Medicines described in this directory that penetrate the blood-brain barrier: antimicrobial agent (antibiotic) nifuratel (trade name of the drug Macmiror) and a number of others.
Do not penetrate: antibacterial agent (antibiotic) amoxicillin ( trade names: Amoxicillin, Amoxicillin, Amoxicillin capsules 0.25 g, Amoxicillin Watham, 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 Gonoform, Gramox-D, Grunamox, Danemox, Ospamox, Flemoxin Solutab, Hiconcil, Ecobol) and others.
| When a nerve cell is irritated, the permeability of the cell membrane increases, as a result of which sodium ions begin to penetrate into the fiber. The arrival of positively charged sodium ions reduces the electronegativity on the inner side of the membrane, and the potential difference across the membrane decreases. The decrease in resting membrane potential is called membrane depolarization. If the stimulation is strong enough, then the change in membrane potential reaches a threshold value, the so-called critical level of depolarization, resulting in an action potential. The development of the action potential is caused by ionic currents. At the moment when the peak of the action potential is recorded, an avalanche-like entry of sodium ions occurs through the sodium channels of the membrane into the nerve fiber. That's why inner side the membrane is temporarily charged positively. Almost simultaneously, a slow increase in permeability for potassium ions leaving the cell begins. High sodium permeability is very short-lived - it lasts only a fraction of milliseconds, after which the sodium channel gates close. At this point, potassium permeability reaches a high value. Potassium ions rush out. During the recovery process after an action potential, the work of the sodium-potassium pump ensures that sodium ions are “pumped out” and potassium ions are “pumped” inward, i.e. a return to the initial asymmetry of their concentrations on both sides of the membrane, which leads to the restoration of the initial level of membrane polarization (resting potential). When a stimulus acts on a nerve, the so-called “all-or-nothing” law is observed: or the action potential does not arise at all - the “nothing” reaction ( if the irritation is subthreshold), or the maximum amplitude of the potential for the given conditions develops - the “All” reaction (if the irritation is above the threshold). During the development of the action potential, the membrane completely loses excitability, i.e. no irritation during this period. may cause the development of a new action potential. This state of complete inexcitability is called absolute refractoriness. As stated above, the development of an action potential is associated with an increase in membrane permeability to sodium ions. During the development of the action potential, the membrane is inactivated for a short time, i.e., it loses the ability to respond to any influences with a new increase in sodium permeability. Inactivation of the membrane eliminates the possibility re-development action potential. Following the period of absolute refractoriness, there follows a period of relative refractoriness with t and, when the excitable formation is capable of responding with excitation (development of an action potential) only to very severe irritation. Gradually, excitability is restored to normal levels. The refractory™ property ensures, in particular, unilateral conduction of the impulse along the nerve fiber. The duration of the refractory period determines an important characteristic of an excitable formation (nerve fiber, nerve and muscle cells) - lability (N. E. Vvedensky). The lability of an excitable formation can be characterized by the maximum number of impulses (action potentials) that it can reproduce in 1 s. The shorter the refractory period, the higher the lability. |
9. A. Neurotransmitters and neurohormones Nerve cells control body functions using chemical signaling substances, neurotransmitters and neurohormones. Neurotransmitters are short-lived substances of local action; they are released into the synaptic cleft and transmit a signal to neighboring cells. Neurohormones are long-lived, long-range substances that enter the blood. However, the boundary between the two groups is quite arbitrary, since most of the mediators simultaneously act as hormones. Signaling substances - neurotransmitters (or neuromodulators) must satisfy a number of criteria. First of all, they must be produced by neurons and stored in synapses; upon receipt of a nerve impulse, they must be released into the synaptic cleft, selectively bind to a specific receptor on the postsynaptic membrane of another neuron or muscle cell, stimulating these cells to perform their specific functions. B. Chemical structure By chemical properties neurotransmitters are divided into several groups. The table in the diagram shows the most important representatives of neurotransmitters - more than 50 compounds. The best known and most commonly encountered neurotransmitter is acetylcholine, an ester of choline and acetic acid. Neurotransmitters include some amino acids, as well as biogenic amines formed during the decarboxylation of amino acids (see Fig. 183). Known purine neurotransmitters are adenine derivatives. The largest group consists of peptides and proteins. Small peptides often carry at the N-terminus a glutamic acid residue in the form of cyclic pyroglutamate (5-oxoproline; one-letter code:
10. Amino acids play an important role in metabolism and the functioning of the central nervous system. This is explained not only by the exclusive role of amino acids as sources of the synthesis of a large number of biologically important compounds, such as proteins, peptides, some lipids, a number of hormones, vitamins, and biologically active amines. Amino acids and their derivatives are involved in synaptic transmission, in the implementation of interneuronal connections as neurotransmitters and neuromodulators. Their energy significance is also significant, since the amino acids of the glutamic group are directly related to the tricarboxylic acid cycle. Summarizing the data on the metabolism of free amino acids in the brain, we can draw the following conclusions:
1. Greater ability of nervous tissue to maintain relative constancy of amino acid levels.
2. The content of free amino acids in the brain is 8–10 times higher than in blood plasma.
3. The existence of a high concentration gradient of amino acids between the blood and the brain due to selective active transport across the BBB.
4. High content of glutamate, glutamine, aspartic, N-acetylaspartic acids and GABA. They make up 75% of the pool of free amino acids in the brain.
5. Pronounced regionality of amino acid content in different parts of the brain.
6. Existence of compartmentalized amino acid pools in various subcellular structures nerve cells.
7. Aromatic amino acids are of particular importance as precursors of catecholamines and serotonin.
12. FEATURES OF NERVOUS TISSUE METABOLISM Respiration The brain accounts for 2–3% of body weight. At the same time, oxygen consumption by the brain in a state of physical rest reaches 20–25% of the total consumption by the entire body, and in children under 4 years of age, the brain consumes even 50% of the oxygen utilized by the entire body. The size of the brain's consumption of various substances from the blood, including oxygen, can be judged by the arteriovenous difference. It has been established that during its passage through the brain, blood loses about 8 vol.% of oxygen. In 1 minute there are 53–54 ml of blood per 100 g of brain tissue. Consequently, 100 g of the brain consumes 3.7 ml of oxygen in 1 min, and the entire brain (1500 g) consumes 55.5 ml of oxygen. The gas exchange of the brain is much higher than the gas exchange of other tissues; in particular, it exceeds the gas exchange of muscle tissue by almost 20 times. The intensity of breathing varies for different areas of the brain. For example, the respiration rate of white matter is 2 times lower than that of gray matter (although there are fewer cells in white matter). The cells of the cerebral cortex and cerebellum consume oxygen especially intensively. Oxygen absorption by the brain is significantly less during anesthesia. On the contrary, the intensity of brain respiration increases with increasing functional activity.
It is no secret that the body must maintain the constancy of its internal environment, or homeostasis, expending energy for this, otherwise it will not differ from inanimate nature. Thus, the skin protects our body from the outside world at the organ level.
But it turns out that other barriers that form between the blood and certain tissues are also important. They are called histohematic. These barriers are necessary for various reasons. Sometimes it is necessary to mechanically limit the penetration of blood into tissues. Examples of such barriers are:
- blood-articular barrier - between blood and articular surfaces;
- blood-ophthalmic barrier - between the blood and the light-conducting media of the eyeball.
Everyone knows from their own experience that when cutting meat it is clear that the surface of the joints is always deprived of contact with blood. If blood flows into the joint cavity (hemarthrosis), it contributes to its overgrowth, or ankylosis. It is clear why a blood-ophthalmic barrier is needed: inside the eye there are transparent media, for example, vitreous. Its task is to absorb passing light as little as possible. If there is no this barrier, then the blood will penetrate into the vitreous body, and we will be deprived of the ability to see.
What is the BBB?
One of the most interesting and mysterious histohematic barriers is the blood-brain barrier, or the barrier between capillary blood and neurons of the central nervous system. In modern, informational language, there is a completely “secure connection” between the capillaries and the substance of the brain.
The meaning of the blood-brain barrier (abbreviation - BBB) is that neurons do not come into direct contact with the capillary network, but interact with the supplying capillaries through “intermediaries”. These mediators are astrocytes, or neuroglial cells.
Neuroglia is an auxiliary tissue of the central nervous system that performs many functions, such as supporting, supporting neurons, and trophic, nourishing them. IN in this case, astrocytes directly take from the capillary everything that neurons need and pass it on to them. At the same time, they control that harmful and foreign substances do not enter the brain.
