Drugs, from those of the description in this Handbook, penetrating through the hemat and antibiotic barrier: antimicrobial means (antibiotic) of the nifuratel (trading name of McMiror medication) and a number of others.
Do not penetrate: antibacterial agent (antibiotic) amoxicillin (trading names: amoxysar, amoxicillin, amoxicillin in capsules 0.25 g, amoxicillin WATHEM, amoxicillin DS, amoxicillin sodium sterile, amoxicillin Sandoz, amoxicillin-ratiopharm, amoxicillin-ratiopharm 250 Tc, amoxicillin powder For suspension 5 g, amoxicillin tablets, amoxicillin trihydrate, amoxicillin trihydrate (Purimox), amosin of horsoform, gramoks-d, Grumunamox, Damemox, Ospamex, SOLUTAB, HIKCYL, ECOCOL), and others.
| When irritating the nervous cells, the permeability of the cell membrane, as a result of which sodium ions begin to penetrate the fiber inside. The receipt of positively charged sodium ions reduces the electronegability of the curtains of the membrane, the potential difference on the membrane is reduced. Reducing the membrane rest potential is called membrane depolarization. If irritation is strong enough, then the change in the membrane potentials of the threshold value, the so-called critical level of depolarization, resulting in the potential of action. The development of the potential of the action is due to ion currents. At the moment when the peak of the action potential is recorded, an avalanche-like occurrence of sodium ions through the sodium channels of the membrane by the nervous fiber is recorded. Therefore, the inner side of the membrane is temporarily charged positively. Almost simultaneously begins a slow increase in permeability for potassium ions emerging from the cell. High sodium permeability is very short-lived - it lasts the entire share of milliseconds, after which the sodium channels are closed. By this moment, the large amount of potassium permeability reaches. Potassium ions rushed out. In the process of recovery after the potential of action, the work of the sodium-potassium pump provides "pumping" sodium ions to the outside and "pumping" "potassium ions inside, i.e. Returning to the initial asymmetry of their concentrations on both sides of the membrane, which leads to restore the initial level of polarization of the membrane (rest potential). In the action of the irritant on the nerve, the so-called "all-or- nothing" is observed: or the action potential is not at all - the reaction "nothing" ( If the stroke irritation), or the maximum capacity of the potential amplitude is developing - the "All" reaction (if the annoyance is an outgoing). The development of the potential of the membrane completely loses the excitability, i.e. no irritation during this period is not. May cause the development of a new action potential. This state of complete non-confidence is called absolute Ref-racket. As indicated above, the development of the potential of action is associated with an increase in the permeability of the membranender of sodium ions. During the development of the potential of the membrane, the membrane for a short time is inactivated, i.e. it loses the ability to respond to any influence with a new increase in sodium permeability. The inactivation of the membrane eliminates the possibility of re-development of the potential of action. Following the period of absolute refractoriness, it follows a period of relative refractory with T and, when excitable education is capable of responding to excitement (development of the potential of action) only on very strong irritations. Gradually, excitability is restored to a normal level. The refractory property ™ provides, in particular, one-sided carrying pulse through the nervous fiber. The duration of the refractoring period determines the important characteristic of excitable formation (nerve fibers, nerve and muscle cells) - lability (N. E. Intrusion). The lability of excitable education can be characterized by the maximum number of impulses (potentials of action), which it can be reproduced in 1 s. The shorter the refractory period, the higher the lability. |
9. A. Neuromediators and neurogormons Nervous cells control the functions of the body using chemical signals, neurotransmitters and neurogormones. Neurotransmitters - short-lived substances of local action; They are highlighted in the synaptic slit and transmit the signal to neighboring cells. Neurogormons - long-lived long-range substances entering blood. However, the border between the two groups is sufficiently conditional, since most mediators simultaneously act as hormones. Signal substances - neurotransmitters (or neuromodulators) must satisfy the number of criteria. First of all, they should produce neurons and stored in synapses; When the nervous impulse is received, they must be released into the synaptic slit, selectively contact the specific receptor on the postsynaptic membrane of the other neuron or muscle cell, stimulating these cells to their specific functions. B. Chemical structure for chemical properties Neurotransmitters are divided into several groups. The table in the scheme contains the most important representatives of neurotransmitters - more than 50 compounds. The most famous and common neurotiator is acetylcholine, choline ester and acetic acid. Neurotransmitters include some amino acids, as well as biogenic amines formed during amino acid decarboxylation (see Fig. 183). The famous neurotransmitters of purine rows are derivatives of adenine. The largest group form peptides and proteins. Small peptides are often carried at the n-end the residue of glutamic acid in the form of a cyclic pyroglutamate (5-oxoprolin; one-bore code:
10. Amino acids play an important role in the metabolism and the operation of the CNS. This is explained not only by the exceptional role of amino acids as sources of synthesis of a large number of biologically important compounds, such as proteins, peptides, some lipids, a number of hormones, vitamins, biologically active amines. The amino acids and their derivatives are involved in synaptic transmission, in the implementation of internecronal bonds as neurotransmitters and neuromodulators. Their energy significance is also significant for the amino acid of the glutamic group directly associated with the cycle of tricarboxylic acids. Summarizing the exchange of free amino acids in the brain, the following conclusions can be drawn:
1. The great ability of the nervous tissue to maintain the relative constancy of the levels of amino acids.
2. The content of free amino acids in the brain is 8 - 10 times higher than in the blood plasma.
3. The existence of a high concentration gradient amino acids between blood and the brain due to selective active transfer through the BGB.
4. High glutamate, glutamine, aspartic, N-acetylagic acid, and gamke. They make up 75% pool of free amino acids of the brain.
5. The pronounced regional content of amino acids in various brain departments.
6. The existence of compartmentized amino acid funds in various subcellular structures of nerve cells.
7. Aromatic amino acids are of particular importance as predecessors of catecholamines and serotonin.
12. Features of the metabolism of the nervous tissue breathing on the share of the brain accounts for 2-3% of the body weight. At the same time, oxygen consumption by the brain in the state of physical peace reaches 20-25% of the total consumption of it by the whole organism, and in children under 4 years old, the brain consumes even 50% of oxygen, utilized by all organism. On the size of consumption by the brain from the blood of various substances, including oxygen, can be judged by arteriovenous difference. It has been established that during the passage through the brain, the blood loses about 8% by volume of oxygen. In 1 min per 100 g of brain fabric accounts for 53-54 ml of blood. Consequently, 100 g of the brain consumes in 1 min 3.7 ml of oxygen, and the entire brain (1500 g) is 55.5 ml of oxygen. The gas exchange of the brain is significantly higher than the gas exchange of other tissues, in particular it exceeds the gas exchange of muscle tissue almost 20 times. Respiratory intensity for various brain areas of Nonodynakov. For example, the respiratory intensity of the white substance is 2 times lower than the gray (though, in the white substance less cells). Especially intensively consumed oxygen cells of the cortex of the brain and cerebellum. Oxygen absorption by the brain is significantly less with anesthesia. On the contrary, the breathing intensity of the brain increases with increasing functional activity.
No one is secret that the body must maintain the constancy of its inner medium, or homeostasis, spending energy for this, otherwise it will not differ from inanimate nature. So, the skin protects our body from the outside world at the organ level.
But it turns out that other barriers that are formed between blood and some tissues have meaning. They are called histohematic. These barriers are needed for various reasons. Sometimes you need to mechanically limit blood penetration to tissues. Examples of such barriers serve:
- hematoarticular barrier - between blood and articular surfaces;
- hematophthalmic barrier - between blood and blue-conductive media of the eyeball.
Everyone knows, on their own experience, that, separating meat it can be seen that the surface of the joints is always devoid of contact with blood. In the event that the blood is poured into the hollowness of the joint (hemarthrosis), it contributes to its urgent, or ankylose. It is clear why a hematophthalmic barrier is needed: there are transparent media inside the eye, for example, a vitreous body. His task - as little as possible to absorb passing light. In the event that there is no this barrier, the blood will penetrate the vitreous body, and we will be deprived of the opportunity to see.
What is BGB?
One of the most interesting and mysterious histohematic barriers is a hematorencephalic barrier, or barrier between capillary blood and neurons of the central nervous system. Speaking modern, information language, there is a completely "secure connection" between the capillaries and substance of the brain.
The meaning of the hematorecephalic barrier (abbreviation - GEB) is that neurons do not enter into direct contact with the capillary network, but interact with the feeding capillaries through intermediaries. These intermediaries are astrocytes, or neuroglia cells.
Neuroglia is an auxiliary tissue of a central nervous system that performs many functions, such as supporting, maintaining neurons, and a trophic, feeding them. In this case, astrocytes are directly taken from the capillary everything that needs neurons, and transmit them. At the same time they control so that harmful and alien substances do not fall into the brain.
