Protein metabolism disorders. Metabolism is an epileptic seizure

(educational and methodological manual for independent work of students)

Coordinating Methodological Council of Kazan State Medical University

PATHOLOGY OF PROTEIN METABOLISM (educational and methodological manual for independent work of students). Kazan 2006. - 20 p.

Compiled by: prof. M.M.Minnebaev, F.I.Mukhutdinova, prof. Boychuk S., associate professor L.D. Zubairova, associate professor A.Yu.Teplov.

Reviewers: prof. A.P. Tsibulkin prof. L.N.Ivanov

Due to the variety of functions of proteins, their peculiar “ubiquity” protein metabolism is a rather vulnerable link in metabolism. Accordingly, in many pathological processes, primary and secondary disorders in various parts of protein metabolism occupy a significant place in their pathogenesis and ultimately determine the degree of implementation of protective-adaptive reactions and adaptive mechanisms.

The method manual has been compiled taking into account the corresponding section of the pathological physiology program.

Introduction

All proteins are in a state of continuous active metabolism - breakdown and synthesis. Protein metabolism ensures the entire plastic aspect of the body’s vital activity. Depending on age, there is a positive and negative nitrogen balance. At a young age, a positive nitrogen balance (increased growth) predominates, and in mature and old age - a state of dynamic nitrogen balance, that is, a stabilizing synthesis that maintains the morphological integrity of the body. In older age, catabolic processes predominate. Regenerative synthesis, found in pathology, is also an example of a positive nitrogen balance. Over a week, up to 50% of nitrogen is renewed in the liver, while in skeletal muscles only 2.5% is renewed during the same time.

Pathology of protein metabolism is a pathology of the correspondence between the processes of protein synthesis and breakdown. The main pathology of protein metabolism is general protein deficiency, which is characterized by a negative nitrogen balance. Along with the possibility of developing this general form of protein metabolism disorder, the same disorder can occur in relation to individual types of proteins (impaired synthesis of any type of protein in the whole body or in some organ).

The intermediate link in protein metabolism is a violation of amino acid metabolism. The pathology of protein metabolism also includes a violation of the formation and excretion of end products in protein metabolism (that is, the pathology of nitrogen metabolism itself).

General protein deficiency

It may be of nutritional origin, or due to a violation of neuroendocrine mechanisms of synthesis and breakdown, or cellular mechanisms of synthesis and breakdown. The occurrence of nutritional general protein deficiency is explained by:

1. There are no reserve forms of proteins in the body (as is the case in carbohydrate and fat metabolism);

Nitrogen animal cell is absorbed only in the form of amino groups, amino acids;

The carbon skeletons of independent amino acids have distinctive structures and cannot be synthesized in the body. Hence, protein metabolism depends on the supply of amino acids from outside with food. The metabolism of amino acids is interconnected with the metabolism of energy substances. Amino acid products can also be used as energy material - these are glucogenic and ketogenic amino acids. On the other hand, protein synthesis always involves the use of energy.

If the supply of energy materials does not meet the body’s needs, then proteins are used for energy needs. Thus, when only 25% of the total necessary energy material (glucose, fat) is received, all the protein received from food is used as energy material. In this case, the anabolic value of proteins is zero. Hence, insufficient intake of fats and carbohydrates leads to disruption of protein metabolism. Vitamins B6, B12, C, A are coenzymes of enzymes that carry out biosynthetic processes. Hence, vitamin deficiency also causes disturbances in protein metabolism.

When there is insufficient intake of proteins or their switching to energy sources (as a result of insufficient intake of fats or carbohydrates), the following phenomena occur:

1. The intensity of anabolic processes of active metabolism of protein structures is sharply limited and the amount of released nitrogen is reduced;

2. Redistribution of endogenous nitrogen in the body. These are adaptation factors to protein deficiency.

Selective protein deficiency(protein starvation) - under these conditions, the limitation of nitrogen excretion and its redistribution in the body comes to the fore. This reveals the heterogeneity of disturbances in protein metabolism in different organs: activity of gastrointestinal enzymes

is sharply limited, and the synthesis of catabolic processes is not disrupted. At the same time, the proteins of the heart muscle suffer less. The activity of deamination enzymes decreases, while transamination enzymes retain their activity much longer. The formation of red blood cells in the bone marrow persists for a long time, and the formation of globin in the hemoglobin structure is disrupted very early. In the endocrine glands, atrophic changes develop. In the clinic, incomplete protein starvation is mainly encountered.

The causes of incomplete protein starvation (partial deficiency) are: a) impaired protein absorption; b) gastrointestinal obstruction; V) chronic diseases with decreased appetite. In this case, protein metabolism is disrupted both as a result of insufficient intake and the use of proteins as an energy material. Against this background, the adaptive processes to some extent compensate for protein deficiency, so protein depletion does not develop for a long time and the nitrogen balance is maintained for a long time (of course, although at a low level). As a result of a decrease in protein metabolism, the structure and function of many organs is disrupted (there is a loss of protein in the structures of the liver, skin, and skeletal muscles). It should be noted that in this case there is a relative preservation of the synthesis of some proteins while the synthesis of other types of proteins is disrupted. The synthesis of plasma proteins, antibodies, enzymes (including the digestive tract) is limited, which leads to a secondary disruption of protein absorption. As a result of disruption of the synthesis of carbohydrate and fat metabolism enzymes, metabolic processes in the metabolism of fats and carbohydrates are disrupted. Adaptation to incomplete protein starvation is only relative (especially in growing organisms). In young organisms there is an adaptive decline

the intensity of protein metabolism (metabolism slowdown) is less complete than in adults. In conditions of regeneration and convalescence, complete restoration of the structure is not observed for a long time and wounds do not heal for a long time. Thus, with prolonged incomplete fasting, severe protein depletion and death can occur. Incomplete protein starvation often occurs with impaired absorption

proteins, which occurs with any combination of changes in the rate of hydrolysis, movement of food masses and absorption of these products - most often with various forms of disruption of the secretory function of the gastrointestinal tract, pancreatic activity and wall pathology small intestine. The function of the stomach in protein hydrolysis is:

1. Endopeptidase - pepsin - breaks internal peptide bonds, resulting in the formation of polypeptides.

2. Reserving role and portioned supply of food mass to the underlying sections of the gastrointestinal tract (this process is disrupted when peristalsis accelerates). These two functions of the stomach are disrupted in acute conditions, with a decrease in pepsin activity (or little pepsinogen is secreted): the swelling of food proteins decreases, and pepsinogen is poorly activated. The result is a relative lack of protein hydrolysis.