Thus, not only various toxins, but also many drugs do not pass through the blood-brain barrier, and this is the subject of research in modern medicine, since 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 little history
The famous physician and microbiologist, Paul Ehrlich, became a world celebrity thanks to the invention of salvarsan, or drug No. 606, which became the first, albeit toxic, but effective drug for the treatment of chronic syphilis. This medicine contained arsenic.
But Ehrlich also experimented a lot with dyes. He was sure that just as the dye sticks tightly to fabric (indigo, purple, carmine), it will stick to a pathogenic microorganism, as soon as such a substance is found. Of course, it must not only be firmly fixed to the microbial cell, but also be lethal to microbes. Undoubtedly, the fact that he married the daughter of a famous and wealthy textile manufacturer “added fuel to the fire.”
And Ehrlich began experimenting with various and very poisonous dyes: aniline and trypan.
By dissecting laboratory animals, he was convinced that the dye penetrated into all organs and tissues, but was not able to diffuse (penetrate) into the brain, which remained pale.
At first, his conclusions were incorrect: he assumed that the dye simply did not stain the brain because it contained a lot of fat, and it repelled the dye.
And then the discoveries preceding the discovery of the blood-brain barrier rained down as if from a cornucopia, and the idea itself gradually began to take shape in the minds of scientists. The following experiments were of greatest importance:
- if the dye is injected intravenously, the maximum that it can stain is the choroidal choroid plexuses of the ventricles of the brain. Then “the path is closed” to him;
- if the dye was forcibly injected into the cerebrospinal fluid by performing a lumbar puncture, the brain was stained. However, the dye did not get “out” from the cerebrospinal fluid, and the remaining tissues remained colorless.
After this, it was completely logical to assume that cerebrospinal fluid is a liquid that is located “on the other side” of the barrier, the main task of which is to protect the central nervous system.
The term BBB first appeared in 1900, one hundred and sixteen years ago. In English medical literature it is called the “blood-brain barrier”, and in Russian the name took root in the form of the “blood-brain barrier”.
Subsequently, this phenomenon was studied in sufficient detail. Before the Second World War, evidence appeared that there is a blood-brain and blood-CSF barrier, and there is also a hematoneural variant, which is not in the central nervous system, but is located in the peripheral nerves.
Structure and functions of the barrier
Our life depends on the uninterrupted operation of the blood-brain barrier. After all, our brain consumes a fifth of the total amount of oxygen and glucose, and at the same time its weight is not 20% of the total body weight, but about 2%, that is, the brain’s consumption of nutrients and oxygen is 10 times higher than the arithmetic average.
Unlike, for example, liver cells, the brain works only “on oxygen”, and aerobic glycolysis is the only possible variant existence of all neurons without exception. If the supply of neurons stops within 10-12 seconds, the person loses consciousness, and after blood circulation stops, being in a state clinical death, chances for full recovery brain functions exist only for 5-6 minutes.
This time increases with strong cooling of the body, but with normal temperature body, the final death of the brain occurs after 8-10 minutes, so only intense activity of the BBB allows us to be “in shape.”
It is known that many neurological diseases develop only due to the fact that the permeability of the blood-brain barrier is impaired, in the direction of its increase.
We will not go into detail about the histology and biochemistry of the structures that make up the barrier. Let us only note that the structure of the blood-brain barrier includes a special structure of capillaries. The following features are known that lead to the appearance of a barrier:
- tight junctions between endothelial cells lining the capillaries from the inside.
In other organs and tissues, the capillary endothelium is made “carelessly”, and there are large gaps between the cells through which there is a free exchange of tissue fluid with the perivascular space. Where the capillaries form the blood-brain barrier, the endothelial cells are located very tightly, and the tightness is not broken;
- energy stations - mitochondria in capillaries exceed the physiological need for those in other places, since the blood-brain barrier requires large amounts of energy;
- the height of endothelial cells is significantly lower than in vessels of other localizations, and the number of transport enzymes in the cell cytoplasm is much higher. This allows us to assign a large role to transmembrane cytoplasmic transport;
- the vascular endothelium in its depth contains a dense, skeletal-forming basement membrane, to which the processes of astrocytes are externally adjacent;
In addition to the characteristics of the endothelium, outside the capillaries there are special auxiliary cells - pericytes. What is pericyte? This is a cell that can regulate the lumen of the capillary from the outside, and, if necessary, can have the functions of a macrophage to capture and destroy harmful cells.
Therefore, before reaching the neurons, we can note two lines of defense of the blood-brain barrier: The first is endothelial cell tight junctions and active transport, and the second is macrophage activity of pericytes.
Further, the blood-brain barrier includes a large number of astrocytes, which make up greatest mass this histohematic barrier. These are small cells that surround neurons and, by definition of their role, can do “almost everything.”
They constantly exchange substances with the endothelium, control the safety of tight junctions, the activity of pericytes and the lumen of capillaries. In addition, the brain needs cholesterol, but it cannot penetrate from the blood into the cerebrospinal fluid or pass through the blood-brain barrier. Therefore, astrocytes take over its synthesis, in addition to the main functions.
By the way, one of the factors in the pathogenesis of multiple sclerosis is impaired myelination of dendrites and axons. And for the formation of myelin, cholesterol is needed. Therefore, the role of BBB dysfunction in the development of demyelinating diseases is established, and in Lately is being studied.
Where there are no barriers
Are there such places in the central nervous system, where there is no blood-brain barrier? It would seem impossible: so much effort has been put into creating several levels of protection from external harmful substances. But it turns out that in some places the BBB does not constitute a single “wall” of protection, but there are holes in it. They are needed for those substances that are produced by the brain and sent to the periphery as commands: these are pituitary hormones. Therefore, there are free areas, just in the zone of the pituitary gland and epiphysis. They exist to allow hormones and neurotransmitters to pass freely into the blood.
There is another zone free from the BBB, which is located in the area of the rhomboid fossa or the bottom of the 4th ventricle of the brain. The vomiting center is located there. It is known that vomiting can occur not only due to mechanical irritation of the back wall of the pharynx, but also in the presence of toxins that have entered the blood. Therefore, it is in this area that there are special neurons that constantly “monitor” the quality of the blood for the presence of harmful substances.
As soon as their concentration reaches a certain value, these neurons are activated, causing a feeling of nausea and then vomiting. To be fair, it must be said that vomiting is not always associated with the concentration of harmful substances. Sometimes, with a significant increase in intracranial pressure (with hydrocephalus, meningitis), the vomiting center is activated due to direct excess pressure during the development of the syndrome
According to Stern's definition, the blood-brain barrier (BBB) is a set of physiological mechanisms and corresponding anatomical formations in the central nervous system involved in regulating the composition of the cerebrospinal fluid (CSF). This definition is from the book by Pokrovsky and Korotko “Human Physiology”.
The blood-brain barrier regulates the penetration of biologically active substances, metabolites, chemicals that affect the sensitive structures of the brain from the blood into the brain, and prevents the entry of foreign substances, microorganisms, and toxins into the brain.
In ideas about the blood-brain barrier, the following are emphasized as the main provisions:
1) penetration of substances into the brain occurs mainly not through the liquor pathways, but through the circulatory system at the level of capillary - nerve cell;
2) the blood-brain barrier is to a greater extent not an anatomical formation, but a functional concept that characterizes a certain physiological mechanism. Like any physiological mechanism existing in the body, the blood-brain barrier is under the regulatory influence of the nervous and humoral systems;
3) among the factors that control the blood-brain barrier, the leading one is the level of activity and metabolism of nervous tissue.
The main function characterizing the blood-brain barrier is the permeability of the cell wall. The required level of physiological permeability, adequate to the functional state of the body, determines the dynamics of the entry of physiologically active substances into the nerve cells of the brain.
The permeability of the blood-brain barrier depends on the functional state of the body, the content of mediators, hormones, and ions in the blood. An increase in their concentration in the blood leads to a decrease in the permeability of the blood-brain barrier to these substances.
Histological structure
The functional diagram of the blood-brain barrier includes, along with the histohematic barrier, neuroglia and the system of cerebrospinal fluid spaces. The histohematic barrier has a dual function: regulatory and protective. The regulatory function ensures the relative constancy of the physical and physicochemical properties, chemical composition, and physiological activity of the intercellular environment of the organ, depending on its functional state. The protective function of the histohematic barrier is to protect organs from the entry of foreign or toxic substances of endo- and exogenous nature.
The leading component of the blood-brain barrier, which ensures its functions, is the wall of the brain capillary. There are two mechanisms for the penetration of a substance into brain cells:
- through the cerebrospinal fluid, which serves as an intermediate link between the blood and the nerve or glial cell, which performs a nutritional function (the so-called cerebrospinal fluid pathway)
- through the capillary wall.