Thus, not only various toxins, but also many drugs, and this is the subject of the study of modern medicine, because every day the number of drugs that are registered for the treatment of brain diseases, as well as antibacterial and antiviral drugs, is increasing .
A bit of history
Famous doctor and microbiologist, Paul Erlich, became a global celebrity, thanks to the invention of Salvarsna, or the drug No. 606, which was the first, let a toxic, but effective drug for the treatment of the solar syphilis. This medicine contained arsenic.
But Erlich also experimented a lot with dyes. He was confident that in the same way as the dye sticks tightly to the fabric (Indigo, Purple, Carmin), he sticks to the pathogenic microorganism, it is only worth finding such a substance. Of course, it should not only firmly fixed on a microbial cell, but also to be fatal for microbes. Undoubtedly, "poured oil into the fire" the fact that he married the daughter of the famous and wealthy manufacturer is a textile service.
And Erlich began to experiment with various and very poisonous paints: aniline and tripanov.
Opening the laboratory animals, he was convinced that the dye penetrates all organs and fabrics, but it does not have the possibility of diffing (penetrating) in the brain, which remained pale.
Initially, his conclusions were incorrect: he suggested that simply the dye was not painting the brain due to the fact that it was a lot of fat, and he repels paint.
And then the discoveries preceding the opening of the hematorecephalic barrier, fell apart from the horns of abundance, and the very idea itself began to gradually be issued in the minds of scientists. The following experiments played the greatest value:
- if you enter the dye intravenously, then the maximum that it is capable of painting is choroidal vascular plexus brain ventricles. Then he is "the way is closed";
- if it is forced to introduce a dye into the liquor, performing a lumper puncture, the brain was painted. However, the dye "out" from the lycvore did not fall, and the remaining tissues remained colorless.
After that, it was quite logical that the lycvore is a liquid that is "on the other side" of obstacles, the main task of which is to protect the central nervous system.
For the first time, the term Gab appeared in 1900, one hundred and sixteen years ago. In English-speaking medical literature, he is called "Blood-Brain Barrier", and in Russian, the name was given in the form of a "hematostephalic barrier".
In the future, this phenomenon was studied quite in detail. Before World War II, there was evidence that there is a hemat and hematoly barrier, as well as a hematoneal version, which is not in the CNS, and is located in peripheral nerves.
Barrier structure and functions
It is from the uninterrupted work of the hematoencephalic barrier depends on our life. After all, our brain consumes the fifth of the entire amount of oxygen and glucose, and at the same time its weight is not 20% of the entire body weight, but about 2%, that is, the body consumption of nutrients and oxygen is 10 times higher than the average arithmetic value.
In contrast, for example, from the liver cells, the brain only works "on oxygen", and aerobic glycoliz is the only possible option of the existence of all neurons without exception. In that case, for 10-12 seconds, neurons are stopped for 10-12 seconds, then a person loses consciousness, and after stopping the blood circulation, being in a state of clinical death, the chances of full restoration of the brain function exist only for 5 -6 minutes.
This time increases with a strong cooling of the body, but at normal body temperature, the final brain death occurs after 8-10 minutes, so only the intensive activity of the BBE allows us to be "in form".
It is known that many neurological diseases develop only due to the fact that the permeability of the blood hematorethelical barrier is disturbed, towards it increase.
We will not go in detail in histology and biochemistry structures that make up the barrier. We only note that the structure of the hematorecephalic barrier includes a special structure of capillaries. The following features are known, leading to the appearance of the barrier:
- dense contacts between endothelial cells lining capillaries from the inside.
In other organs and tissues, the endothelium capillaries were performed "carelessly", and between cells there are large gaps through which the free exchange of tissue fluid with perivascular space occurs. Where the capillaries form a blood hemat and endothelium cells are very tight, and the tightness is not disturbed;
- energy stations - mitochondria in capillaries exceed the physiological need for those in other places, since the hematostephalic barrier requires high energy costs;
- the height of the endothelium cells is significantly lower than in the vessels of another localization, and the number of transport enzymes in the cytoplasm of the cell is significantly higher. This allows you to take a large role in transmembrane cytoplasmic transport;
- the endothelium of the vessels in its depth contains a dense, skeletal-forming basal membrane, to which the outside of astrocytes is adjacent;
In addition to the features of the endothelium, there are special auxiliary cells outside the capillaries - pericitis. What is percitis? This is a cell that can be adjusted to adjust the clearance of the capillary, and if necessary, it may have the functions of macrophage to capture and destroy the harmful cells.
Therefore, without having reached neurons, we can celebrate two hemat and hemattephalic barrier protection lines: The first is the dense compounds of endotheliocytes and active transport, and the second is the macrophage activity of percitis.
Next, the hematorecephalic barrier includes a large number of astrocytes, which constitute the greatest mass of this histohematic barrier. These are small cells that surround neurons, and, by definition, their role can "almost everything".
They are constantly exchanged by substances with endothelium, control the safety of dense contacts, the activity of pericitis and the clearance of capillaries. In addition, cholesterol is needed the brain, but it cannot penetrate the blood into the liquor, nor pass through the hematorencephalic barrier. Therefore, astrocytes take on its synthesis, in addition to basic functions.
By the way, one of the factors of pathogenesis of multiple sclerosis is the violation of the myelination of dendrites and axons. And for the formation of myelin, cholesterol is needed. Therefore, the role of the BEB dysfunction in the development of demyelinizing diseases is established, and is recently studied.
Where there are no barriers
Are there such places in the central nervous system where there is no hemat andtheal barrier? It would seem that it is impossible: so many works were applied to creating several levels of protection against external harmful substances. But it turns out that in some places the BGB is not a single "wall" of protection, and it has holes. They are needed for those substances that are produced by the brain and go to the periphery as teams: these are pituitary hormones. Therefore, there are free plots, just in the pituitary zone, and epiphyse. They exist so that hormones and neurotransmitters can freely penetrate the blood.
There is a different zone free from the BBB, which is located in the area of \u200b\u200bthe diamond pits or the bottom 4 of the brain ventricle. There is a vomit center. It is known that vomiting may occur not only due to mechanical irritation of the rear wall of the pharynx, but also in the presence of toxins in the blood. Therefore, it is precisely in this area that there are special neurons that constantly produce "monitoring" quality blood for harmful substances.
As soon as their concentration reaches a certain amount, these neurons are activated, causing a feeling of nausea, and then vomiting. Justice should be said that it is not always vomiting associated with the concentration of harmful substances. Sometimes, with a significant increase in intracranial pressure (with hydrocephalius, meningitis), the vomit is activated due to direct overpressure in the development of syndrome
By definition of the Stern, (BBB, Blood-Brain Barrier (BBB)) is a combination of physiological mechanisms and corresponding anatomical formations in the central nervous system involved in the regulation of the composition of the cerebrospinal fluid (CSW). This is a definition from the book of Pokrovsky and Know "Human Physiology".
The hematostephalic barrier regulates penetration from blood to the brain of biologically active substances, metabolites, chemicals acting on the sensitive structures of the brain, prevents foreign substances in the brain, microorganisms, toxins.
In ideas about the hematorecephalic barrier, the following is emphasized as the main provisions:
1) the penetration of substances into the brain is carried out mainly not through the liquor paths, but through the circulatory system at the level of capillary - the nerve cell;
2) The hematostephalic barrier is a greater extent with anatomical formation, but a functional concept characterizing a certain physiological mechanism. Like any physiological mechanism existing in the body, the hematostephalic barrier is under the regulatory effect of nervous and humoral systems;
3) Among the governing hematorecephalic barrier factors leading is the level of activity and metabolism of nervous tissue.
The main function characterizing the hematostephalic barrier is the permeability of the cell wall. The required level of physiological permeability, adequate to the functional state of the body, causes the dynamics of admission to the nerve cells of the brain of physiologically active substances.
The permeability of the hematorecephalic barrier depends on the functional state of the body, the content in the blood of mediators, hormones, ions. The increase in their blood concentration leads to a decrease in the permeability of the hematorecephalic barrier for these substances.
Histological structure
The functional diagram of the hematorecephalic barrier includes along with the histohematic barrier neurogly and the system of likvarny spaces. The histagematic barrier has a double function: regulatory and protective. The regulatory function ensures the relative constancy of the physical and physicochemical properties, the chemical composition, the physiological activity of the intercellular environment of the organ, depending on its functional state. The protective function of the histohematic barrier is to protect the organs from the receipt of alien or toxic substances of the endo and exogenous nature.
The leading component of the hematorecephalic barrier providing its function is the wall of the brain capillary. There are two mechanisms for penetration of the substance in brain cells:
- through a cerebrospinal fluid that serves as an intermediate link between blood and nervous or glial cell, which performs the nutritional function (the so-called liquor path)
- through the wall of the capillary.