Impaired absorption of proteins in upper sections The gastrointestinal tract can be: with a lack of pancreatic juice (pancreatitis). Moreover, the disturbance of trypsin activity can be primary or secondary. There may be insufficient activity and insufficient amounts intestinal juice, since it contains enterokinase, which activates the conversion of trypsinogen into trypsin, chymotrypsinogen into chymotrypsin. Insufficient activity or amount of trypsin, in turn, leads to disruption of the action of intestinal proteolytic enzymes - exopeptidases of intestinal juice: aminopolypeptidases and dipeptidases, which cleave off individual amino acids.

With enterocolitis, accompanied by a decrease in juice secretion, accelerated motility and impaired absorption of the small intestinal mucosa, a complex failure of protein absorption develops. Special significance has accelerated peristalsis, since the contact of the chyme and the intestinal wall is disrupted (this disrupts parietal digestion, which is important for the elimination of amino acids and subsequent absorption). The process of absorption in the intestine is an active process: 1. Adsorption of amino acids on the surface of the intestinal mucosa; epithelial cell membrane contains

a lot of lipids, which reduces the negative charge of the mucosa. 2. Enzymes involved in the transport of amino acids (phosphoamidase, possibly also transferase) through the intestinal epithelium probably have a group affiliation (that is, for different groups of amino acids there are different transport systems, since competitive relationships are created between amino acids during absorption). With enterocolitis, the edematous state of the mucous membrane, acceleration of motility and weakening of the energy supply for the absorption process disrupt absorption in the intestine. Thus, the qualitative balance of incoming amino acids is disrupted (uneven absorption of individual amino acids over time, disturbance of the ratio of amino acids in the blood - imbalance). The development of an imbalance between individual amino acids in the pathology of absorption occurs because the absorption of individual amino acids occurs in different times during the digestion process as amino acids are eliminated. For example, tyrosine and tryptophan are split off in the stomach. The entire transition into amino acids of food proteins is carried out in 2 hours (during this time they already appear in the blood), and in case of pathology this period is extended. From the blood, amino acids enter cells, where they are either used for synthesis or deaminated. And for synthesis to occur, all amino acid partners must be together at the same time and in certain proportions. If the absorption processes are disrupted, this ratio is disrupted and the amino acids do not go to protein synthesis, but along the path of deamination and degrade. An amino acid imbalance occurs. This phenomenon also occurs when eating only one type of food protein (monotonous diet). The state of imbalance and disruption of synthesis can manifest itself in the development of intoxication (when the body is overloaded with any particular types of amino acids, they have a toxic effect, or as a result of excessive deamination). Individual amino acids, when broken down, form toxic products. In the end, a general protein deficiency occurs as a result of insufficient intake or impaired digestion and absorption, etc. Another side of the imbalance is a violation of protein metabolism during selective

deficiency of individual amino acids (meaning, essential ones) and here the synthesis of protein, in which this amino acid predominates, is predominantly disrupted. This is an amino acid deficiency. So, nutritional disorders of protein metabolism can be associated with a quantitative deficiency, qualitative uniformity, a quantitative deficiency of individual amino acids, with a quantitative predominance of individual amino acids - all of them are united in the concept of imbalance.

Disturbances in neurohumoral processes may also underlie disturbances in the processes of protein synthesis and breakdown. In highly developed animals, protein synthesis is regulated by the nervous system and hormones. Nervous regulation occurs in two ways: 1. Direct influence (trophic). 2. Through indirect effects - through hormones (changes in the function of the endocrine glands, the hormones of which are directly related to protein metabolism).

Classification of species protein synthesis and hormonal

Protein has important function in the body, since it is a plastic material from which the construction of cells, tissues and organs of the human body occurs. In addition, protein is the basis of hormones, enzymes and antibodies that perform growth functions in organisms and protect them from exposure negative factors environment. At normal metabolism protein in the body, a person has high immunity, excellent memory and endurance. Proteins affect the complete metabolism of vitamins and mineral salts. Energy value 1 g of protein is 4 kcal (16.7 kJ).

When there is a lack of proteins in the body, serious violations: slower growth and development of children, changes in the liver of adults, gland activity internal secretion, blood composition, weakening of mental activity, decreased performance and resistance to infectious diseases.

Protein metabolism plays important role during the life of the organism. Disruption of protein metabolism causes a decrease in activity, and resistance to infections also decreases. At insufficient quantities proteins in children's body- there is a slowdown in growth, as well as a decrease in concentration. It is necessary to understand that violations are possible different stages protein synthesis, but all of them are dangerous for the health and full development of the body.

Stages of protein synthesis:

Absorption and synthesis;
Amino acid metabolism;
The final stage of the exchange.

At all stages, there may be violations that have their own characteristics. Let's look at them in more detail.