In an adult organism, the main route of movement of substances into nerve cells is hematogenous (through the walls of capillaries); the liquor pathway becomes auxiliary, additional.
The morphological substrate of the BBB is the anatomical elements located between the blood and nerve cells (the so-called interendothelial contacts, enveloping the cell in the form of a tight ring and preventing the penetration of substances from the capillaries). The processes of glial cells (astrocytic end feet) surrounding the capillary tighten its wall, which reduces the filtration surface of the capillary and prevents the diffusion of macromolecules. According to other ideas, glial processes are channels capable of selectively extracting from the bloodstream substances necessary to nourish nerve cells and returning their metabolic products to the blood. The so-called enzyme barrier is important in the function of the BBB. In the walls of the microvessels of the brain, the surrounding connective tissue stroma, as well as in the choroid plexus, enzymes were found that help neutralize and destroy substances coming from the blood. The distribution of these enzymes is unequal in the capillaries of different brain structures; their activity changes with age and under pathological conditions.
Functioning of the BBB
The functioning of the BBB is based on the processes of dialysis, ultrafiltration, osmosis, as well as changes in electrical properties, lipid solubility, tissue affinity or metabolic activity of cellular elements. Important importance is attached to the functioning of the enzyme barrier, for example, in the walls of the microvessels of the brain and the surrounding connective tissue stroma (blood-brain barrier) - high activity of enzymes was found - cholinesterase, carbonic anhydrase, DOPA decarboxylase, etc. These enzymes, breaking down some biologically active substances, prevent them penetration into the brain.
Water-soluble molecules cannot diffuse freely between the blood and CSF due to the impermeable tightly coupled junctions between the epithelial cells of the choroid plexus; instead, the epithelial cells transport certain molecules from one side of the barrier to the other. Once the molecules enter the CSF, they diffuse through the leaky epithelial layer and reach the interstitial fluid surrounding neurons and glial cells. 
1.Endothelial cell
2.Tight connection
3.Cerebral capillary
4.Neuron
5.Glucose
6. Interstitial fluid
7. Glial cell
8.Ependymal layer
1. Choroid plexus, epithelial cell
2.Capillary
3.Tight connection
4.Ependymal layer
Epithelial cells transport certain molecules from the capillaries into the ventricles of the brain. The flow of ions crossing the BBB (blood-CSF) is regulated by several mechanisms in the choroid plexus: 
1.Blood vessel (plasma)
2.Basolateral (inferolateral) surface
3. Epithelial cell of the choroid plexus
4.Hard coupling
5. Ventricles
6. Apical (upper) surface
7.CSF in the ventricle
8.Ion exchange
Water molecules in epithelial cells dissociate into hydrogen ions and hydroxyl ions. Hydroxyl ions combine with carbon dioxide, which is a product of cellular metabolism. At the surface of the basolateral cells, hydrogen ions are exchanged for extracellular sodium ions from the plasma. In the ventricles of the brain, sodium ions are actively transported across the apical surface of the cell (apex). This is accompanied by a compensatory movement of chloride and bicarbonate ions into the CSF. To maintain osmotic balance, water moves into the ventricles.
BBB permeability and regulation
The BBB is considered as a self-regulating system, the state
which depends on the needs of nerve cells and the level of metabolic
processes not only in the brain itself, but also in other organs and tissues
body. The permeability of the BBB varies in different parts of the brain,
selective for different substances and regulated by nervous and humoral
mechanisms. Important role in neurohumoral regulation functions of the BBB
belongs to changes in the intensity of metabolic processes in tissue
brain, which is proven by the inhibitory effect of metabolic inhibitors
processes on the rate of transport of amino acids into the brain and their stimulation
absorption by oxidation substrates.
Regulation of the functions of the blood-brain barrier is carried out by the higher parts of the central nervous system and humoral factors. The hypothalamic-pituitary adrenal system plays a significant role in regulation. With various types of cerebral pathology, for example injuries, various inflammatory lesions of brain tissue, there is a need to artificially reduce the level of permeability of the blood-brain barrier. Pharmacological effects it is possible to increase or decrease the penetration into the brain of various substances introduced from the outside or circulating in the blood. Penetration of various pathological agents into the brain in the area of the hypothalamus, where the blood-brain barrier is “broken,” is accompanied by a variety of symptoms of disorders of the autonomic nervous system. There is ample evidence of a decline protective function BBB under the influence of alcohol, in conditions emotional stress, overheating and hypothermia of the body, exposure to ionizing radiation, etc. At the same time, the ability of some drugs, for example pentamine, sodium etaminal, vitamin P, to reduce the penetration of certain substances into the brain has been experimentally established.
The BBB is a system for protecting the brain from external damaging factors. As mentioned above, with injuries or pathological processes it can be disrupted. In addition, some microbes have developed highly specialized mechanisms (still poorly understood) to overcome this barrier. It is known that rabies viruses and herpes simplex viruses (in humans) and reovirus (in experimental animals) enter the central nervous system by moving along nerves, and encapsulated bacteria and fungi have surface components that allow them to pass through the blood-brain barrier.
Thus, the mechanisms for overcoming the blood-brain barrier are highly specialized. Thus, they are present only in certain serotypes of pathogens capable of causing meningitis. Neonatal meningitis, for example, is caused only by Streptococcus agalactiae that belongs to serotype III. Other serotypes are also pathogenic, but cause infectious processes outside the central nervous system. This selectivity is apparently determined by the spatial structure of the capsular polysaccharide of serotype III, since capsular polysaccharides of other serotypes contain the same components, but have a different spatial structure.
The BBB works as a selective filter, allowing some substances into the cerebrospinal fluid and not others, which may circulate in the blood but are foreign to the brain tissue. Thus, adrenaline, norepinephrine, acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA), penicillin, streptomycin do not pass through the BBB.
Bilirubin is always in the blood, but never, even with jaundice, does it pass into the brain, leaving only the nervous tissue unstained. Therefore, it is difficult to obtain an effective concentration of any drug to reach the brain parenchyma. Morphine, atropine, bromine, strychnine, caffeine, ether, urethane, alcohol and gamma-hydroxybutyric acid (GHB) pass through the BBB. When treating, for example, tuberculous meningitis, streptomycin is injected directly into the cerebrospinal fluid, bypassing the barrier using a lumbar puncture.
It is necessary to take into account the unusual action of many substances injected directly into the cerebrospinal fluid. Trypan blue, when injected into the cerebrospinal fluid, causes convulsions and death, similar action provides bile. Acetylcholine, injected directly into the brain, acts as an adrenergic agonist (similar to adrenaline), and adrenaline, on the contrary, acts as a cholinomimetic (similar to acetylcholine): arterial pressure decreases, bradycardia occurs, body temperature first decreases and then increases.
It causes narcotic sleep, lethargy and analgesia. K+ ions act as a sympathomimetic, and Ca2+ - a parasympathomimetic. Lobeline is a reflex stimulator of respiration, penetrating the BBB, causing a number of adverse reactions(dizziness, vomiting, convulsions). Insulin at intramuscular injections reduces blood sugar, and when directly introduced into the cerebrospinal fluid, it increases.
All drugs produced in the world are divided into those that penetrate and those that do not penetrate the BBB. This is a big problem - some drugs should not penetrate (but do), and some, on the contrary, must penetrate to achieve therapeutic effect, but they cannot due to their properties. Pharmacologists are working to resolve this problem using computer modeling and experimental studies.
BBB and aging
As mentioned above, one of the most important parts of the BBB is astrocytes. The formation of the BBB is their main function in the brain.
The problem of transformation of cells (RG) into stellate astrocytes in
the postnatal period of development underlies the astrocyte theory
aging of mammals.
There is a disappearance of embryonic radial cell migration pathways
from the place of their proliferation to the places of their final localization in the brain
adult, which is the cause of postmitotic brain
mammals. The disappearance of RG induces a whole cascade of systemic
processes that are named as an age-dependent mechanism
self-destruction of mammals (MSDM). The disappearance of RG cells makes
it is impossible to replace neurons that have exhausted their life resources
(Boyko, 2007).
Age-related changes in the BBB have not yet been fully studied. Atherosclerosis, alcoholism and other diseases play an undoubted role in damage to the BBB. With insufficient functioning of the BBB, cholesterol and apolipoprotein begin to penetrate into the brain tissue, which leads to greater damage to the BBB.
Perhaps, by studying age-related changes in the BBB, scientists will be able to get closer to solving the problem of aging.