In an adult organism, the main means of the substance in the nerve cells is hematogenic (through the walls of the capillaries); The liquor path becomes auxiliary, optional.
The morphological substrate of the BEB are the anatomical elements located between blood and nerve cells (the so-called inter-endothelial contacts, covering the cell in the form of a close ring and preventing the penetration of substances from capillaries). The processes of glial cells (end legs of astrocytes) surrounding the capillary are tightened by its wall, which reduces the filtration surface of the capillary, prevents the diffusion of macromolecules. According to other ideas, clay processes are channels capable of selectively extracting from the blood flow of the substance necessary for the nutrition of nerve cells, and return their exchange products into the blood. The so-called enzyme barrier is given important in the GEB function. In the walls of the brain microsuds surrounding their connective tissue stroma, as well as in vascular plexus, enzymes that contribute to neutralization and the destruction of the substances coming out of the blood are detected. The distribution of these enzymes is not the same in capillaries of different structures of the brain, their activity varies with age, in the context of pathology.
Functioning Gab
The basis of the functioning of the BEB is the processes of dialysis, ultrafiltration, osmosis, as well as the change in electrical properties, solubility in lipids, tissue affinity or metabolic activity of cell elements. An important value in operation is attached to an enzyme barrier, for example, in the walls of the brain microsudes and their surrounding strass (the hematoreencephalic barrier) - the high activity of enzymes - cholinesterase, carbaneshydrase, dof-decarboxylase, etc. These enzymes, breaking some biologically active substances, prevent them penetration into the brain.
Water soluble molecules cannot freely diffuse between blood and CCS due to impermeable rigidly related compounds between epithelial cells of vascular plexuses, instead epithelial cells carry certain molecules on one side of the barrier to another. As soon as molecules fall into the CSC, they diffuse through the "flowing" epithelial layer and reach an interstitial fluid surrounding neurons and glial cells. 
1.Nestelial cell
2. Conduct connection
3.Sebral capillary
4.Namer
5. Glucose
6. Interstial liquid
7. Glial cell
8.Endime layer
1. Heoroidal plexus, epithelial cell
2. Capillary
3. Conductive connection
4.Endime layer
Epithelial cells carry certain capillar molecules inside the brain ventricles. The flow of ions crossing the GEB (blood-csu) is regulated by several mechanisms in vascular plexus: 
1. Calibular vessel (plasma)
2. Baselateral (bottom block) surface
3.Pitelial cell vascular plexus
4.Lest communication
5. A ferrics
6.Apical (top) surface
7. SMG in the ventricle
8. Ion exchange
Water molecules in epithelial cells are dissociated on hydrogen ions and hydroxyl ions. Hydroxyl ions are combined with carbon dioxide, which is a product of cell metabolism. On the surface of baso-cell cells, hydrogen ions are exchanged for extracellular sodium ions from plasma. In the ventricles of the brain ions sodium are actively transferred through the apical surface of the cell (the top). This is accompanied by a compensatory movement of chloride and bicarbonate ions in the CES. To maintain osmotic equilibrium, water moves into the ventricles.
Permeability and regulation of BEB
BEB view as a self-regulating system, condition
which depends on the needs of nerve cells and the level of metabolic
processes not only in the very brain, but also in other organs and tissues
organism. The permeability of the BGB is non-etinakov in different brain departments,
Selective for different substances and is regulated by nervous and humoral
mechanisms. An important role in the neurohumoral regulation of the GEB functions
belongs to a change in the intensity of metabolic processes in the tissue
brain, which is proved by the oppressive effect of metabolic inhibitors
processes for the vehicle speed of amino acids in the brain and stimulation of them
Absorption of oxidation substrates.
The regulation of the functions of the hematorecephalic barrier is carried out by the highest sections of the CNS and humoral factors. A significant role in the regulation is given by the hypothalamic-pituitary adrenal system. With different types of cerebral pathology, such as injuries, various inflammatory lesions of the brain tissue, there is a need to artificially reduce the level of permeability of the hematorecephalic barrier. Pharmacological effects can be increased or reduced to the brain penetration of various substances administered from outside or circulating in the blood. Penetration into the brain in the region of the hypothalamus, where BGB "is breaking", various pathological agents are accompanied by a variety of symptoms of violations of the autonomic nervous system. There are numerous evidence of a reduction in the protective function of the BEB under the influence of alcohol, under the conditions of emotional stress, overheating and supercooling the body, the effects of ionizing radiation, etc. At the same time, the ability of some drugs, such as Pentamine, etopal sodium, vitamin p to reduce penetration In the brain of certain substances.
BEB is a brain protection system from external damaging factors. As mentioned above, in injuries, pathological processes, it may violate. In addition, some microbes produced highly specialized mechanisms (so far poorly studied) overcoming this barrier. It is known that rabies viruses and simpleness viruses (in humans) and Reorovirus (experimental animals) fall into the central nervous system, moving around the nerves, and encapsulated bacteria and mushrooms have surface components that allow them to pass through the hematorecephalic barrier.
Thus, the mechanisms to overcome the hematostephalic barrier are highly specificized. So, they are available only in certain serotypes of pathogens who can cause meningitis. Meningitis of newborns, for example, causes only those Streptococcus Agalactiae, which relate to Serotype III. Other serotypes are also pathogenic, but cause infectious processes outside the CNS. Such selectivity is apparently determined by the spatial structure of the Capsule Polysaccharide of Serotype III, since the capsule polysaccharides of other serotypes contain the same components, but have a different spatial structure.
The BCP operates as a selective filter that passes into the cerebrospinal fluid of some substances and non-transmitting others, which can circulate in the blood, but alien brain tissue. So, do not pass through the Gab adrenaline, norepinephrine, acetylcholine, dopamine, serotonin, gamma-amine-oil acid (gamc), penicillin, streptomycin.
Bilirubin is always in the blood, but never, even during jaundice, it does not go into the brain, leaving the nervous tissue unpainted. Therefore, it is difficult to obtain an effective concentration of any medicinal product so that it reaches the parenchyma of the brain. Pass through the Gab morphine, atropine, bromine, strikhnin, caffeine, ether, urethane, alcohol and gamma-hydroxyma salted acid (GOMK). In the treatment, for example, tuberculous meningitis, streptomycin is administered directly into the cerebrospinal fluid, bypassing the barrier using a lumbar puncture.
It is necessary to take into account the unusual of the action of many substances introduced directly into the cerebrospinal fluid. Trypan blue when administered to a cerebrospinal fluid causes convulsions and death, a similar effect has bile. Acetylcholine, introduced directly to the brain, acts as adrenaline (similar to adrenaline), and adrenaline, on the contrary, as a cholinomimet (similar to acetylcholine): Blood pressure drops, bradycardia occurs, the body temperature is at first decreased, and then rises.
It causes a narcotic sleep, inhibition and analgesia. Ions K + act as sympathomimetics, and Ca2 + - parasympathomimetics. Lobelin is a reflex stimulator of breathing, penetrating through the BC, causes a number of adverse reactions (dizziness, vomiting, cramps). Insulin at intramuscular injections reduces blood sugar content, and with direct introduction to the cerebrospinal fluid - increases.
All medicines produced in the world are divided into penetrating and penetrating over the BC. This is a big problem, some drugs should not penetrate (but penetrate), and some are the opposite, should penetrate to achieve the therapeutic effect, but may not because of their properties. Fumakologists are engaged in resolving this problem with the help of computer modeling and experimental studies.
Gab and aging
As mentioned above, one of the most important parts of Gab- astrocytes. The formation of the GEB is their main function in the brain.
The problem of transformation of cells (WG) to star astrocytes in
Postnatal development period underlies astrocytic theory
aging mammals.
There is the disappearance of embryonic radial cell migration pathways
from the place of their proliferation to the places of their final localization in the brain
adult individuals, which is the cause of postmotatic brain
mammals. The disappearance of the RG induces a whole cascade of systemic
processes that are named as an age-dependent mechanism
mammalian self-destruction (MVSM). The disappearance of the cells of the RG does
Its impossible to replace the neurons exhausted their life resource
(Boyko, 2007).
The age changes have not yet been studied completely. Atherosclerosis, alcoholism and other diseases are played by damage to the GEB. In case of insufficient operation of the BGB, cholesterol penetration and apolipoprotein in the brain tissue begins, which leads to greater damage to the BGB.
Perhaps studied the age-related geb changes, scientists will be able to approach the rays of the aging problem.