First stage: Absorption and synthesis

A person gets the main amount of protein from food. Therefore, when digestion and absorption are impaired, protein deficiency develops. For normal protein synthesis, the proper functioning of the synthesis system is necessary. Disturbances in this process can be acquired or hereditary. Also, a decrease in the amount of protein synthesized may be associated with problems in work immune system. It is important to know that disturbances in the process of protein absorption lead to nutritional deficiency(dystrophy of intestinal tissue, fasting, unbalanced composition of food in terms of amino acid component). Also, disruption of protein synthesis processes most often leads to a change in the amount of synthesized protein or to the formation of a protein with an altered molecular structure. As a result, there are hormonal changes , dysfunction of the nervous and immune systems, genomic errors are also possible.

Second stage: Amino acid metabolism

Disorders of amino acid metabolism may also be associated with hereditary factors. Problems at this stage most often manifest themselves in a lack of tyrosine. This, in particular, provokes congenital albinism. A more terrible disease caused by a lack of tyrosine in the body is hereditary tyrosenemia. Chronic form the disease is accompanied frequent vomiting, general weakness, painful thinness (up to the onset of anorexia). Treatment consists of following special diet with a high content of vitamin D. Disorders of amino acid metabolism lead to an imbalance in the processes of transamination (formation) and oxidative destruction of amino acids. Fasting, pregnancy, liver disease, and myocardial infarction can influence the negative development of this process.

Third stage: final exchange

At the final stages of protein metabolism, a pathology in the process of formation of nitrogenous products and their final removal from the body may occur. Similar violations observed during hypoxia (oxygen starvation of the body). You should also pay attention to such a factor as the protein composition of the blood. Abnormal levels of proteins in the blood plasma may indicate liver problems. Kidney problems, hypoxia, and leukemia can also be a catalyst for the development of the disease. The restoration of protein metabolism is carried out by a therapist, as well as a nutritionist.

Symptoms of protein metabolism disorders

If there is a large amount of protein in the body, there may be an excess of it. This is primarily due to poor nutrition when the patient’s diet consists almost entirely of protein products. Doctors identify the following symptoms:

Decreased appetite;
Development renal failure;
Salt deposition;
Stool disorders.

Excess protein can also lead to gout and obesity. A risk factor for gout may be overuse eating large amounts of meat, especially with wine and beer. Gout is more common in older men, who are characterized by age-related hyperuricemia.

Symptoms of gout:

swelling and redness in the area of the first metatarsophalangeal joint;
hyperthermia up to 39 C;
gouty polyarthritis,
gouty nodes (tophi) on the elbows, feet, ears, fingers.

Symptoms of obesity:

frequent shortness of breath;
significant increase in body weight;
bone fragility;
hypertension (increased hydrostatic pressure in blood vessels).

If you have the above problems, you need to reduce your intake of protein foods and drink more clean water, exercise. If, on the contrary, the body does not have enough proteins for synthesis, it reacts to the situation as follows: general drowsiness, sudden weight loss, general muscle weakness and decreased intelligence occur. Note that the “risk group” includes vegetarians and vegans who, for ethical reasons, do not consume animal protein. People who adhere to a similar eating style need to additionally take orally vitamin complexes. Pay special attention to vitamin B12 And D3.

Hereditary disorders of amino acid metabolism

It is important to know that when hereditary disorder synthesis of enzymes, the corresponding amino acid is not included in metabolism, but accumulates in the body and appears in biological environments: urine, feces, sweat, cerebrospinal fluid. If you look at clinical picture manifestations of this disease, it is determined primarily by the appearance of a large amount of a substance that should have been metabolized with the participation of a blocked enzyme, as well as a deficiency of the substance that should have been formed.

Tyrosine metabolism disorders

Tyrosinosis - This is a hereditary disease caused by a disorder in the metabolism of tyrosine (necessary for the life of the human body and animals, since it is part of the molecules of proteins and enzymes). This disease manifests itself with severe damage to the liver and kidneys. Exchange tyrosine in the body is carried out in several ways. If the conversion of parahydroxyphenylpyruvic acid formed from tyrosine into homogentisic acid is insufficient, the former, as well as tyrosine, are excreted in the urine.

Violations protein composition blood

It is also worth mentioning disturbances in the protein composition in the blood. Changes in the quantitative and qualitative ratio of blood proteins are observed in almost all pathological conditions , which affect the body as a whole, as well as when congenital anomalies protein synthesis. Disturbances in the content of blood plasma proteins can be expressed by a change in the total amount of proteins (hypoproteinemia, hyperproteinemia) or the ratio between individual protein fractions (dysproteinemia) with normal general content proteins.

Hypoproteinemia occurs due to a decrease in the amount of albumin and can be acquired (due to starvation, liver disease, impaired protein absorption) and hereditary. Hypoproteinemia can also be caused by the release of proteins from the bloodstream (blood loss, plasma loss) and the loss of proteins in the urine.

Scientists have found that increasing the production of a protein that is involved in the formation of long-term memory prevents epilepsy attacks. During the study, scientists were able to use genetic engineering significantly increase protein synthesis eEF2 in laboratory mice. The connection between the action of this protein and epilepsy was not previously known, which gives hope for the development of new possibilities in the treatment of the disease.

The study was conducted at the University of Haifa (Israel) together with scientists from the University of Milan and several other European universities. Professor Coby Rosenblum, the study's principal investigator, said: "By changing the genetic code, we were able to prevent mice that would have been born with the condition from developing epilepsy, as well as cure mice that were already suffering from the condition."

Epilepsy - neurological disease, in which sudden and uncontrolled activity occurs in the nerve cells of the cerebral cortex, which is expressed in epileptic seizures of varying frequency and power. The drugs used today to treat epilepsy can eliminate or reduce the number of attacks of the disease only in some patients. In some cases, they resort to minimally invasive neurosurgical operations, which give good results. However, they also may not be used for all patients.