BBB and Alzheimer's disease
Brain aging and neurodegenerative diseases are associated with oxidative stress, metal depletion and inflammation, and the BBB plays a significant role in this. For example, glycated protein receptors (GPR) and low-density lipoprotein receptor-related protein 1 (LPR-1-LRP), embedded in the BBB structure, play a major role in the regulation of beta-amyloid metabolism in the CNS, and changes in the activity of these two receptors may contribute to accumulation of beta-amyloid in the central nervous system with subsequent development of inflammation, imbalance between cerebral circulation and metabolism, changes in synaptic transmission, neuronal damage and amyloid deposition in the parenchyma and blood vessels of the brain. The result is Alzheimer's disease. The accumulation of apolipoprotein in the perivascular (perivascular) space is a key point in the development of this terrible disease, which is spreading at an increasing speed and is already affecting people under 40 years of age. German authors under the leadership of Dr. write about the role of apolipoprotein and damage to BBB astrocytes. Dietmar R. Thal from the Department of Neuropathology, University of Bonn.
In addition, some researchers believe that Alzheimer's disease may also be of an autoimmune nature—the penetration of cerebral protein into the bloodstream through a deficient BBB. IN vascular system Antibodies are formed that attack the brain when it crosses the barrier again.
Many scientists associate the development of neurodegenerative diseases and the maintenance of neural stem cells with the activity of ABC transporters—ATP-binding transporters. The ABCB family of these transporters is found in the BBB. A recent paper by a research group led by Professor Jens Pahnke from the Neurodegeneration Research Laboratory (NRL), Department of Neurology, University of Rostock discusses the accumulated evidence. Scientists believe that by studying the role and functioning of ABC transporters, it will be possible to better understand the pathogenesis of Alzheimer's disease, create new approaches to therapy and mathematical methods for calculating risk.
In April 2008, a report by Jonathan Geiger appeared in BBC News 
from the University of North Dakota that drinking one cup of coffee a day strengthens the blood-brain barrier, protecting the brain from the harmful effects of cholesterol. Researchers led by Jonathan Geiger fed rabbits a high-cholesterol diet. In addition, some animals received water containing 3 mg of caffeine (equivalent to one cup of coffee) daily. After 12 weeks, the caffeine-fed rabbits had a significantly stronger blood-brain barrier than their counterparts who drank plain water, Geiger reported. A histological study of the brain of rabbits showed an increase in the activity of astrocytes - microglial cells of the brain, as well as a decrease in the permeability of the BBB. New data can help in the fight against Alzheimer's disease, in which there is an increase in cholesterol levels in the blood of patients and, as a result, destruction of the BBB, scientists believe.
Another treatment for Alzheimer's disease could be 8-hydroxyquinoline analogue ionophores (PBT2), which act on metal-induced amyloid aggregation. About this In 2006, scientists from the Department of Chemical and Biological Engineering, University of Wisconsin-Madison, led by Eric V. Shusta, demonstrated the ability of neural stem cells in the embryonic rat brain to stimulate blood vessel cells to acquire the properties of the blood-brain barrier.
The work used brain stem cells grown in the form of neurospheres. Such cells synthesize factors, the effect of which on endothelial cells lining the inner surface of brain vessels causes them to form a dense barrier that does not allow small molecules to pass through, which usually freely penetrate the vascular wall.
The authors note that the formation of such a rudimentary blood-brain barrier occurs even in the complete absence of astrocytes—cells that maintain the structure and functioning of brain structures, including the blood-brain barrier, but appear in large numbers only after birth.
The fact that developing brain cells stimulate the transformation of endothelial cells into blood-brain barrier cells not only sheds light on the mechanisms that ensure brain safety. The authors plan to create a similar model of the blood-brain barrier using human endothelial and neural stem cells. If their efforts are successful, then pharmacological researchers will soon have a functioning model of the human blood-brain barrier at their disposal, helping to overcome the obstacles that stand in the way of neuroscientists, doctors and drug developers trying to find ways to deliver certain drugs to the brain.
Finally
In conclusion, I would like to say that the blood-brain barrier is an amazing structure that protects our brain. Nowadays, many studies of the BBB are being conducted, mainly by pharmaceutical companies, and these studies are aimed at determining the permeability of the BBB to various substances, mainly candidates for the role of drugs for certain diseases. But this is not enough. The permeability of the BBB is associated with a terrible age-associated illness - disease Alzheimer's. Brain aging is associated with BBB permeability. Aging of the BBB leads to the aging of other brain structures, and metabolic changes in the aging brain lead to changes in the functioning of the BBB.
There are several tasks for researchers:
1)
Determining the permeability of the BBB for various substances and analyzing the accumulated experimental data is necessary for the creation of new drugs.
2) Study of age-related changes in the BBB.
3) Studying the possibilities of regulating the functioning of the BBB.
4) Studying the role of BBB changes in the occurrence of neurodegenerative diseases
Research on these issues is needed now because Alzheimer's disease is getting younger. Maybe by learning to properly regulate the functional state of the BBB, by learning to strengthen it, by learning to understand the underlying metabolic processes in the brain, scientists will finally find cures for age-associated brain diseases and
aging...
M.I. Savelyeva, E.A. Sokova
4.1. GENERAL VIEWS ABOUT DRUG DISTRIBUTION AND RELATIONSHIP WITH BLOOD PLASMA PROTEINS
After gaining access to the systemic bloodstream through one of the routes of administration, xenobiotics are distributed in organs and tissues. Series of physical and physiological processes, which occur simultaneously, depend on the physicochemical properties of drugs and thereby form different ways of their distribution in the body. Examples of physical processes are simple dilution or dissolution of a drug in intracellular and extracellular fluids. Examples of physiological processes are binding to plasma proteins, accessibility of tissue channels, and penetration of the drug through various body barriers. The following factors may influence the distribution of drugs:
Blood flow;
Degree of binding to plasma proteins;
Physico-chemical characteristics of drugs;
The degree (depth) and extent of penetration of drugs through physiological barriers;
The degree of elimination by which a drug is continuously removed from the body and which competes with the distribution phenomenon.
blood flow
blood flow- the volume of blood reaching a certain area in the body per unit of time. The volume/time ratio and the amount of blood flow in different areas of the body differ. Total blood flow is 5000 ml/min and corresponds to cardiac throughput at rest. Cardiac throughput(cardiac minute volume) - the volume of blood pumped by the heart in one minute. In addition to cardiac output, there is an important factor called blood volume. various parts systemic circulation. On average, the heart contains 7% of the total blood volume, the pulmonary system - 9%, arteries - 13%, arterioles and capillaries - 7%, and veins, venules and the entire venous system - the remaining 64%. Through the permeable walls of the capillaries, drugs, nutrients and other substances are exchanged with the interstitial fluid of organs/tissues, after which the capillaries merge with venules, which gradually converge into large veins. As a result of transcapillary exchange, the drug is transported through the capillary wall into the tissue due to the difference in pressure (osmotic and hydrostatic pressure) between the inner and outer parts of the capillary or concentration gradient. Delivery of a xenobiotic to certain areas of the body depends on the speed of blood flow and the site of drug administration.
Blood flow 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. Blood flow significantly determines the rate of drug delivery to a certain area of the body and reflects the relative growth rate of xenobiotic concentration, at which equilibrium is established between the organ/tissue and the blood. The amount of drugs stored or distributed in the tissue depends on the size of the tissue and the physicochemical characteristics of the drug, the separation coefficient between the organ/tissue and the blood.
Blood flow limiting phenomenon(distribution limited by perfusion; phenomenon of limited transmission; distribution limited by patency) - dependence of transcapillary exchange
and storage of the drug in tissue depending on the physical and chemical characteristics of the drug.
Perfusion-limited transcapillary drug exchange
In order to differentiate between the two types of distribution, assume that the capillary is a hollow cylinder with a length L and radius r , in which blood flows at speed ν in the positive direction X. The concentration of the drug in the tissue around the capillary is C fabric, and the concentration in the blood is C blood. The drug passes through
capillary membrane due to the concentration gradient between blood and tissue. Consider the area or segment of the direction between X And x+dx, where is the difference in the mass of the drug flow between the beginning and end of the segment dx equal to the mass of flow through the capillary wall. Let's write the equality in the following form (4-1):
then equation (4-4) will take the form:
Mass flow through the capillary wall into the tissue - J fabric in terms of
the change in the net mass of the flow leaving the capillary at a certain length L(4-6):
Having transformed equation (4-6) using equation (4-5), we obtain:
Let's find the capillary clearance:
Capillary clearance is the volume of blood from which a xenobiotic is distributed into the tissue per unit time. Extraction ratio (extraction ratio) distribution:
Equation (4-9) can be rearranged:
Equation (4-10) shows that the recovery ratio expresses the balancing fraction between the drug concentration in the tissue, the arterial capillaries, and the venous side of the capillaries. Comparing equations (4-5) and (4-10) we find that capillary clearance is equal to blood flow multiplied by the extraction ratio.