Gab and Alzheimer's disease
The aging of the brain and neurodegenerative diseases are associated with oxidative stress, impaired maintenance of metals and inflammation, and the GEB plays a latter role. For example, glycosylated protein receptors (RGB) and protein-1 associated with low density lipoprotein receptors (P1-RLP) built into the BC structure play a major role in the regulation of beta-amyloid exchange in the CNS, and the change in the activity of these two receptors can contribute The accumulation of beta-amyloid in the central nervous system, with the subsequent development of inflammation, impaired balance between brainwater and metabolism, a change in synaptic transmission, damage to neurons and the deposition of amyloid in the parenchyma and brain vessels. And as a result of Alzheimer's disease. The accumulation of apolipoprotein in perivascular (by the near) space-key moment in the development of this terrible disease, which is distributed with a greater speed and is already striking persons under 40 years old. On the role of apolipoprotein and damage to astrocytes, German authors are written under the direction of Dr. Dietmar R. Thal from Department of Neuropathology, University of Bonn.
In addition, some researchers believe that Alzheimer's disease can also be an autoimmune nature and the penetration of cerebral protein into the bloodstream through a deficient BC. In the vascular system, antibodies, attackers of the brain, are formed during a re-transition through the barrier.
Many scientists bind the development of neurodegenerative diseases and maintaining nerve stem cells with ABC Transporters- ATF-binding conveyors. ABCB family of these conveyors was found in the BC. In the recent article of the research team under the guidance of Professor Jens Pahnke from Neurodegeneration Research Laboratory (NRL), Department of Neurology, University of Rostock discussed accumulated data. Scientists believe that, thanks to the study of the role and operation of ABC Transporters, the pathogenesis of Alzheimer's disease can be deeper, to create new approaches in therapy and mathematical methods for calculating risk.
In April 2008, a message from Jonathan Geiger appeared in BBC News 
From University of North Dakota that the daily use of one cup of coffee per day strengthens the hematoencephalic barrier, protecting the brain from the harmful effects of cholesterol. Researchers under the guidance of Jonathan Geiger fed rabbits with high cholesterol. In addition, some animals received water containing 3 mg of caffeine (which is equivalent to one cup of coffee). After 12 weeks, the rabbits who received caffeine, the hematoencephalic barrier turned out to be much stronger than their fellows who used ordinary water, said Geiger. Histological study of the brain of rabbits showed an increase in the activity of astrocytes - the cells of the microglia of the brain, as well as a decrease in the permeability of the BGB. New data I can help in the fight against Alzheimer's disease, in which there is an increase in the level of cholesterol in the blood of patients and, as a result, the destruction of the Gab, scientists believes.
An ionoforms of 8-hydroxy-chinoline (PBT2), which act on the metal-induced aggregation of the amyloid, may become another tool from Alzheimer's disease. About this in 2006, scientists from Department of Chemical and BioLogical Engineering, University of Wisconsin-Madison, under the leadership of Eric V. Shusta, demonstrated the ability of nerve stem cells of the rats of rats to stimulate the acquisition of blood vessels of the blood vessels of the properties of the hematorecephalic barrier.
The work used brain stem cells grown in the form of neurosphere. Such cells synthesize factors, the effect of which on endothelial cells, linked the inner surface of the vessels of the brain, causes them to form a dense barrier that does not transmit small molecules, usually fluently penetrating through the vascular wall.
The authors note that the formation of such a ridiculous hematorencephalic barrier occurs even with the complete absence of astrocytes - cells that ensure the maintenance of the structure and functioning of the structures of the brain, including the hematorecephalic barrier, but appearing in large quantities after birth.
The fact that developing brain cells stimulate the conversion of endothelial cells into the cells of the hematorecephalic barrier, not only sheds light on mechanisms that ensure brain safety. The authors plan to create a similar model of the hematostephalic barrier using human endothelial and nerve stem cells. If their attempts are crowned with success, then the pharmacology researchers in the near future will appear the functioning model of the human hematorencephalic barrier, which helps in overcoming obstacles on the paths of neurobiologists, doctors and drug developers trying to find ways to deliver to the brain of certain drugs.
Finally
In conclusion, I would like to say that the hematorencephalic barrier is an amazing structure that protects our brain. There are now many research of BEB, they mainly lead to pharmacological companies and these studies are aimed at determining the permeability of the BGB for various substances, mainly candidates for the role of drugs from certain diseases. But this is not enough. A terrible age age-associated disease is connected with the permeability of the BCB. Alzheimer's disease. The aging of the brain is connected with the permeability of the BBE. The aging of the GEB leads to the aging of other brain structures, and metabolic changes in the aging brain lead to changes in the functioning of the BGB.
You can select several tasks for researchers:
1)
Determination of the permeability of the BGB for various substances and the analysis of accumulated experimental data is to create new drugs.
2) Research of age-related BBC changes.
3) Studying the possibilities of regulating the functioning of the BGB.
4) Study of the role of changes in the BGB in the emergence of neurodegenerative diseases
The studies of these issues are needed, because Alzheimer's disease is "youth." Maybe I have learned how to properly adjust the functional state of the BEB, learning to strengthen it, having learned to understand the deep metabolic processes in the brain, scientists will finally find funds from age-associated brain diseases and
aging ...
M.I. Savelyeva, E.A. Sokova
4.1. General ideas about the distribution of medicines and communication with blood plasma proteins
After receiving access to systemic blood flow through one of the routes of administration, xenobiotics are distributed in organs and tissues. A series of physical and physiological processes that occur simultaneously depend on the physicochemical properties of drugs and thereby form various ways to distribute them in the body. Examples of physical processes are simple dilution or dissolution of the drug in intracellular and extracellular fluids. Examples of physiological processes - binding to plasma proteins, the availability of tissue channels and penetration of the drug through various barriers to the body. The distribution of drugs may affect the following factors:
Blood flow;
The degree of binding with plasma proteins;
Physico-chemical features of drugs;
Degree (depth) and the length of the penetration of drugs through physiological barriers;
The degree of elimination, due to which the drug is continuously removed from the body, and which constitutes the competition to the phenomenon of the distribution.
Bloodstock
Bloodstock- The volume of blood reaching a certain area in the body per unit of time. The ratio volume / time and the value of blood flow in different fields of the body differ. Full blood flow is 5000 ml / min and corresponds to cardiac bandwidth at rest. Cardic capacity(minute of heart) - blood volume, pumped out in one minute. In addition to the minute of the heart, there is such an important factor as the blood volume in various parts of the systemic circulation. The middle heart contains 7% of the total blood volume, the light system is 9%, the arteries - 13%, arterioles and capillaries - 7%, and veins, venous and the whole venous system - the remaining 64%. Through the permeable walls of the capillaries, there is an exchange of drugs, nutrients and other substances with an interstitial liquid of organs / tissues, after which the capillaries merge with venules, which gradually converge into large veins. As a result of the transcapillary metabolism, the drug due to the difference in pressure (osmotic and hydrostatic pressure) between the inner and the outer part of the capillary or the concentration gradient is transported through the capillary wall into the tissue. Delivery of xenobiotic to those or other areas of the body depends on the rate of blood flow and the place of administration of the drug.
The bloodstream is the main factor in the distribution of drugs in the human body, while the concentration gradient plays a minor role (or does not participate at all) in the mass delivery of the drug to organs and tissues. The blood flow significantly determines the rate of delivery of drugs to a certain area of \u200b\u200bthe body and reflects the relative growth rate of the concentration of xenobiotic, in which the equilibrium is established between the organ / cloth and blood. The amount of LS preserved or distributed in tissue depends on the size of the tissue and the physicochemical features of the drug, the separation coefficient between the organ / cloth and blood.
Phenomenon limiting blood flow(distribution bounded by perfusion; limited transmission phenomenon; distribution limited by permeability) - the dependence of the transcapillary exchange
and storage of the drug in tissue from the physicochemical features of the drug.
Transcapillary effects of drugs limited to perfusion
In order to differentiate between two types of distribution, assume that the capillary is a hollow cylinder with a length L.and radius R. , in which blood flows at the rate ν in the positive direction x.Concentration of the drug in the fabric around the capillary - C fabric, and blood concentration - C blood. The drug passes through
the capillary membrane at the expense of the concentration gradient between blood and cloth. Consider a plot or segment of the direction between h.and x + dx,where the difference in the mass of the flow of the drug between the beginning and end of the segment dX.equally the mass of flow through the capillary wall. We write equality in the following form (4-1):
that equation (4-4) will take the form:
Flow weight through the capillary wall into the fabric - J fabricin express
clean weight thread leaving the capillary on a certain length L.(4-6):
By making the transformation of equation (4-6) using equation (4-5), we obtain:
Find capillar clearance:
Capillary clearance - blood volume from which xenobiotic applies to fabric per unit of time. Extraction relation (retrieval ratio) distribution:
Equation (4-9) can be transformed:
Equation (4-10) shows that the ratio of the extraction expresses the balancing fraction between the concentration of the drug in the tissue, arterial capillaries, on the venous side of the capillaries. Compare equations (4-5) and (4-10) we obtain that the capillary clearance is equal to the blood flow multiplied by the removal ratio.