Interestingly, Israeli scientists initially planned to conduct a study to study the mechanisms that influence the formation of long-term memory. The scientists' goal was to study the molecular mechanisms that contribute to the formation of long-term memory and are located in the hypothalamus (a region of the brain). To do this, they focused on studying protein eEF2, which takes part in the processes of memory formation and the formation of new cells nervous system. Using genetic engineering methods, scientists were able to achieve enhanced protein production, which led to changes in activity nerve cells, responsible for the formation of epileptic seizures.

In order to test how the production of this protein affects the development of epileptic attacks, the mice were divided into two groups. The first group had gene mutation and, accordingly, intensively produced protein eEF2, and the second control group of mice was without any genetic changes. Scientists injected mice from both groups with a solution that causes epileptic seizures. This led to epileptic seizures in mice from the control group, and mice with genetic mutation did not develop signs of epilepsy.

However, scientists did not stop there and decided to test the effect of the mutation in hereditary epilepsy. To do this, they crossed mice with a gene mutation eEF2 with mice that had a gene responsible for the development of epilepsy. According to the results of the experiment, epilepsy attacks were not observed in mice with a protein mutation. Throughout the study, mice underwent various texts, determining motor, cognitive and behavioral functions. All of them remained normal in mice that had a mutation in this protein.

“The results of the study give us more understanding about the processes of excitation and inhibition in the hypothalamus, the disruption of which is associated with various pathologies of the nervous system,” says Professor Rosenblum, “We continue research in this direction to better understand the cause of the development of epileptic seizures. This will allow us to create new treatments for the disease in the future.”

Heat shock in the developing brain and genes that determine epilepsy

N. E. Chepurnova

Moscow State University named after. M.V. Lomonosov

Etiology and pathogenesis of febrile seizures

Each new step in solving fundamental biological problems helps to understand the age-old problems of human diseases, their nature and again turns us to hereditary factors. “Inexhaustible hereditary biochemical heterogeneity cannot but entail,” wrote V.P. Efroimson, “inexhaustible hereditary mental heterogeneity...”. This is true for the severity of neurological and mental diseases.

Epilepsy manifests itself in 2-4% of the human population; it poses the greatest danger in childhood. Febrile seizures (FS) account for up to 85% of all convulsive syndromes observed in children. The total number of children aged 6 months to 6 years with FS ranges from 2 to 5% (9% in Japan), the largest number of such children is observed in Guam - 15%. More than half of FS attacks occur during the second year of a child’s life, with peak frequency occurring between 18 and 22 months. Seizures can be provoked by diseases occurring with a temperature above 39-41 ºС, but doctors have always assumed the presence of a hidden genetic predisposition in a child to paroxysmal conditions if an increase in temperature causes FS. Boys get sick four times more often than girls. Suggestions have been made about autosomal dominant inheritance, autosomal recessive inheritance of FS, but polygenic or multifactorial inheritance is not excluded. Genetic heterogeneity of epilepsy manifests itself in different levels. It is revealed in a variety of clinical features of the phenotype, heritable characteristics (patterns), primary gene products, among which may be factors for the development and differentiation of neurons, enzymes, receptor proteins, channel proteins, and finally, products of another gene. Abnormalities of the genetic code also vary, and several loci on different chromosomes may be involved.

According to the US national program (California Comprehensive Epilepsy Program), between 2 and 2.5 million Americans suffer from epilepsy. Over 10 years of studies of American families, six different loci on different chromosomes were identified in patients with epilepsy. When mapping chromosomes, it is customary to denote its number as the first digit; letters p or q shoulders, followed by numbers segments of regions (for more details, see). It was found that loci on chromosomes 6p and 15q are responsible for juvenile myoclonic epilepsy; for classic juvenile epilepsy with grand mal seizures and mixed with absence seizures on chromosome 6p (absences are sudden short-term blackouts lasting 2-15 s). Two loci have been identified for childhood absence epilepsy (pycnolepsy), which occurs with severe seizures - in 8q24 and for developing into juvenile myoclonic epilepsy - in 1p. In patients in Italian families, other loci were identified: for idiopathic (from the Greek idios - own; pathos - suffering; idiopathic - primarily occurring without external causes) generalized epilepsy - in chromosome 3p, and for generalized epilepsy with febrile convulsions and absence seizures - also in chromosome 8q24.

The gene that determines the development of FS turned out to be in different regions of the 8th and 19th chromosomes than previously determined by DNA markers. Their position indicates a connection between FS and other genetically determined forms of epilepsy.

The study of families with inheritance of FS identified a genetic component and autosomal dominant inheritance. The work of Japanese geneticists, when examining 6,706 children aged three years in the Fuchu province of Tokyo with a population of about 182,000 people, showed that 654 children had FS. New interesting facts were obtained by S. Berkovich as a result of many years of research on families in Australia. It was discovered that the main PS gene is located at 8q13-21 and is associated with Na+ channel protein synthesis. Peculiarities immune status in Egyptian children who underwent FS, it was suggested that genetically determined FS were observed in children with the HLA-B5 antigen, low level immunoglobulin IgA and low content T-lymphocytes. All this allows us to talk about feedback: children had not only a predisposition to FS, but also an increased sensitivity to acute infections occurring with fever, which becomes physiological reason seizures The combination of intrauterine encephalopathy syndromes with a hereditary family history of epilepsy only worsens the outcome of FS. Since the main condition for the occurrence of PS in a child is an increase in temperature, hyperthermia should be considered as a factor in epileptogenesis.

The role of the thermoregulatory center of the hypothalamus in the initiation of febrile seizures

Why is a prolonged increase in temperature so dangerous for developing brain child? The facilitation of the occurrence of PS is determined by the low level of the inhibitory mediator - gamma-aminobutyric acid (GABA) and the absence of full-fledged receptors for it, as well as a decrease in the level of ATP in the brain for one reason or another, especially under the influence of hypoxia. In a child, the level of lipid peroxidation products increases, brain microcirculation is disrupted, and brain hyperthermia is accompanied by edema. All neurochemical systems of inhibition of neurons, and primarily hypothalamic ones, are immature. In the brain, connections are just being established between brain cells responsible for the constancy of body temperature.