Consider a diffusion-limited distribution (or permeability-limited distribution). At Q>PS or C artery≈ C vein
the drug is slightly lipophilic and the recovery ratio is less than unity, and the distribution of the drug is limited to very rapid diffusion through the capillary membrane. Let us determine the mass transfer of the drug into the tissue:
The driving force for the transfer of xenobiotics into tissue is the concentration gradient. Consider perfusion-limited distribution (or flow-limited distribution). At Q
with the drug concentrated on the venous side of the capillaries, and the drug is highly lipophilic. The extraction ratio is equal to or close to unity, and therefore the absorption of the drug into the tissue is thermodynamically much more favorable than its presence in the blood, and distribution is limited only by the rate of delivery of the drug to the tissue. Once the drug reaches the tissue, it is immediately absorbed. Let us determine the mass transfer of the drug into the tissue:
Binding of drugs to proteins
The binding of drugs to plasma proteins significantly affects their distribution in the body. Small drug molecules bound to proteins can easily penetrate barriers. In this regard, the distribution of the xenobiotic bound to the protein will differ from the distribution of the unbound drug. The interaction of drug functional groups with membrane or intracellular receptors can be short. Protein binding not only affects the distribution of the drug in the body, but also affects the therapeutic outcome. Therefore, it is necessary to use plasma free drug concentrations for pharmacokinetic analysis, dosage adjustment, and optimal therapeutic effect.
The protein binding of drugs used with other drugs may be different than drugs taken alone. Changes in protein binding are the result of replacing one drug with another in combination with plasma proteins. Similar substitution can also occur at the cellular level with other tissue proteins and enzymes. Substitution causes an increase in the free fraction of the drug in plasma and its accumulation at receptor sites in proportion to the concentration of the drug. It is important to adjust the dosage regimen of drugs when they are administered together. Alteration of protein binding of drugs is an important issue, especially for drugs with a narrow therapeutic index.
Plasma proteins that are involved in protein-drug interactions
Albumen- the main plasma and tissue protein responsible for binding to drugs, which is synthesized exclusively by liver hepatocytes. Albumin molecular weight - 69,000 Da; half-life is approximately 17-18 days. The protein is mainly distributed in the vascular system and, despite its large molecular size, can additionally be distributed in the extra-ravascular zone. Albumin has negatively and positively charged areas. The drug interacts with albumin due to hydrogen bonds (hydrophobic bonding) and van der Wals forces. Some factors that have a significant impact on the body, such as pregnancy, surgery, age, ethnic and racial differences, can affect the interaction of drugs with albumin. The kidneys do not filter albumin, and therefore drugs that are bound to albumin are also not filtered. The degree of binding affects not only the distribution of the drug, but also the renal elimination and metabolism of the drug. Only free drug can be taken up by liver hepatocytes. Therefore, the higher the percentage of protein bound drug, the lower the hepatic absorption and metabolic rate of the drug. As mentioned previously, the extent of drug binding to plasma albumin can also be significantly altered by the administration of other drugs that replace the primary drug, resulting in an increase in plasma free drug concentration.
Other plasma proteins are fibrinogen, globulins (γ- and β 1 -globulin - transferrin), ceruloplasmin and α- and β-lipoproteins. Fibrinogen and its polymerized form fibrin are involved in the formation of blood clots. Globulins, namely γ-globulins, are antibodies that interact with certain antigens. Transferin is involved in the transport of iron, ceruloplasmin is involved in the transfer of copper, and α- and β-lipoproteins are couriers of fat-soluble components.
Estimation of protein binding parameters
The binding of drugs to plasma proteins is usually determined in vitro under physiological conditions of pH and body temperature. Determination methods - equilibrium dialysis, dynamic dialysis, ultrafiltration, gel filtration chromatography, ultracentri-
fugation, microdialysis and several new and rapidly evolving methodologies for high throughput experiments. The goal is to estimate the concentration of free drug in equilibrium with the protein-drug complex. The selected methodology and experimental conditions must be such that complex stability and equilibrium are maintained and the free drug concentration is not overestimated due to too rapid breakdown of the complex during measurement. After this, most drug-protein complexes are held together by weak chemical interactions, electrostatic type (van der Wals forces), and hydrogen bonding tends to separate at elevated temperatures, osmotic pressure and non-physiological pH.
The usual method of dialysis of plasma, or a protein solution with a pH of 7.2-7.4, is not effective at various drug concentrations. The mixture after dialization becomes isotonic with NaCl [at 37°C through the dialysis membrane with molecular contractions of approximately 12,000-14,000 Da against an equivalent volume of phosphate buffers (≈67, pH 7.2-7.4)]. A bag-shaped dialysis membrane containing protein and drug is placed in a buffer solution. The factory-made modified version of the bag has two compartments that are separated by a dialysis membrane. Equilibrium of the free drug passing through the membrane is usually reached in approximately 2-3 hours. The concentration of the free drug is measured on the buffer side, i.e. outside a bag or compartment separated by a membrane that must be equal to the concentration of free drug inside the bag or compartment; the concentration of free drug in the bag must be in equilibrium with the drug attached to the protein. In dialysis, an albumin solution or a pure plasma sample containing albumin is used. Drug binding parameters - free fraction or associated constant, which can be determined using the law of mass action:
Where K a- association constant; C D- concentration of free drug in molecules; C Pr- concentration of protein with free attachment sites; CDP- concentration of the drug complex with protein; k 1 and k 2 - level constants of forward and reverse reactions,
respectively. Reciprocal connections are constant and are known as dissociation constants (4-14):
The value of the associated constant K a represents the degree of binding of the drug to the protein. Drugs that bind extensively to plasma proteins usually have a large association constant. Based on equation (4-14), the concentration of the drug-protein complex can be determined:
If the concentration of total protein (C) at the beginning of the test tube experiment is known, and the concentration of the drug-protein complex (C) is estimated experimentally, then the concentration of free protein can be determined (With Pr), in equilibrium with the complex:
Replacing equation (4-15) with equation (4-16) for With Pr leads:
Let's transform equation (4-18):
When installed CDP/ With PT(the number of moles of attached drug per mole of protein for equilibrium) is equal to r, i.e. r = CDP/ C PT, then equation (4-19) will change:
When multiplying equation (4-20) by n(n- number of attachment sites per mole of protein) we obtain the Langmoor equation:
Langmuir equation (4-21) and graph r against C D leads to a hyperbolic isotherm (Figure 4-1). Let's simplify equation (4-21). Let's take the Langmoor equation (4-21) in reverse form. The double reciprocal equation (4-22) shows that the plot of 1/r versus 1/C D is linear with a slope equal to 1/nKa and the intersection point along the ordinate axis 1/ n(Figure 4-2):
Rice. 4-1. Langmoor isotherm. The y-axis is the number of moles of drug attached per mole of protein; x axis - concentration of free drug
By transforming equation (4-21), two versions of the linear equation can be obtained:
The Scatchard graph describes the relationship between r/C D And r as a straight line with a slope equal to the associative constant K a(Figure 4-3). Axis intersection point X equal to the number of connected sections n, the point of intersection with the axis at equal to pK a..
Additionally, Equation (4-21) can be rearranged to provide a linear relationship in terms of free and bound drug concentrations:
Rice. 4-2. Double reciprocal Klotz plot
Equation (4-21) shows the relationship between reciprocal r(moles of bound drug per mole of protein) and C D
Rice. 4-3. Line plot of CDP/CD (ratio of bound sites to free drug) versus CDP (concentration of bound drug)
(free drug concentration). Axis intersection point at is reciprocal of the number of bound sites per mole of protein, and the ratio of the slope to the intercept at- associative equilibrium constant.
Schedule c dp/c d against c dp -
line with slope equal to -K a and y-intercept nKC PT . This equation is used if the protein concentration is unknown. The K a estimate is based on the drug concentration measured in the buffer compartment. Determination of protein-bound drug is based on free fraction assessment
Scatchard plot (Fig. 4-4) - a straight line (for one type of connected sections).