Consider the distribution limited by diffusion (or distribution bounded by the patency). For Q\u003e PS.or C artery≈ C Vienna
the drug is weakly philic and the remission ratio is less than a unit, and the distribution of the drug is limited to a very fast diffusion through a capillary membrane. We define the mass transfer of the drug into the fabric:
The driving force for the transfer of xenobiotic to the fabric is a concentration gradient. Consider the distribution bounded by perfusion (or distribution limited by blood flow). For Q.
with the concentration of the drug on the venous side of the capillaries, and the drug is very lipophilic. The ratio of the extraction is equal to either close to one, and therefore the absorption of the drug with a tissue is thermodynamically much more profitable than its presence in the blood, and the distribution is limited only by the rate of delivery of the drug into the tissue. As soon as the drug reaches the tissue, it is immediately absorbed. We define the mass transfer of the drug into the fabric:
Binding of drugs with proteins
The binding of drugs with plasma proteins significantly affects their distribution in the body. Small LS molecules associated with proteins can easily penetrate barriers. In this regard, the distribution of xenobiotic associated with the protein will differ from the distribution of an unbound drug. The interaction of FF functional groups with membrane or intracellular receptors may be short. Protein binding not only affects the distribution of the drug in the body, but also affects the therapeutic result. Therefore, it is necessary to use the concentration of the free preparation in the plasma for pharmacokinetic analysis, regulating the dosing mode and the optimal therapeutic effect.
Protein binding of drugs used in conjunction with other drugs may differ from drugs taken separately. Changes in protein binding is the result of replacing one drug to others in a complex with plasma proteins. Such a substitution can also occur at the cellular level with other proteins and fabric enzymes. The substitution causes an increase in the free fraction of the drug in the plasma and its accumulation in the receptor sections is proportional to the concentration of the drug. It is important to adjust the dosing mode of drugs when they are jointly administered. The change in protein binding of drugs is an important problem, especially for drugs with a narrow therapeutic range.
Plasma proteins that are involved in the interaction between protein and drug
Albumen- The main plasma protein and tissues responsible for binding to drugs, which is synthesized exclusively by hepatocytes of the liver. Molecular weight of albumin - 69 000 DA; The life of the half-life is approximately 17-18 days. The protein is mainly distributed in the vascular system and, despite the large molecular size, it is additionally distributed in an ex-ravascular zone. Albumin possesses negatively and positively charged areas. The drug interacts with albumin at the expense of hydrogen bonds (hydrophobic binding) and Wan der Waltz forces. Some factors that have a significant impact, for example, pregnancy, surgery, age, inter-ethnic and racial differences - can affect the interaction of drugs with albumin. The kidneys are not filtered albumin, and therefore drugs that are associated with albumin are also not filtered. The degree of binding affects not only the distribution of the drug, but also on the renal elimination, the metabolism of the drug. Only a free drug can be captured by hepatocytes of the liver. Therefore, the greater the percentage of the protein associated with the drug, the lower the liver absorption and level of metabolism of the drug. As mentioned earlier, the degree of drug binding with albumin plasma can also be significantly changed by the introduction of other drugs, which replace the main drug, resulting in the concentration of the free preparation in the plasma.
Other plasma proteins are fibrinogen, globulins (γ- and β 1-Globulin - transferer), ceruloplasmin and α- and β-lipoproteins. Fibrinogen and its polymerized form of fibrin are involved in the formation of blood clots. Globulins, namely, γ-globulins - antibodies interacting with certain antigens. Transferin is involved in the transport of iron, Cerulululzmin is involved in the transmission of copper, and α- and β-lipoproteins - couriers of fat-soluble components.
Evaluation of protein binding parameters
The binding of drugs with plasma proteins is usually determined in the test tube under physiological conditions of the pH and body temperature. Definition methods - equilibrium dialysis, dynamic dialysis, ultrafiltration, gel filtration chromatography, ultracentric
fugging, microdialism and several new and fast-growing methodologies for high bandwidth experiments. The goal is to estimate the concentration of the free drug in equilibrium with the protein complex and the drug. The selected methodology and experimental conditions should be such that the stability of the complex and equilibrium is preserved, and the concentration of the free drug was not overvalued due to too fast destruction of the complex during the measurement. After that, most of the complexes of the drug with a protein are kept together due to weak chemical interaction, electrostatic type (van der Waltz strength), and hydrogen binding tends to separation with elevated: temperature, osmotic pressure and non-physiological pH.
The usual plasma dialysis method, or a protein solution with pH 7.2-7.4 is not effective at different concentrations of the drug. The mixture after dialysis becomes isotonic together with NaCl [at 37 ° C through the dialysis membrane with molecular abbreviations of approximately 12,000-14,000 DA against the equivalent volume of phosphate buffers (≈67, pH 7.2-7.4)]. The dialysis membrane in the form of a bag containing protein and the drug is placed in a buffer solution. A modified version of the bag has been manufactured by the factory method, which are separated by dialysis membrane. Equilibrium of a free preparation passing through the membrane is usually achieved in approximately 2-3 hours. The concentration of the free drug is measured on the buffer side, i.e. Outside the bag or separation, separated by the membrane, which should be equal to the concentration of free preparation inside the bag or separation; The concentration of the free preparation in the bag should be equilibrium with a drug attached to the protein. During dialysis, an albumin solution is used or a pure plasma sample containing albumin. The binding parameters of the drug is a free fraction or an associated constant, which can be determined using the law action law:
where To A.- Constant Association; C D.- concentration of free drug in molecules; C pr.- protein concentration with free areas of attachment; C DP.- concentration of the complex of the drug with protein; k 1.and k 2 - the constants of the level of direct and reverse reactions,
respectively. Reciprocal connections are constant and known as dissociation of constants (4-14):
The magnitude of the associated constant To A.represents the degree of binding the drug with protein. Preparations that bind to plasma proteins extensively usually have a large constant of the association. Based on equation (4-14), it is possible to determine the concentration of the complex of the drug with protein:
If the concentration of the general protein (C) at the beginning of the experiment in the tube is known, and the concentration of the drug complex with protein (C) is estimated experimentally, then you can determine the concentration of free protein (With PR),equilibrium with complex:
Replacing equation (4-15) by equation (4-16) for With pr.leads:
We transform equation (4-18):
When establishing C DP./ With Pt.(The number of moles of the attached drug on the mole of protein for equilibrium) is equal to R, i.e. r \u003d C DP/ With PT, then equation (4-19) will be modified:
When multiplying equation (4-20) on n (N.- The number of areas of attachment to the mole of protein) obtain the Langmura equation:
Langmura Equation (Langmuir) (4-21) and schedule r.vs C D.leads to hyperbolic isotherm (Fig. 4-1). Simplifies equation (4-21). Take the Langmura equation (4-21) in the opposite form. Double reciprocal equation (4-22) shows that the 1 / R vs. 1 / C D is linear with a slope equal to 1 / NK aand intersection point over the ordinate 1 / n. (Fig. 4-2):
Fig. 4-1.Isothermary of Langmura. Along the axis of the ordinate - the number of poles attached to the mole of protein; on the abscissa axis - the concentration of free drug
By conversion of equation (4-21), two variants of the linear equation can be obtained:
Skatchard schedule (ScatcharD) describes the relationship between r / C Dand r.as a straight line with an inclination equal to associative constant To A.(Fig. 4-3). Point of intersection with axis h.equal to the number of related plots n, the intersection point with the axis w.equal pC a ..
In addition, equation (4-21) can be rebuilt to provide rectilinear relations in terms of the concentrations of the free and associated drug:
Fig. 4-2.Double reciprocal clot graph
Equation (4-21) shows the relationship between the reciprocal r.(moths of the associated drug on the mole of protein) and C D.
Fig. 4-3.Linear CDP / CD graph (the ratio of related areas to the free preparation) against CDP (concentration of the associated drug)
(free drug concentration). Point of intersection with axis w.- reciprocal from the number of related sites on the mole of protein, and the attitude of the inclination to the intersection point w.- Associative equilibrium constant.
Schedule C DP / C D vs C DP. -
line with an inclination equal to -K and and point of intersection along the ordinate axis nKC PT.This equation is used if the protein concentration is unknown. Evaluation K A is based on the concentration of the drug measured in the buffer compartment. The definition of a drug associated with a protein is based on the estimate of the free fraction
Skatchard schedule (SCATCHARD) (Fig. 4-4) is a straight line (for one type of linked sites).