The temperature regulation center is located in the anterior hypothalamus. More than a third of the neurons in this area are thermoreceptors, and they receive information from peripheral thermoreceptors of the skin and internal organs via nerve pathways. Approximately a third of these cells are thermal receptors; they increase the frequency of discharges with increasing blood temperature (0.8 imp "s-1" °C-1), less than 5% of the cells are cold receptors. Recently, experiments on isolated brain slices showed that an increase in the temperature of the washing blood changes the rate of neuronal depolarization, determined by the properties of the Na+ channels of the membrane, while at the same time the interspike intervals decrease, which partly depends on the K+ channels. As a result, the frequency of cell discharges increases sharply. When the inhibitory systems are underdeveloped, this leads to hyperexcitability, the occurrence of paroxysmal excitations covering the motor cortex, and the appearance of seizures.

Heat production and heat transfer are two important physiological mechanisms for maintaining temperature in the optimal range for the body. But it is precisely these peripheral mechanisms in the child that are also immature and cannot stop the increasing hyperthermia.

Modeling of febrile seizures in newborn animals

The developed models of PS in newborn animals - rat pups - helped to identify vulnerable, critical periods of brain development, temperature thresholds at which PS occur, to study the long-term consequences of PS, and to study the effect of anticonvulsants. Working together with Park Jin Kyu in Daejeon (South Korea), we found that systemic administration of a specific combination of ginsenosides, biologically active substances isolated from ginseng root, provides unique opportunities for preventing or reducing the severity of FS in rat pups. Of all the techniques developed by physiologists: endogenous hyperthermia, external warming with air, microwave, infrared rays, we chose simple heating with an incandescent lamp. As body temperature rises, there is a gradual development of external signs of motor seizures, the severity of which was determined according to the generally accepted scale of P. Maresh and G. Kubova. Hyperthermia was stopped when tonic-clonic convulsions with loss of posture appeared in the rat pups, and in the absence of PS, after 15 minutes. To measure infrared radiation Thermal imaging method was used from the intact surface of the animal’s skin – an Inframetrics 522L infrared detector.

Neuroendocrine regulation of febrile seizures

The brain's response to hyperthermia involves the neurohormone arginine vasopressin (AVP). This hypothesis of K. Pitman is supported by the following facts: in Brattleboro rats with a genetically determined deficiency of AVP and in rats passively immunized to this peptide, a convulsive response to elevated temperature occurs at higher temperatures than in animals with a normal level of its synthesis. Electrical stimulation of neurons that synthesize AVP helps to stop fever. On the one hand, clinical data indicate an increase in the level of AVP in the blood plasma in children after convulsive seizures, on the other hand, perfusion of AVP through the transparent septum of the brain in animals leads to a decrease elevated temperature bodies. The hypothesis allows us to talk about the discovery of an endogenous antipyretic (from the Greek pyretos - heat, fever, pyretica - medicine causing fever). Paradoxically, it turned out that the antipyretic function of the neurohormone AVP is combined with a proconvulsant effect.

In our experiments performed with Soros student A.A. Ponomarenko, new facts were obtained about the proepileptic effect of AVP using the example of PS in the early postnatal ontogenesis of the brain of rat pups. AVP actually significantly shortens the time of appearance of generalized, hyperthermic convulsions on the 3rd and 5th days after birth, their duration clearly increases compared to those in animals of the control group. On the 9th postnatal day, with a combination of hyperthermia and AVP administration in the experimental group, febrile status epilepticus lasting more than 2 hours resulted in the death of all rat pups receiving AVP. Such events leading to death cannot but be controlled at the hormonal and neurochemical levels. It was necessary to find out which regulators aggravated the effect of high temperature.

AVP is an antidiuretic hormone that retains water in the body, so its secretion depends on the water-salt balance, but in addition, its release is controlled by the recently discovered peptide that activates pituitary adenylate cyclase (abbreviated by its first Latin letters - PACAP). The effect of the latter does not depend on an increase or decrease in the concentration of salts in the blood. Only in 1999, Nomura proved that PACAP stimulates the transcription of the AVP gene in the cells of those hypothalamic nuclei that are responsible for the regulation of water-salt metabolism and drinking behavior. Our experiments have shown that when PACAP is administered to rat pups, it can act through the secretion of AVP at the time of hyperthermia (see Fig. 2). Multidirectional changes in experimental febrile seizures were found in rat pups after administration of high (0.1 μg per rat) and low (0.01 μg per rat) doses of PACAP. The effect also depends on the age of the rat, that is, the maturity of the hypothalamus.

So, AVP combines the functions of an endogenous antipyretic agent and an inducer of a convulsive motor reaction during rapid rise body temperature, and one of the regulators of its secretion - PACAR - can accelerate these processes. Seems likely direct action AVP and PACAP on the membranes of nerve cells through their receptors (Fig. 3). But other regulatory pathways cannot be excluded, for example through the hypothalamic releasing factor – corticoliberin. Cells that synthesize PACAP send their axons to the bodies of neurosecretory cells of the hypothalamus that synthesize corticoliberin. The release of corticoliberin into the blood provokes epileptic seizures.