Langmoor's equation for several types of connected sections:
where n 1 and K a1 are parameters of one type of identically connected sections; n 2 and K a2 are parameters of the second type of identically connected sections, and so on. For example, an aspartic or glutamic acid residue, -COO - , may be one type of bound site, and -S - a cysteine residue or -NH 2 ± a histidine residue is a second type of bound site. When a drug has affinity for two types of bound sites, then the graph
Rice. 4-4. Scatchard chart
Scatchard r/D against r represents not a straight line, but a curve (Fig. 4-5). Extrapolation of the initial and final linear segments of the curve results in straight lines that correspond to the equations:
Rice. 4-5. Scatchard chart
The Scatchard plot represents the binding of two different classes of sites to a protein. The curve represents the first two elements
equations (4-26), which are defined as straight lines - continuations of linear segments of the initial and final parts of the curve. Line 1 represents high affinity and low capacity binding sites, and line 2 represents low affinity and high capacity binding sites.
When the affinity and capacity of two connecting sites are different, then the line with the larger intersection point at and the smaller intersection point X defines high affinity and low capacity regions, whereas the line with the lower intercept at and the larger intersection point X determines low affinity and high capacity of binding sites.
4.2. PENETRATION OF DRUGS THROUGH HISTOGEMATIC BARRIERS
Most drugs, after absorption and entry into the blood, are distributed unevenly into different organs and tissues and it is not always possible to achieve the desired concentration of the drug in the target organ. The nature of the distribution of drugs is significantly influenced by histohematic barriers that occur along the path of their distribution. In 1929, academician L.S. Stern reported for the first time at the International Physiological Congress in Boston about the existence of
the body has physiological protective and regulating histohematological barriers (HGB). It has been proven that the physiological histohematic barrier is a complex of complex physiological processes occurring between blood and tissue fluid. GGBs regulate the supply of substances necessary for their activity from the blood to organs and tissues and the timely removal of the final products of cellular metabolism, ensuring the constancy of the optimal composition of tissue (extracellular) fluid. At the same time, HGBs prevent the entry of foreign substances from the blood into organs and tissues. A feature of the HGB is its selective permeability, i.e. the ability to pass some substances and retain others. Most researchers recognize the existence of specialized physiological GGBs that are important for normal life. individual organs and anatomical structures. These include: hematoencephalic (between the blood and the central nervous system), hematoophthalmic (between the blood and intraocular fluid), hematolabyrinthine (between the blood and endolymph of the labyrinth), the barrier between the blood and the gonads (hematoovarian, hematotesticular). The placenta also has “barrier” properties that protect the developing fetus. The main structural elements of histohematic barriers are the endothelium of blood vessels, the basement membrane, which includes a large amount of neutral mucopolysaccharides, the main amorphous substance, fibers, etc. The structure of the HGB is determined to a large extent by the structural features of the organ and varies depending on the morphological and physiological characteristics of the organ and tissue.
Penetration of drugs through the blood-brain barrier
The main interfaces between the central nervous system and the peripheral circulation are the blood-brain barrier (BBB) and the blood-CSF barriers. The surface area of the BBB is approximately 20 m2, and is thousands of times greater than the area of the blood-CSF barrier, so the BBB is the main barrier between the central nervous system and the systemic circulation. The presence of the BBB in the brain structures, separating the circulation from the interstitial space and preventing the entry of a number of polar compounds directly into the brain parenchyma, determines the features of drug therapy.
PI of neurological diseases. The permeability of the BBB is determined by the endothelial cells of the brain capillaries, which have epithelial-like, highly resistant tight junctions, which excludes paracellular pathways of fluctuation of substances through the BBB, and the penetration of drugs into the brain depends on transcellular transport. Glial elements lining the outer surface of the endothelium and, obviously, playing the role of an additional lipid membrane are also of certain importance. Lipophilic drugs generally diffuse easily across the BBB, in contrast to hydrophilic drugs, the passive transport of which is limited by highly resistant tight junctions of endothelial cells. The coefficient of solubility in fats is of decisive importance in penetration through the blood-brain barrier. A typical example is general anesthetics - the speed of their narcotic effect is directly proportional to the coefficient of solubility in fats. Carbon dioxide, oxygen and lipophilic substances (which include most anesthetics) easily pass through the BBB, while for most ions, proteins and large molecules (for example, mannitol) it is practically impermeable. There is virtually no pinocytosis in the brain capillaries. There are other ways for compounds to penetrate the BBB, indirectly through the receptor, with the participation of specific transporters. The endothelium of brain capillaries has been shown to express specific receptors for some of the circulating peptides and plasma proteins. The peptide receptor system of the BBB includes receptors for insulin, transferrin, lipoproteins, etc. The transport of large protein molecules is ensured by their active uptake. It has been established that the penetration of drugs and compounds into the brain can be carried out through active transport with the participation of active “pumping” and “pumping out” transport systems (Fig. 4.6). This makes it possible to control the selective transport of drugs across the BBB and limit their non-selective distribution. The discovery of the efflux transporters P-glycoprotein (MDR1), the multidrug resistance-associated protein (MRP) family of transporters, and breast cancer resistance protein (BCRP) has made a significant contribution to the understanding of drug transport across the BBB. P-glycoprotein has been shown to limit the transport of a number of substances into the brain. It is located on the apical part of endothelial cells and carries out the excretion of predominantly hydrophilic cationic compounds from the brain into the lumen of blood vessels.
Rice. 4.6. Transporters involved in the transport of drugs across the BBB (Ho R.H., Kim R.B., 2005)
new drugs, for example, cytostatics, antiretroviral drugs, etc. The importance of glycoprotein-P in limiting the transport of drugs across the BBB can be demonstrated by the example of loperamide, which, by its mechanism of action on the receptors of the gastrointestinal tract, is a potential opioid drug. However, there are no effects on the central nervous system (euphoria, respiratory depression), since loperamide, being a substrate of glycoprotein-P, does not penetrate the central nervous system. In the presence of an inhibitor mdrl quinidine, the central effects of loperamide increase. Transporters from the MRP family are located either on the basal or apical part of endothelial cells. These transporters remove glucuronidated, sulfated or glutathionated drug conjugates. The experiment established that the multidrug resistance protein MRP2 is involved in the functioning of the BBB and limits the activity of antiepileptic drugs.
Endothelial cells of brain capillaries express some members of the organic anion transporter (OAT3) family, which also play an important role in the distribution of a number of drugs in the central nervous system. The drug substrates of these transporters are, for example, fexofenadine and indomethacin. Expression of isoforms of polypeptides transporting organic anions (OATP1A2) to the BBB is important for the penetration of drugs into the brain. However, it is believed that the expression of efflux transporters (MDR1, MRP, BCRP) is the reason for the limited pharmacological access of drugs into the brain and other tissues, when the concentration may be lower than that required to achieve the desired effect. Significant
the number of mitochondria in the endothelium of brain capillaries indicates the ability to maintain energy-dependent and metabolic processes available for the active transport of drugs across the BBB. In the endothelial cells of brain capillaries, enzymes were discovered that were capable of oxidizing and conjugating compounds to protect the cells themselves and, accordingly, the brain from possible toxic effects. Thus, there are at least two reasons that limit the entry of drugs into the central nervous system. Firstly, these are the structural features of the BBB. Secondly, the BBB includes an active metabolic enzyme system and a pump-out transporter system, which forms a biochemical barrier to most xenobiotics. This combination of physical and biochemical properties of the BBB endothelium prevents more than 98% of potential neurotropic drugs from entering the brain.
Factors influencing drug transport to the brain
The pharmacodynamic effects of endogenous substances and diseases affect the functions of the BBB, leading to changes in the transport of drugs into the brain. Various pathological conditions can disrupt the permeability of the blood-brain barrier, for example, with meningoencephalitis, the permeability of the blood-brain barrier sharply increases, which causes various kinds of violations of the integrity of the surrounding tissues. An increase in BBB permeability is observed in multiple sclerosis, Alzheimer's disease, dementia in HIV-infected patients, encephalitis and meningitis, high blood pressure, and mental disorders. A significant number of neurotransmitters, cytokines, chemokines, peripheral hormones, and the effects of active forms of O2 can change the functions and permeability of the BBB. For example, histamine, acting on H 2 receptors facing the lumen of part of the endothelial cells, increases the permeability of the barrier to low molecular weight substances, which is associated with disruption of tight junctions between epithelial cells. The permeability of histohematic barriers can be changed in a targeted manner, which is used in the clinic (for example, to increase the effectiveness of chemotherapy drugs). Reducing the barrier functions of the BBB due to disruption of the structure of tight junctions is used to deliver drugs to the brain, for example, the use of mannitol, urea. Osmotic “opening” of the BBB makes it possible to provide
brain and glioblastoma, increased transport into the brain for a limited period of time of cytostatics (for example, methotrexate, procarbazine). A more gentle method of influencing the BBB is its “biochemical” opening, based on the ability of prostaglandins, inflammatory mediators, to increase the porosity of brain vessels. A fundamentally different possibility of increasing the delivery of drugs to the brain is the use of prodrugs. The presence in the brain of specific transport systems for the delivery of its life support components (amino acids, glucose, amines, peptides) allows them to be used for the purpose of targeted transport of hydrophilic drugs to the brain. The search for means to transport polar compounds characterized by low permeability across the BBB 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 development of new effective drugs can be achieved by improving methods for selecting promising chemical compounds and optimizing delivery routes for drugs of peptide and protein nature, as well as genetic material. Studies have shown that certain nanoparticles are capable of transporting into the brain compounds of a peptide structure (delargin), hydrophilic substances (tubocurarine), and drugs “pumped out” from the brain by glycoprotein-P (loperamide, doxorubicin). One of the promising directions in the creation of drugs that penetrate histagema barriers is the development of nanospheres based on modified silicon dioxide, capable of ensuring effective delivery of genetic material to target cells.