Langmura equation for several types of related sites:
where N 1 and to A1 are the parameters of the same type of identically connected sites; N 2 and to A2 - the parameters of the second type of identically connected sites and so on. For example, the residue of aspartic or glutamic acid, -coo -, may be one type of associated area, A -S - - the remainder of cysteine \u200b\u200bor -NH 2 ± - the residue of the histidine is the second type of bound area. When the drug has affinity with two types of related sites, then the schedule
Fig. 4-4.Skatchard schedule
Skatchard r / D.vs r.it is not a straight line, but a curve (Fig. 4-5). The extrapolation of the initial and finite linear segments of the curve leads to direct lines that correspond to the equations:
Fig. 4-5.Skatchard schedule
Skatchard graph represents binding to protein of two different classes of plots. Curve represents the first two elements
equations (4-26), which are defined as straight lines - the continuation of linear segments of the initial and finite parts of the curve. Line 1 represents high affinity (affinity) and low capacity of bonding sites, and Line 2 is low affinity and high capacity of linking sites.
When the affinity and capacity of two binding sections are different, then the line with a larger intersection point w.and a smaller point of intersection h.determines the high affinity and low capacity of the plots, while the line with a smaller point of intersection w.and greater intersection point h.determines low affinity and high capacity of linking sites.
4.2. Penetration of medicines through histohematic barriers
Most of the drugs after absorption and ingress of blood are distributed in different organs and fabric unevenly and it is not always possible to achieve the desired concentration of the drug in the target organ. A significant impact on the nature of the LS distribution is provided by histohematic barriers that are found on the path of their distribution. In 1929, Academician L.S. Stern for the first time at the International Physiological Congress in Boston reported on existence in
the organism of physiological protective and regulating histohematic barriers (GGB). It has been proven that the physiological histohematic barrier is a complex of the most complex physiological processes occurring between blood and tissue fluid. GGB regulates flow from blood to organs and fabrics necessary for their activities substances and timely elimination of finite products of cell metabolism, ensure the constancy of the optimal composition of the tissue (extracellular) fluid. At the same time, the GGB prevent foreign substances from the blood to organs and tissues. A feature of GGB is its selective permeability, i.e. The ability to skip some substances and delay others. Most researchers recognize the existence of specialized physiological GBBs that are important for the normal life of individual organs and anatomical structures. These include: hematostefalic (between blood and central nervous system), hematophthalmic (between blood and intraocular fluid), hematolybile (between blood and endolymph of the labyrinth), barrier between blood and gender glands (gematic, hematotestistic). "Barrier" properties that protect developing fruits, has a placenta. The main structural elements of histohematic barriers are the endothelium of blood vessels, the basal membrane, which includes a large number of neutral mucopolysaccharides, the main amorphous substance, fibers, etc. The structure of GGB is determined largely by the characteristics of the structure of the body and varies depending on the morphological and physiological characteristics of the organ and tissue.
Penetration of medicines through the hematostephalic barrier
The main interfaces between the central nervous system and peripheral blood circulation are the hematorecephalic barrier (GEB) and hematolic vast barriers. The surface area of \u200b\u200bthe BEB is approximately 20 m 2, and a thousand times the area of \u200b\u200bthe hematolic vehicle barrier is thousands, so the BGB is the main barrier between the central nervous system and the systemic circulation. The presence of a BEB in brain structures separating circulation from an interstitial space and prevents the admission of a number of polar compounds directly into the parenchyma of the brain, determines the features of the drug thera
fDI neurological diseases. The permeability of the BGB determine the endothelial cells of the brain capillaries, which have epithelial-like, high-essential dense contacts, which eliminates the paracellular paths of fluctuations of substances through the BGB, and the penetration of drugs in the brain depends on the transcellular transport. The glial elements lining the outer surface of the endothelium and obviously playing the role of an additional lipid membrane are also determined. Lipophilic drugs are mainly easily diffundated through the GEB, as opposed to hydrophilic drugs, the passive transport of which is limited to high-essential dense endothelocyte contacts. The determining value in penetration through the blood-imatelacy barrier has a solubility coefficient in fats. A typical example is common anesthetics - the speed of their narcotic effect is directly proportional to the solubility coefficient in fats. Carbon dioxide, oxygen and lipophilic substances (which include most of the anesthetics) easily pass through the BC, while for most ions, proteins and large molecules (for example, mannitol) it is practically impervious. In the capillaries of the brain there is practically no pinocytosis. There are other ways of penetration of compounds through the BGB, indirectly through the receptor, with the participation of specific carriers. It was shown that specific receptors for some of the circulating peptides and plasma proteins are expressed in brain capillary endothelium. The peptide receptor system of the BEB includes receptors for insulin, transferrin, lipoproteins, etc. The transport of large protein molecules is provided by their active grip. It has been established that the penetration of drugs and compounds into the brain can be carried out by active transport with the participation of active "pumping" and "pumping" transport systems (Fig. 4.6). This makes it possible to control the selective LS transport via the BC and limit their non-selective distribution. The discovery of "pumping" conveyors - glycoprotein-P (MDR1), conveyors of a family of proteins associated with multiple drug resistance (MRP), breast cancer resistance protein (BCRP) has made a significant contribution to the understanding of the LS transport via Gab. It was shown that glycoprotein-p limits the transport of a number of substances in the brain. It is located on the apical part of endothelocytes and excrete from the brain into the clearance of vessels of predominantly hydrophilic cathiology
Fig. 4.6.Transporters involved in LS transport via Gab (Ho R.h., Kim R.B., 2005)
lS, for example, cytostatics, antiretroviral drugs, etc. The value of the glycoprotein-P in limiting the LS transport via BEB can be demonstrated by an example of a loperamic, which, according to the mechanism of action on the gastrointestinal receptors, is a potential opioid drug. However, the effects on the CNS (Euphoria, the oppression of breathing) are absent, since Loperamide, being a substrate of Glycoprotein-P, does not penetrate into the central nervous system. In the presence of an inhibitor mDRLcynidine, the central effects of Loperamide are growing. Conveyors from the MRP family are located either in the basal or on the apical part of endothelocytes. These conveyors remove glucon, sulfated or glutathionized LS conjugates. The experiment found that the MRP2 protein of multiple drug stability is involved in the operation of the BC and limits the activity of anti-epileptic drugs.
In the endothelocytes of brain capillaries, some members of the family of organic anions (OAT3) family of conveyors are expressed, which also play an important role in the distribution of a number of LS in the central nervous system. LS-substrates of these conveyors are, for example, fexofenadine, indomethacin. The expression of polypeptide isofections transporting organic anions (OAT1A2) in BEB is important for the penetration of LS into the brain. However, it is believed that the expression of "pumping" conveyors (MDR1, MRP, BCRP) is the cause of limited pharmacological access of the LS into the brain and to other fabrics when the concentration may be lower than that need to achieve the desired effect. Significant
the amount of mitochondria in the endothelium of the brain capillaries indicates the ability to maintain energy-dependent and metabolic processes available for the active transport of LS via the BGB. In endothelial cells of the brain capillaries, enzymes capable of oxidation, conjugation of compounds for the protection of the cells themselves and the brain respectively from possible toxic effects were discovered. Thus, there are at least two reasons that limit the admission of drugs in the CNS. First, it is the structural features of the BC. Secondly, the BGB includes an active metabolic system of enzymes and the system of "pumping" conveyors, which forms a biochemical barrier for most xenobiotics. This combination of the physical and biochemical properties of the Hab endothelium prevents the proceed in the brain more than 98% of potential neurotropic LS.
Factors affecting the transport of LS in the brain
Pharmacodynamic effects of endogenous substances and diseases affect the function of the BGB, leading to changes in LS transport to the brain. Various pathological conditions may disrupt the permeability of histohematic barriers, for example, with meningoencephalitis, the permeability of the blood-behaneencephalic barrier increases sharply, which causes various kinds of disturbance of the integrity of the surrounding tissues. An increase in the permeability of the BEB is observed in multiple sclerosis, alzheimer's disease, dementia in HIV-infected patients, encephalitis and meningitis, with elevated arterial pressure, mental disorders. A significant amount of neurotransmitters, cytokines, chemokines, peripheral hormones, the effects of active forms of 2 are capable of changing the functions and permeability of the BGB. For example, histamine, affecting H 2 -receptors facing the lumen of the part of the endothelial cells, increases the permeability of the barrier for low molecular weight substances, which is associated with a violation of dense contacts between epithelial cells. The permeability of histohematic barriers can be changed to the direction of use in the clinic (for example, to increase the efficiency of chemotherapeutic drugs). Reducing the barrier functions of the GEB due to the violation of the structure of dense contacts is used to deliver the LS to the brain, for example, the use of mannitol, urea. Osmotic "opening" of BEB allows for patients with primary lymphoma
brain and glioblastoma increase in transport in the brain for a limited period of cytostatic time (for example, methotrexate, prokarbazin). A more sparing effect on the BGB is its "biochemical" opening based on the ability of prostaglandins, inflammation mediators increase the contagion of the brain vessels. A fundamentally different possibility of increasing the delivery of drugs in the brain is to use prodrugs. The presence in the brain of specific transport systems for the delivery of components of its livelihoods (amino acids, glucose, amines, peptides) allows them to be used for the purpose of directional transport of hydrophilic drugs into the brain. The search for means for transporting polar compounds characterized by low permeability through the BGB is constantly expanding. The creation of transport systems based on natural cationic proteins - histones may be promising in this regard. It is believed that progress in the creation of new effective drugs can be achieved on the basis of improving the methods of selection of promising chemical compounds and optimizing ways to deliver peptide and protein-natural drugs, as well as genetic material. Studies have shown that certain nanoparticles are capable of transporting a peptide structure (deargin), hydrophilic substances (tubocurarine) in the brain, hydrophilic substances (tubocurarine), drugs, "bought" glycoprotein-p (Loperamide, doxorubicin). One of the promising directions in the creation of drugs penetrating through histaghematic barriers is the development of a nanosphew based on modified silica, capable of ensuring efficient delivery to the target cells of genetic material.