Intracellular protection of neurons – heat shock proteins

In some cases of genetically determined neuropathology, molecular events are secondary. Febrile seizures are no exception. A significant increase in body temperature leads to the expression of genes for a huge number of proteins called “heat shock proteins” (HSPs). Transcription of HSP begins several minutes after heating. This reaction has always been considered protective against death from heat shock. The latest evidence for this theory comes from the Cancer Institute in Copenhagen. In tissue culture, it has been shown that severe heat stress causes apoptosis (from the Greek apoptosis - falling of leaves or petals from a flower - genetically

programmed death of one or more cells, see for more details), but moderate stress (and hyperthermia is classified as moderate stress), due to the preservation of the cell’s ability to synthesize HSPs, protects them from both apoptosis and necrosis. This property will allow the use of HSPs in vivo (in the clinic) to protect the heart and brain from ischemia, the lungs from sepsis, moreover, they can be used in anti-cancer therapy. HSPs can also be used for urgent brain protection in the event of FS in children.

HSP synthesis is a nonspecific stress response. In the cells and tissues of the body, HSPs are induced by many factors in addition to hyperthermia, namely: ischemia, peroxidation, the action of cytokines (cytokines are endogenous protein regulators involved in the most effective manifestation of the immune response), muscle stress, glucose deprivation, disturbances in the level of Ca2 + and pH. Dutch physiologists in Nijmegen recently showed that defensive reactions in the form of HSP expression are observed in patients with parkinsonism in the late stage of the disease with the development of dementia and in Alzheimer's disease. A direct correlation was found between HSP expression and the severity of Alzheimer's disease, especially with damage to the hippocampus.

Thus, during PS, HSP genes are expressed, but such nonspecific protection is not always sufficient to preserve inhibitory cells, especially in the hippocampus. Therefore there is a threat long-term consequences in the form of mesial hippocampal sclerosis, causing temporal lobe epilepsy. If there is a genetic predisposition to temporal lobe epilepsy develops with a predisposition to FS, the prognosis of the disease is especially difficult.

The question of the consequences of FS in the form of the development of temporal lobe epilepsy is important for the subsequent fate of the child. The main discussion in the clinic revolved around the question of whether cells die as a result of PS, or whether they die for other reasons (for example, as a result of a violation of the protective synthesis of HSPs, the development of apoptosis). Molecular biological studies in the laboratory of K. Wasterline in Los Angeles showed that seizure processes in the developing brain delay its development, and in particular the growth of axons, since the seizure disrupts the expression of the gene for the marker of the axon growth cone - the GAP-43 protein.

Surgeons who operate on the temporal region to treat temporal lobe epilepsy note that many of their patients have had episodes of FS in childhood. However, this is a retrospective assessment. Recent research in Canada has shown that a positive family history and FS are inseparable factors in the development of temporal lobe epilepsy. It can be assumed that the longer the FS attacks were, the longer the generalized seizure engulfed the child’s brain and the more nerve cells died. No matter how small the percentage of such children is (only 1.5-4.6% of children with FS subsequently develop epilepsy), they will be doomed to suffering and treatment for the rest of their lives due to the death of hippocampal inhibitory cells due to hyperthermia.

Genetics of potassium and sodium channels and epilepsy

The causes of paroxysmal states may be changes in the structure and functions of Na+-, Ca2+-, Cl--, K+ channels. The channel is one protein molecule, it is characterized by strict selectivity with respect to the type of ion passed through, and has a gate device that is controlled by the potential on the membrane (Fig. 4, a). Origin and implementation nerve impulses depends on the state of the ion channels. The last ten years have been studied hereditary diseases nervous system, which received a new name - “channelopathy”. The disorders are associated with the localization of genes in chromosomes: 19q13.1 (Na+ channel), 12p13, 20q13.3, 8q24 (K+ channel), 7q (Cl- channel). Disclosure molecular structure channels helped to understand the inheritance of epilepsy.

A nerve impulse is a consequence of the movement of Na+ into the cell through membrane channels, and K+ out of the cell. Positively charged Na+ ions entering along the ion gradient create a current that depolarizes the membrane, reducing membrane potential to zero, and then recharging the membrane to + 50 mV. Since the state of these channels depends on the sign of the charge on the membrane, a positive membrane potential promotes the inactivation of sodium channels and the opening of potassium channels. Now the K+ ions leaving the cell create a current that recharges the membrane and restores its resting potential. Disturbances of Na+ channels lead to changes in cell depolarization, and disturbances of K+ channels lead to disruption of polarization. The discovery in 1980 by D. Brown and P. Adams of low-threshold M-currents through non-inactivating KCNQ2/KCNQ3 potassium channels helped to understand the nature of susceptibility to epilepsy. M-currents change the excitability of the cell and prevent the occurrence of epileptic neuron activity. Disruption of the KCNQ2/KCNQ3 potassium channel genes leads to the disease “familial neonatal seizures”, which occurs in a child on the 2-3rd days after birth. The newly synthesized drug retigabine helps patients with epilepsy by opening KCNQ2/KCNQ3 channels in neuronal membranes. This is an example of how fundamental study of channels can help synthesize new drugs against channelopathies.

We have already mentioned two loci responsible for PS. New studies have shown the involvement of another region of 19q13.1, responsible for the synthesis of the b1 subunit of the Na+ channel. Mutations in this region determine the occurrence febrile seizures in combination with generalized epilepsy. The Na+ channel consists of one a- (forming a pore) and two b-subunits, the latter modulate the process of inactivation of the channel, that is, the work of the a-subunit (see Fig. 4, a). The effect of the a-subunit on the gate system depends on the structure of the extracellular domain of the b1-subunit. The SCN1B gene responsible for the b1 subunit was reasonably chosen for research, since the action of the main anticonvulsants phenytoin and carbamazepine is to inactivate sodium channels. Moreover, it was already known that mutations of this gene in muscle cell lead to paroxysmal excitations (myotonia, periodic paralysis), and in cardiac cells - to an increase in the QT interval in the ECG. It is in the region of the disulfide bridge that a mutation occurs, leading to its destruction and a change in the structure of the extracellular domain b1 (Fig. 4, b). Transfer of the gene into the Xenopus laevis oocyte and induction of the synthesis of the defective channel made it possible to electrophysiologically study the mutant channel and prove that it is inactivated more slowly (see Fig. 4, b). It is very important that in such patients there are no changes in the cells of the heart muscle and skeletal muscles, and the mutation is observed only for the neural isoform of Na+ channels. This mutation was identified as a result of research by Australian geneticists. A study was conducted of six generations of families (378 people), living mainly in Tasmania and having a family history of FS in combination with generalized epilepsy. These works opened new way to study idiopathic forms of epilepsy, which may result from as yet unknown forms of channelopathies.

