opposite side of the cell, and the receptor is re-embedded in the membrane. For polycationic proteins and lectins, the method of penetration through the BBB is also transcytosis, but it is not associated with the operation of specific receptors.

Many neurotransmitters present in the blood are not able to penetrate the BBB. Thus, dopamine does not have this ability, while L-Dopa penetrates through the BBB using a neutral amino acid transport system. In addition, capillary cells contain enzymes that metabolize neurotransmitters (cholinesterase, GABA transaminase, aminopeptidase, etc.), medicinal and toxic substances, which provides brain protection not only from circulating neurotransmitters, but also from toxins.

GEB also participates in carrier proteins that transport substances from the endothelial cells of the capillaries of the brain to the blood, preventing their penetration into the brain, for example, the b-glycoprotein.

In the course of ontogeny, the transport velocity of various substances through the BBB changes significantly. Thus, the transport speed of b-hydroxybutyrate, tryptophan, adenine, choline, and glucose in newborns is significantly higher than in adults. This reflects the relatively higher need of the developing brain in energy and macromolecular substrates.

[1], [2], [3], [4], [5]