Transportation LS through hematoplazent barrier
Previously, the assumption that the placental barrier ensures the natural protection of the fetus from the effects of exogenous substances, and including drugs, it is true only to a limited degree. The human placenta is a complex transport system that acts as a semi-permeable barrier separating the maternal organism from the fetus. During pregnancy, the placenta regulates the exchange of substances, gases, endogenous and exogenous molecules in the fruit-maternal complex, including drugs. In a number of studies, it was shown that the placenta is morphologically and functionally fulfills the role of the body responsible for the LS transport.
The human placenta consists of fruit tissues (chorionic plate and chorionic vile) and maternal (decidual shell). Decidal partitions divide the organ at 20-40 quotes, which represent structural and functional vascular units of the placenta. Each quotylene is represented by a naval tree, consisting of the endothelium of the capillaries of the fetus, a rigid stroma and a trophoblastic layer, washed by the blood of a mother in the intervalistic space. The outer layer of each felling tree is formed by a multi-core syncytopoblast. Polarized syncytotrophoblastic layer consisting of a microwave apical membrane facing the blood of a mother and basal (fruit) membrane is a hemoplacementar barrier for transplacental vehicles of most substances. During pregnancy, the thickness of the placental barrier decreases mainly due to the disappearance of the cytotrofroblastic layer.
The placenta transport function is determined mainly by the placental membrane (hematoplazent barrier), which has a thickness of about 0.025 mm, which shares the process of the mother's blood circulation and the process of blood circulation of the fetus.
In physiological and pathological conditions, placental metabolism should be considered as the active function of the placental membrane, which makes electoral control over the passage through it xenobiotics. The transfer of drugs through the placenta can be considered on the basis of the study of the same mechanisms that function when substances pass through other biological membranes.
It is well known that the placenta performs numerous functions, such as gas exchange, the transfer of nutrients and decay products, the production of hormones, functioning as an active endocrine body, vital for successful pregnancy. Nutrients such as glucose, amino acids and vitamins pass through a placenta by special transport mechanisms that flow in the maternal portion of the apical membrane and the fruit part of the syncytotropoblast basal membrane. At the same time, the removal of metabolic products from the blood circulation system of the fetus through the placenta to the mother's blood circulation system occurs also by special transport mechanisms. For some compounds, the placenta serves as a protective barrier for a developing fetus that impede the
personal xenobiotics from mother to the fetus, while for others it facilitates their passage both to the fruit and from the fruit compartment.
Transportation LS in the placenta
Five transplantary mechanisms are known: passive diffusion, light diffusion, active transport, phagocytosis and pinocytosis. The last two mechanisms are relative importance in the LS transport in the placenta, and for most drugs is characterized by active transport.
Passive diffusion is the dominant shape of the metabolism in the placenta, which allows the molecule to move down the concentration gradient. The number of drugs moving through the placenta by passive diffusion in any period of time depends on the concentration of it in the plasma of the blood of the mother, its physicochemical properties and properties of the placenta, which determine how quickly it happens.
The process of this diffusion is regulated by the law of the fic.
However, the rate of passive diffusion is as far as the equilibrium concentration in the blood of the mother and the fetus is not installed.
The placenta is similar to a two-layer lipid membrane and, thus, only an LS fraction that is not associated with a protein can diffuse via it.
Passive diffusion is characteristic of low molecular weight, fat-soluble, preferably non-ionized Forms of LS. The lipophilic substances in the non-ionized form are easily diffused through the placenta in the blood of the fetus (antipirin, thiopental). The transfer rate through the placenta depends mainly on the concentration of the non-ionized form of a particular drug at a given value of blood pH, fat-solventness and on the size of molecules. LANs with molecular weight\u003e 500 DA often do not completely pass through the placenta, and the LAN with molecular weight\u003e 1000 Da penetrate the placental membrane slower. For example, various heparins (3000-15000 DA) do not pass through the placenta due to relatively high molecular weight. Most of the LANs have a molecular weight of\u003e 500 DA, so the dimensions of the molecule rarely limit their passage through the placenta.
Basically, LS is weak acids or bases and their dissociation occurs during the physiological value of the pH. In the ionized form, the LS usually can not pass through the lipid membrane
placetes. The difference between the PH of the fetus and the mother affects the ratio of the concentrations of the fruit / mother for the free fraction of the drug. Under normal conditions, the PH of the fetus is practically no different from the mother pH. However, under certain conditions, the polar value of the fetus can significantly decrease, as a result of which the transport of the main LS from the fetus to the maternal compartment decreases. For example, the study of the placental transfer of lidocaine on Megx test showed that the concentration of lidocaine in the fetus is higher than that of the mother during childbirth, which can cause undesirable effects in the fetus or newborn.
Light diffusion
This transport mechanism is characteristic of a small amount of HP. Often this mechanism complements the passive diffusion, for example, in the case of Gancyclovir. For lightweight diffusion, no energy is required, a substance-carrier is necessary. Usually, the result of this type of transport of drugs through the placenta is the same concentration in the plasma of the blood of the mother and the fetus. This mechanism of transport is specific to endogenous substrates (for example, hormones, nucleic acids).
Active transport LS.
The studies of the molecular mechanisms of the active transport of drugs through the placental membrane showed its important role in the functioning of the hematoplazent barrier. This mechanism of transport is characteristic of LS with structural similarity with endogenous substances. In this case, the process of transferring substances depends not only on the size of the molecule, but also on the presence of a substance operator (conveyor).
The active transportation of drugs through the placental membrane by the protein pump requires energy costs, usually due to hydrolysis of ATP or the energy of the transmembrane electrochemical gradient of Na +, Cl + or H + cations. All active conveyors can work against a concentration gradient, but may become neutral.
Active LS conveyors are located either on the maternal portion of the apical membrane, or on the fruit part of the basal membrane, where they carry out LS transport in syncytotrophoblast
or from it. The placenta contains conveyors that contribute to the movement of substrates from the placenta into the blood circulation of the mother or fetus ("pumping"), as well as conveyors that move substrates and in the placenta and from it, thus contributing to the wheels of xenobiotics in the fruit and maternal compartments and of them (" pumping "/" pumping "). There are conveyors that regulate the movement of substrates only in the placenta ("pumping").
Studies of the last decade were devoted to the study of "pumping conveyors" as an "active component" of the placental "barrier". This is glycoprotein-p (MDR1), a family of proteins associated with multiple drug resistance (MRP) and breast cancer resistance protein (BCRP). The discovery of these conveyors made a significant contribution to the understanding of transplacentar pharmacokinetics.
Glycoprotein-P is a transmembrane glycoprotein encoded by the human MDR1 multiple drug resistance gene, expressed on the motherboard of the placental membrane of the syncytiotrofoblast, where it carries out the active removal of lipophilic drugs from the fruit compartment due to the energy of hydrolysis ATP. Glycoprotein-P is a "pumping" conveyor, actively removing xenobiotics from the fruit circulatory system into the mother's blood circulation system. Glycoprotein-P has a wide substrate spectrum, transfers lipophilic drugs, neutral and charged cations, which belong to various pharmacological groups, including antimicrobials (for example, rifampicin), antiviral (for example, HIV inhibitors of proteases), antiarrhythmic drugs (for example, verapamil) , antitumor (for example, vincristine).
In the apical membrane of the Sincithiotrofoblast, the expression of three types of "pumping" conveyors from the MRP family (MRP1-MRP3) were revealed, which are involved in the transport of many LS substrates and their metabolites: Metatrexate, Vincristin, Vinblastin, Cisplatin, antiviral preparations, paracetamol, ampicillin, etc.
The placenta detected a high activity of the ATP-dependent protein of breast cancer resistance (BCRP). BCRP can activate the resistance of tumor cells to antitumor drugs - topotekan, doxorubicin, etc. It was shown that
the placental BCRP limits the transport of topotekhan and mitoxantrone to the fruit in pregnant mice.