Equally important are disturbances in the synthesis of protein receptors for mediators. Autosomal dominant inheritance of nocturnal frontal lobe epilepsy is associated with chromosome 20 (gene localization in q13.2 - q13.3), and the manifestation of this form of epilepsy is associated with the S248F mutation of the genetic code of the a4 subunit of the H-cholinergic receptor. The “wall” of the channel protein, its transmembrane 2nd segment, in which the amino acid serine is replaced by phenylalanine, is subject to change. Disturbances in the regulation of the gene expression of the b-subunit of the NMDA receptor protein for the excitatory transmitter - glutamate, the release of which by brain cells initiates an epileptic attack, were also discovered. If, during the process of mRNA editing, glutamine is replaced by arginine in the membrane domain, the resulting disruption of alternative splicing (for more details, see) is already sufficient to significantly increase the excitability of hippocampal neurons.

Inheritance of "hot water epilepsy"

In one of the poster presentations by Indian neurologists at the Epilepsy Congress in Oslo in 1993, we suddenly saw something reminiscent of a medieval Chinese execution: hot water was dripped onto the head of a motionless rat until a severe epileptic seizure occurred. An unbiased study of this report showed that the created torment of the rat is caused by the desire to understand a serious illness, which in populous India affects almost 7% of all patients with epilepsy and accounts for 60 cases per 100 thousand diseases. This phenomenon is similar to the hyperthermia-induced convulsions discussed above.

Occurrence epileptic seizure when washing your hair hot water was first described in New Zealand in 1945. A sick person, when washing his hair (and in Hindu traditions, this procedure is repeated once every 3-15 days) with hot water at a temperature of 45-50 ° C, experiences an aura, hallucinations, ending in partial or generalized convulsions with loss of consciousness (men are 2-2.5 times more likely than women). It is possible to measure the temperature of the brain as closely as possible by inserting a special electrothermometer into the ear canal close to the eardrum. It turned out that in patients the brain temperature at the beginning of washing their hair rises very quickly (every 2 minutes by 2-3°C) and very slowly

decreases after stopping washing. Their brains “cool down” slowly (10-12 minutes), while in healthy volunteers participating in such experiments, the brain “cools down” almost instantly after stopping bathing. The question naturally arose: what deviations in thermoregulation are the cause of the disease and are they determined genetically? The true reason was revealed by twin studies and family analysis data. It turned out that in India up to 23% of all cases of epilepsy hot water" is repeated in subsequent generations.

PS, as we have already said, are a consequence of autosomal dominant inheritance at one chromosome locus - 8q13-21. In “hot water epilepsy,” changes in one locus are not sufficient to explain the entire complex of the disease. The appearance of the diseased phenotype (both sexes) may be associated with an autosomal recessive mutation leading to this disease. Observations of five generations of several families in India showed that the disease occurs in children of closely related parents, for example in marriages between nephews. In southern India, the tradition of such consanguineous marriages has been preserved, which, apparently, can explain the high percentage of patients compared to other states.

Conclusion

The neurogenetic approach has made it possible to definitively establish the genetic predisposition to febrile seizures. This is why not every child who has been in very high temperature(40-41°C), motor convulsions occur. The main PS gene is associated with the membrane mechanisms of neuron excitability, with the control of the synthesis of the protein channel through which Na+ ions pass. A depolarizing excitation of the neuron is created. It is not surprising that the “genes” of these disorders related to FS are somewhat “aloof” from the specific genes responsible for other forms of epilepsy. External cause FS is overheating, which occurs under the influence of either endogenous pyretics (for example, during an infectious disease), or actually under the influence of an increase in environmental temperature. In response to hyperthermia, physiological defense is the first to turn on - functional system maintaining the temperature in the optimal range. It is aimed at reducing body temperature. Nerve signals go to the vegetative centers - commands aimed at releasing heat and reducing heat production. The cells of the hypothalamus, having the ability to measure blood temperature, themselves use feedback mechanisms to monitor the results of these commands. Since they are neurosecretory and secrete liberins and statins, they can simultaneously trigger complex biochemical changes by regulating the secretion of pituitary hormones. TO autonomic regulation connect almost simultaneously endocrine mechanisms and behavioral defensive reactions. The release of synaptic AVP as an antipyretic substance leads to an increase in the convulsive response. The secretion of AVP, in turn, is enhanced by the neuropeptide PACAP, which activates the energy of pituitary cells. Unfortunately, this protective attempt to lower body temperature ends in provoking seizures. Genetic predisposition and low seizure threshold lead to irreversible development of events. Paroxysmal pathological convulsive activity of neurons occurs, first in the hippocampus, amygdala, associative parts of the cortex, and then in the motor cortex. For all types of seizures, the main cause remains a violation of the ratio of the release of excitatory (glutamate) and inhibitory (GABA) mediators. This violation is a pre-trigger mechanism. Unlimited excitation in the nerve networks covers the parts of the brain responsible for tone and movement, and leads to convulsions. Before this, loss of consciousness occurs, as pathological excitation covers the structures of the brain stem and thalamus. Of course, the brain also has other protective mechanisms, such as compensatory expression of early oncogenes (c-fos, c-jun), accumulation of cAMP, secretion of thyrotropin-releasing hormone, and long-term release of an inhibitory transmitter. However, the question of why these mechanisms are ineffective in the case of a genetic predisposition to PS requires further research.