Transport of drugs across the hematoplacental barrier
The previously existing assumption that the placental barrier provides natural protection of the fetus from the effects of exogenous substances, including drugs, is true only to a limited extent. The human placenta is a complex transport system that acts as a semipermeable barrier separating the maternal body from the fetus. During pregnancy, the placenta regulates the metabolism of substances, gases, endogenous and exogenous molecules, including drugs, in the fetal-maternal complex. A number of studies have shown that the placenta morphologically and functionally plays the role of an organ responsible for the transport of drugs.
The human placenta consists of fetal tissues (chorionic plate and chorionic villus) and maternal tissues (decidua). The decidual septa divide the organ into 20-40 cotyledons, which represent the structural and functional vascular units of the placenta. Each cotyledon is represented by a villous tree, consisting of the endothelium of the fetal capillaries, villous stroma and trophoblastic layer, washed by the mother’s blood located in the intervillous space. The outer layer of each villous tree is formed by a multinucleated syncytiotrophoblast. The polarized syncytiotrophoblast layer, consisting of a microvillous apical membrane facing the maternal blood and a basal (fetal) membrane, represents a hemoplacental barrier for the transplacental transport of most substances. During pregnancy, the thickness of the placental barrier decreases, mainly due to the disappearance of the cytotrophoblastic layer.
The transport function of the placenta is determined mainly by the placental membrane (blood-placental barrier), which has a thickness of about 0.025 mm, which separates the maternal circulatory system and the fetal circulatory system.
Under physiological and pathological conditions, placental metabolism should be considered as an active function of the placental membrane, which exercises selective control over the passage of xenobiotics through it. The transfer of drugs across the placenta can be considered based on the study of the same mechanisms that function during the passage of substances through other biological membranes.
It is well known that the placenta performs numerous functions, such as gas exchange, transport of nutrients and waste products, and production of hormones, functioning as an active endocrine organ vital for a successful pregnancy. Nutrients such as glucose, amino acids and vitamins pass through the placenta through special transport mechanisms that occur in the maternal part of the apical membrane and the fetal part of the syncytiotrophoblast basement membrane. At the same time, the removal of metabolic products from the fetal circulatory system through the placenta into the maternal circulatory system also occurs through special transport mechanisms. For some compounds, the placenta serves as a protective barrier for the developing fetus, preventing the ingress of
personal xenobiotics from mother to fetus, while for others it facilitates their passage both to the fetus and from the fetal compartment.
Transport of drugs in the placenta
There are five known mechanisms of transplacental exchange: passive diffusion, facilitated diffusion, active transport, phagocytosis and pinocytosis. The last two mechanisms are of relative importance in the transport of drugs in the placenta, and most drugs are characterized by active transport.
Passive diffusion is the dominant form of metabolism in the placenta, which allows a molecule to move down a concentration gradient. The amount of a drug that moves across the placenta by passive diffusion at any time depends on its concentration in the mother’s blood plasma, its physicochemical properties and the properties of the placenta, which determine how quickly this happens.
The process of this diffusion is governed by Fick's law.
However, the rate of passive diffusion is so low that the equilibrium concentration in the blood of the mother and fetus is not established.
The placenta is similar to a two-layer lipid membrane and, thus, only the drug fraction not bound to protein can diffuse freely through it.
Passive diffusion is characteristic of low-molecular, fat-soluble, predominantly non-ionized forms of drugs. Lipophilic substances in non-ionized form easily diffuse through the placenta into the fetal blood (antipyrine, thiopental). The rate of transfer across the placenta depends mainly on the concentration of the non-ionized form of a particular drug at a given blood pH value, fat solubility and molecular size. Drugs with a molecular weight > 500 Da often do not completely cross the placenta, and drugs with a molecular weight > 1000 Da cross the placental membrane more slowly. For example, various heparins (3000-15000 Da) do not cross the placenta due to their relatively high molecular weight. Most drugs have a molecular weight > 500 Da, so the size of the molecule rarely limits their passage through the placenta.
Basically, drugs are weak acids or bases and their dissociation occurs at a physiological pH value. In ionized form, a drug usually cannot pass through the lipid membrane
placenta. The difference between fetal and maternal pH affects the fetal/maternal concentration ratio for the free drug fraction. Under normal conditions, the fetal pH is practically no different from the maternal pH. However, under certain conditions, the fetal pH value can decrease significantly, resulting in reduced transport of essential drugs from the fetus to the maternal compartment. For example, a study of placental transfer of lidocaine using the MEGX test showed that lidocaine concentrations in the fetus are higher than in the mother during labor, which may cause adverse effects in the fetus or newborn.
Facilitated diffusion
This transport mechanism is typical for a small amount of drugs. Often this mechanism complements passive diffusion, for example, in the case of ganciclovir. Facilitated diffusion does not require energy; it requires a carrier substance. Typically, the result of this type of drug transport across the placenta is the same concentration in the blood plasma of the mother and fetus. This transport mechanism is specific mainly for endogenous substrates (eg, hormones, nucleic acids).
Active transport of drugs
Research molecular mechanisms active transport of drugs across the placental membrane showed its important role in the functioning of the blood-placental barrier. This transport mechanism is typical for drugs that are structurally similar to endogenous substances. In this case, the process of transfer of substances depends not only on the size of the molecule, but also on the presence of a carrier substance (transporter).
Active transport of drugs across the placental membrane by a protein pump requires energy expenditure, usually due to ATP hydrolysis or the energy of the transmembrane electrochemical gradient of Na+, Cl+ or H+ cations. All active transporters can work against a concentration gradient, but can also become neutral.
Active drug transporters are located either on the maternal part of the apical membrane or on the fetal part of the basement membrane, where they transport drugs into the syncytiotrophoblast
or from it. The placenta contains transporters that facilitate the movement of substrates from the placenta into the maternal or fetal circulation (“pumpers”), as well as transporters that move substrates both into and out of the placenta, thereby facilitating the transport of xenobiotics into and out of the fetal and maternal compartments (“pumpers”). pumping"/"pumping out"). There are transporters that regulate the movement of substrates only into the placenta (“pumping”).
Research over the last decade has been devoted to the study of “efflux transporters” as an “active component” of the placental “barrier.” This is P-glycoprotein (MDR1), a family of multidrug resistance-associated proteins (MRP) and breast cancer resistance protein (BCRP). The discovery of these transporters has made significant contributions to the understanding of transplacental pharmacokinetics.
Glycoprotein-P is a transmembrane glycoprotein encoded by the human multidrug resistance gene MDR1, expressed on the maternal side of the placental membrane of the syncytiotrophoblast, where it actively removes lipophilic drugs from the fetal compartment due to the energy of ATP hydrolysis. Glycoprotein-P is a pump-out transporter, actively removing xenobiotics from the fetal circulatory system into the maternal circulatory system. Glycoprotein-P has a wide substrate spectrum, transports lipophilic drugs, neutral and charged cations that belong to various pharmacological groups, including antimicrobial (for example, rifampicin), antiviral (for example, HIV protease inhibitors), antiarrhythmic drugs (for example, verapamil) , antitumor (for example, vincristine).
In the apical membrane of the syncytiotrophoblast, expression of three types of “pumping” transporters from the MRP family (MRP1-MRP3) was detected, which are involved in the transport of many drug substrates and their metabolites: metatrexate, vincristine, vinblastine, cisplatin, antiviral drugs, paracetamol, ampicillin, etc.
High activity of ATP-dependent breast cancer resistance protein (BCRP) was detected in the placenta. BCRP can activate the resistance of tumor cells to antitumor drugs - topotecan, doxorubicin, etc. It has been shown that
placental BCRP limits transport of topotecan and mitoxantrone to the fetus in pregnant mice.