Combators of organic cations
The conveyor of two organic cations (OCT2) is expressed in the syncytotropoblast basal membrane and tolerates carnitine placenta from the mother's blood circulation system into the blood of the fetus. LS-substrates of placental OCT2 are methamphetamine, quinidine, verapamil and pyrillamine, which compete with carnitine, limiting his passage through the placenta.
Monocarboxylate and dicarboxylate transporters
Monocarboxylates (lactate) and dicarboxylate (succinate) are actively transported in the placenta. Monocarboxylate transporters (MCTS) and Dicarboxylate transporters (NADC3) are expressed in the placenta apical membrane, although MCTS may also be present in the basement membrane. These conveyors move due to an electrochemical gradient; MCTS are associated with the movement of n + cations, and NADC3 - with Na +. However, information on the potential for the influence of these conveyors for the movement of drugs through the placenta is few. So, valproic acid, despite the obvious risk of toxic influence on the fetus, including teratogenicity, is often used to treat epilepsy during pregnancy. In the physiological value of the pH, the valproic acid easily penetrates the placenta and the concentration ratio of the fruit / mother is 1.71. Studies of a number of authors have shown that there is an active transport system for valproic acid. This transport system includes cations H + - associated MCTs, which cause a high speed of moving the valproic acid to the fetus through a placental barrier. Although the valproic acid competes with lactate, but it turned out that it is simultaneously a substrate and for other conveyors.
Thus, for some compounds of the placenta serves as a protective barrier for a developing fetus, which prevents various xenobiotics from the mother to the fetus, while for others it facilitates their passage both to the fetus and from the fruit compartment, as a whole, functioning as a system of deoxying xenobiotics . Leading role in the process of active trans
lAN ports through the placenta carry out placental conveyors with substrate specificity.
It is now quite obvious that the understanding and knowledge of the role of various conveyors in the displacement of drugs through the hematoplascent barrier is necessary to assess the likely impact of drugs on the fetus, as well as to assess the benefit / risk ratio for mother and fetus during pharmacotherapy during pregnancy.
Transportation LS through the hematophalmic barrier
The hematophthalmic barrier (GOB) performs a barrier function in relation to transparent media, regulates the composition of intraocular fluid, providing selective intake in a lean and the cornea of \u200b\u200bthe necessary nutrients. Clinical studies allowed to clarify and expand the concept of a hematophthalmic barrier, including the histagatematic system in it, as well as talk about the existence in the norm and pathology of the three components: iridocillar, chorioretinal and papillary (Table 4.1.).
Table 4.1.Hematophthalmic barrier
Blood capillaries in the eye are not directly in contact with cells and tissues. All the most difficult exchange between capillaries and cells occurs through an interstitial fluid at the ultrastructural level and is characterized as the mechanisms of capillary, cellular and membrane permeability.
Transportation LS through a hematotestical barrier
The normal function of spermatogenic cells is possible only due to the presence of a special, having the selective permeability of the hematotesticular barrier (GTB) between the blood and the contents of the seed tubules. GTB is formed by endotheliocytes of capillaries, a basal membrane, its own shell of seed tubules, cytoplasm of sertoli cells, an interstitial tissue and a protein shell of testicles. Lipophilic LS penetrate through GTB by diffusion. Studies of recent years have shown that the penetration of drugs and compounds in the testicles can be carried out by active transport with the participation of Glycoprotein-P (MDR1), trans portters of the protein family associated with multiple drug resistance (MRP1, MRP2), breast cancer protein BCRP (ABCG2 ), which carry out an effuxury role in the testicles for a number of drugs, including toxic (for example, cyclosporine).
Penetration of LS through the ovarian hematofollicular barrier
The main structural elements of the ovarian hematofollicular barrier (GFB) are the cells of the ripening follicle, the follicular epithelium and its basal membrane, which cause its permeability and selective properties relative to hydrophilic compounds. Currently, the role of Glycoprotein-P (MDR1) is shown as the active component of the GFB, which implements a protective role, preventing the penetration of xenobiotics into the ovaries.
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Histohematic barrier - This is a combination of morphological structures, physiological and physicochemical mechanisms that function as a single integer and regulating the flows of substances between blood and organs.
Gistohematatic barriers are involved in maintaining the homeostasis of the body and individual organs. Due to the presence of histohematic barriers, each organ lives in its special environment, which can differ significantly from the composition of individual ingredients. Especially powerful barriers are between and the brain, blood and fabric of the floor glands, blood and moisture cameras of the eyes, the blood of the mother and the fetus.
The histohematic barriers of various organs have both differences and a number of general traits of the structure. Direct contact with blood in all organs has a barrier layer formed by endothelium of blood capillaries. In addition, the GGB structures are the basal membrane (medium layer) and adventitial cells of organs and tissues (outer layer). Gistohematatic barriers, changing their permeability for various substances, can limit or facilitate their delivery to the organ. For a series of toxic substances, they are impenetrable, in which their protective function is manifested.
The most important mechanisms that ensure the functioning of histohematic barriers are further viewed by the example of the hematorecephalic barrier, the presence and properties of which the doctor especially often have to take into account when using drugs and various impacts on the body.
Hematostefalic barrier
Hematostefalic barrier- This is a combination of morphological structures, physiological and physicochemical mechanisms that function as a single whole and regulating streams of substances between blood and brain fabric.
The morphological basis of the hematorencephalic barrier is the endothelium and the basal membrane of the brain capillaries, interstitial elements and glycocalix, the astrocytes of neuroglia, covering the entire surface of the capillaries with their legs. In the displacement of substances through the hematorestephalic barrier, transport systems of capillary walls are involved, including vesicular transport of substances (pinoto- and exocytosis), transport via channels with participation or without the participation of carrier proteins, enzyme systems, modifying or destroying incoming substances. It has already been mentioned that specialized water transport systems that use AQP1 and AQP4 proteins function in nervous tissue. The latter form water channels regulating the formation of cerebrospinal fluid and the exchange of water between blood and brain fabric.
Brain capillaries differ from the capillaries of other organs by the fact that endothelial cells form a continuous wall. In contact places, the outer layers of endothelial cells merge, forming the so-called "dense contacts".
The hematosphalic barrier performs protective and regulatory functions for the brain. It protects the brain from the action of a number of substances formed in other tissues, alien and toxic substances, participates in the transport of substances from blood to the brain and is the most important member of the mechanisms of homeostasis of the intercellular brain fluid and liquor.
The blood hematoresphalic barrier has election permeability for various substances. Some biologically active substances, such as catecholamines, are practically not pass through this barrier. The exceptions are only small areas of the barrier on the border with a pituitary gland, epiphysis and some sites, where the penetability of the hematorecephalic barrier for many substances is high. In these areas, penetrating endothelium channels and inter-hendelial gaps, according to which the penetration of substances from the blood into the extracellular liquid of the cerebral tissue or in themselves are found. High permeability of the blood hematorecephalic barrier in these areas allows biologically active substances (cytokines,) to reach those neurons of the hypothalamus and glandular cells where the regulatory contour of the neuroendocrine systems of the organism is closed.
A characteristic feature of the functioning of the hematostephalic barrier is the possibility of changing its permeability for a number of substances in various conditions. Thus, the hematostephalic barrier is capable of adjusting the permeability, change the relationship between blood and the brain. Regulation is carried out by changing the number of open capillaries, blood flow velocities, changes in the permeability of cell membranes, the state of the intercellular substance, the activity of cellular enzyme systems, pinot and exocytosis. The permeability of the BGB can be essentially violated under the conditions of ischemia of cerebral tissue, infection, the development of inflammatory processes in the nervous system, its traumatic damage.
It is believed that the hematorecephalic barrier, creating a significant obstacle to the penetration of many substances from the blood to the brain, at the same time hesitates the same substances formed in the brain in the opposite direction - from the brain to blood.
The permeability of the blood-immature barrald of various substances is very different. Fat-soluble substances tend to penetrate the bee easier than water-soluble. Oxygen, carbon dioxide, nicotine, ethyl alcohol, heroin, fat-soluble antibiotics penetrate easily penetrate chloramphenic and etc.)
Insoluble glucose lipids and some essential amino acids cannot pass into the brain by simply diffusion. Carbohydrates are recognized and transported by special carriers GLUT1 and GLUT3. This transport system is so specific that it distinguishes the stereoisomers of D- and L-glucose: D-glucose is transported, and L-glucose is not. Glucose transport in brain tissue is insensitive to insulin, but suppressed by cytochlazine V.
Carriers are involved in the transport of neutral amino acids (for example, phenylalanine). For carrying a number of substances, mechanisms of active transport are used. For example, due to active transport against concentration gradients, Na +, K + ions, glycine amino acid, performing the function of the brake mediator are transferred.
Thus, the transfer of substances using various mechanisms is carried out not only through plasma membranes, but also through the structures of biological barriers. The study of these mechanisms is necessary to understand the essence of regulatory processes in the body.
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