Transporters of organic cations
The organic cation transporter (OCT2) is expressed in the syncytiotrophoblast basement membrane and transports carnitine from the maternal circulation to the fetal circulation across the placenta. Drug substrates of placental OCT2 are methamphetamine, quinidine, verapamil and pyrilamine, which compete with carnitine, limiting its passage through the placenta.
Monocarboxylate and dicarboxylate transporters
Monocarboxylates (lactate) and dicarboxylates (succinate) are actively transported in the placenta. Monocarboxylate transporters (MCTs) and dicarboxylate transporters (NaDC3) are expressed in the apical membrane of the placenta, although MCTs may also be present in the basement membrane. These transporters move via an electrochemical gradient; MCTs are associated with the movement of H + cations, and NaDC3 - with Na + . However, there is limited information about the potential influence of these transporters on the movement of drugs across the placenta. Thus, valproic acid, despite the obvious risk of toxic effects on the fetus, including teratogenicity, is often used to treat epilepsy during pregnancy. At physiological pH, valproic acid easily crosses the placenta and the fetal/maternal concentration ratio is 1.71. Studies by a number of authors have shown that there is an active transport system for valproic acid. This transport system includes H + -bound MCT cations, which cause a high rate of movement of valproic acid to the fetus through the placental barrier. Although valproic acid competes with lactate, it turned out that it is also a substrate for other transporters.
Thus, for some compounds, the placenta serves as a protective barrier for the developing fetus, preventing the passage of various xenobiotics from the mother to the fetus, while for others it facilitates their passage both to the fetus and from the fetal compartment, generally functioning as a xenobiotic detoxification system . A leading role in the process of active trans-
The drug port through the placenta is carried out by placental transporters that have substrate specificity.
It is now quite obvious that understanding and knowledge of the role of various transporters in the movement of drugs across the blood-placental barrier is necessary to assess the likely effects of drugs on the fetus, as well as to assess the benefit/risk ratio for the mother and fetus when conducting pharmacotherapy during pregnancy.
Transport of drugs across the blood-ophthalmic barrier
The blood-ophthalmic barrier (BOB) performs a barrier function in relation to the transparent media of the eye, regulates the composition of the intraocular fluid, ensuring the selective supply of necessary nutrients to the lens and cornea. Clinical studies have made it possible to clarify and expand the concept of the blood-ophthalmic barrier, including the histagematical system, as well as to talk about the existence of its three components in health and pathology: iridociliary, chorioretinal and papillary (Table 4.1.).
Table 4.1. Blood-ophthalmic barrier
The blood capillaries in the eye do not come into direct contact with cells and tissues. The entire complex exchange between capillaries and cells occurs through the interstitial fluid at the ultrastructural level and is characterized as mechanisms of capillary, cellular and membrane permeability.
Transport of drugs across the blood-testis barrier
The normal function of spermatogenic cells is possible only due to the presence of a special, selectively permeable blood-testis barrier (BTB) between the blood and the contents of the seminiferous tubules. The GTB is formed by capillary endothelial cells, the basement membrane, the lining of the seminiferous tubules, the cytoplasm of Sertoli cells, interstitial tissue and tunica albuginea testicles. Lipophilic drugs penetrate the GTB by diffusion. Research recent years showed that the penetration of drugs and compounds into the testicles can be carried out by active transport with the participation of glycoprotein-P (MDR1), transporters of the family of proteins associated with multidrug resistance (MRP1, MRP2), breast cancer resistance protein BCRP (ABCG2), which perform an efflux role in the testes for a number of drugs, including toxic ones (for example, cyclosporine).
Penetration of drugs through the ovarian hematofollicular barrier
The main structural elements of the ovarian blood-follicular barrier (HFB) are the theca cells of the maturing follicle, the follicular epithelium and its basement membrane, which determine its permeability and selective properties in relation to hydrophilic compounds. Currently, the role of glycoprotein-P (MDR1) has been shown as an active component of GFB, which plays a protective role by preventing the penetration of xenobiotics into the ovaries.
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Histohematic barrier - it is a set of morphological structures, physiological and physicochemical mechanisms that function as a whole and regulate the flow of substances between the blood and organs.
Histohematic barriers are involved in maintaining homeostasis of the body and individual organs. Due to the presence of histohematic barriers, each organ lives in its own special environment, which can differ significantly from the composition of individual ingredients. Particularly powerful barriers exist between the brain, blood and tissue of the gonads, blood and moisture in the chambers of the eye, and the blood of the mother and fetus.
The histohematic barriers of different organs have both differences and a number of common features buildings. Direct contact with blood in all organs has a barrier layer formed by the endothelium of blood capillaries. In addition, the structures of the HGB are the basement membrane (middle layer) and adventitial cells of organs and tissues (outer layer). Histohematic barriers, changing their permeability to various substances, can limit or facilitate their delivery to the organ. They are impenetrable to a number of toxic substances, which demonstrates their protective function.
The most important mechanisms that ensure the functioning of histohematic barriers are further discussed using the example of the blood-brain barrier, the presence and properties of which the doctor especially often has to take into account when using medicines and various effects on the body.
Blood-brain barrier
Blood-brain barrier is a set of morphological structures, physiological and physicochemical mechanisms that function as a whole and regulate the flow of substances between blood and brain tissue.
The morphological basis of the blood-brain barrier is the endothelium and basement membrane of the brain capillaries, interstitial elements and glycocalyx, astrocytes of neuroglia, covering the entire surface of the capillaries with their legs. The transport systems of the endothelium of the capillary walls participate in the movement of substances across the blood-brain barrier, including vesicular transport of substances (pino- and exocytosis), transport through channels with or without the participation of carrier proteins, enzyme systems that modify or destroy incoming substances. It has already been mentioned that specialized water transport systems operate in nervous tissue using the aquaporin proteins AQP1 and AQP4. The latter form water channels that regulate the formation of cerebrospinal fluid and the exchange of water between blood and brain tissue.
Brain capillaries differ from capillaries in other organs in that the endothelial cells form a continuous wall. At points of contact, the outer layers of endothelial cells fuse, forming so-called “tight junctions”.
The blood-brain 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, foreign and toxic substances, is involved in the transport of substances from the blood to the brain and is an important participant in the mechanisms of homeostasis of the intercellular fluid of the brain and cerebrospinal fluid.
The blood-brain barrier is selectively permeable to various substances. Some biologically active substances, such as catecholamines, practically do not pass through this barrier. The only exceptions are small areas of the barrier at the border with the pituitary gland, pineal gland and some areas where the permeability of the blood-brain barrier for many substances is high. In these areas, channels and interendothelial gaps penetrating the endothelium are found, through which substances penetrate from the blood into the extracellular fluid of the brain tissue or into the brain itself. The high permeability of the blood-brain barrier in these areas allows biological active substances(cytokines) reach those neurons of the hypothalamus and glandular cells on which the regulatory circuit of the body's neuroendocrine systems is closed.
A characteristic feature of the functioning of the blood-brain barrier is the possibility of changing its permeability for a number of substances in different conditions. Thus, the blood-brain barrier is able, by regulating permeability, to change the relationship between the blood and the brain. Regulation is carried out by changing the number of open capillaries, blood flow speed, changes in the permeability of cell membranes, the state of the intercellular substance, the activity of cellular enzyme systems, pino- and exocytosis. The permeability of the BBB can be significantly impaired under conditions of ischemia of brain tissue, infection, development inflammatory processes in the nervous system, its traumatic damage.
It is believed that the blood-brain barrier, while creating a significant obstacle to the penetration of many substances from the blood into the brain, at the same time allows the same substances formed in the brain to pass well in the opposite direction - from the brain to the blood.
The permeability of the blood-brain barrier to different substances varies greatly. Fat-soluble substances, as a rule, penetrate the BBB more easily than water-soluble substances. Easily penetrates oxygen, carbon dioxide, nicotine, ethanol, heroin, fat-soluble antibiotics ( chloramphenicol and etc.)
Lipid-insoluble glucose and some essential amino acids cannot pass into the brain by simple diffusion. Carbohydrates are recognized and transported by special transporters GLUT1 and GLUT3. This transport system is so specific that it distinguishes between stereoisomers of D- and L-glucose: D-glucose is transported, but L-glucose is not. Glucose transport into brain tissue is insensitive to insulin but is inhibited by cytochalasin B.
Transporters are involved in the transport of neutral amino acids (for example, phenylalanine). Active transport mechanisms are used to transport a number of substances. For example, due to active transport, Na +, K + ions and the amino acid glycine, which acts as an inhibitory mediator, are transferred against concentration gradients.
Thus, the transfer of substances using various mechanisms occurs 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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