It is known that proteins undergo hydrolysis under the influence of endo- and exopeptidases formed in the stomach, pancreas and intestines. Endopeptidases (pepsin, trypsin and chymotrypsin) cause the breakdown of protein in its middle part into albumin and peptones. Exopeptidases (carbopeptidase, aminopeptidase and dipeptidase), formed in the pancreas and small intestine, ensure the cleavage of the terminal sections of protein molecules and their breakdown products into amino acids, which are absorbed in the small intestine with the participation of ATP.

Disorders of protein hydrolysis can be caused by many reasons: inflammation, tumors of the stomach, intestines, pancreas; resection of the stomach and intestines; general processes such as fever, overheating, hypothermia; with increased peristalsis due to disorders of neuroendocrine regulation. All of the above reasons lead to a deficiency of hydrolytic enzymes or acceleration of peristalsis when peptidases do not have time to ensure the breakdown of proteins.

Undigested proteins go to large intestine, where, under the influence of microflora, decay processes begin, leading to the formation of active amines (cadaverine, tyramine, putrescine, histamine) and aromatic compounds such as indole, skatole, phenol, cresol. These toxic substances are neutralized in the liver by combining with sulfuric acid. In conditions of a sharp increase in decay processes, intoxication of the body is possible.

Absorption disorders are caused not only by breakdown disorders, but also by ATP deficiency associated with inhibition of the coupling of respiration and oxidative phosphorylation and blockade of this process in the wall of the small intestine during hypoxia, poisoning with phloridzin, monoiodoacetate.

Impaired breakdown and absorption of proteins, as well as insufficient intake of proteins into the body, lead to protein starvation, impaired protein synthesis, anemia, hypoproteinemia, a tendency to edema, and immune deficiency. As a result of activation of the hypothalamic-pituitary-adrenal cortex system and the hypothalamic-pituitary-thyroid system, the formation of glucocorticoids and thyroxine increases, which stimulate tissue proteases and protein breakdown in the muscles, gastrointestinal tract, and lymphoid system. In this case, amino acids can serve as an energy substrate and, in addition, are intensively excreted from the body, ensuring the formation of a negative nitrogen balance. Protein mobilization is one of the causes of dystrophy, including in muscles, lymph nodes, and the gastrointestinal tract, which aggravates the disruption of protein breakdown and absorption.

When absorbing unsplit protein, allergization of the body is possible. So, artificial feeding children often leads to allergization of the body in relation to protein cow's milk and other protein products. The causes, mechanisms and consequences of disorders of protein breakdown and absorption are presented in Scheme 8.

Scheme 8. Disorders of protein hydrolysis and absorption
	Hydrolysis disorders	Absorption disorders
Reasons	Inflammation, tumors, resection of the stomach and intestines, increased peristalsis (nervous influences, decreased stomach acidity, ingestion of poor quality food)
Mechanisms	Deficiency of endopeptidases (pepsin, trypsin, chymotrypsin) and exopeptidases (carbo-, amino- and dipeptidases)	ATP deficiency (absorption of amino acids is an active process and occurs with the participation of ATP)
Consequences	Protein starvation -> hypoproteinemia, edema, anemia; immunity disorder -> tendency to infectious processes; diarrhea, disruption of hormone transport. Activation of protein catabolism -> atrophy of muscles, lymph nodes, gastrointestinal tract with the subsequent aggravation of disturbances in the processes of hydrolysis and absorption of not only proteins, vitamins, but also other substances; negative nitrogen balance. Absorption of unsplit protein -> allergization of the body. When undigested proteins enter the large intestine, the processes of bacterial breakdown (putrefaction) increase with the formation of amines (histamine, tyramine, cadaverine, putrescine) and aromatic toxic compounds (indole, phenol, cresol, skatole)

This type of pathological processes includes insufficiency of synthesis, increased breakdown of proteins, and disturbances in the conversion of amino acids in the body.

Disturbance of protein synthesis.
Protein biosynthesis occurs on ribosomes. With the participation of transfer RNA and ATP, a primary polypeptide is formed on ribosomes, in which the sequence of amino acids is determined by DNA. The synthesis of albumin, fibrinogen, prothrombin, alpha and beta globulins occurs in the liver; Gamma globulins are formed in the cells of the reticuloendothelial system. Disorders of protein synthesis are observed during protein starvation (as a result of starvation or impaired breakdown and absorption), with liver damage (circulatory disorders, hypoxia, cirrhosis, toxic-infectious lesions, deficiency of anabolic hormones). An important reason is hereditary damage to the B-immune system, in which the formation of gamma globulins in boys is blocked (hereditary agammaglobulinemia).
Insufficient protein synthesis leads to hypoproteinemia, impaired immunity, dystrophic processes in cells, blood clotting may slow down due to a decrease in fibrinogen and prothrombin.
An increase in protein synthesis is caused by excess production of insulin, androgens, and somatotropin. Thus, with a pituitary tumor involving eosinophilic cells, an excess of somatotropin is formed, which leads to activation of protein synthesis and increased growth processes. If excessive formation of somatotropin occurs in an organism with incomplete growth, then the growth of the body and organs increases, manifesting itself in the form of gigantism and macrosomia. If increased secretion of somatotropin occurs in adults, then an increase in protein synthesis leads to the growth of protruding parts of the body (hands, feet, nose, ears, brow ridges, lower jaw, etc.). This phenomenon is called acromegaly (from the Greek acros - tip, megalos - large). With a tumor of the reticular zone of the adrenal cortex, birth defect formation of hydrocortisone, as well as tumors of the testes, the formation of androgens is enhanced and protein synthesis is activated, which is manifested in an increase in muscle volume and the early formation of secondary sexual characteristics. Increased protein synthesis is the cause of positive nitrogen balance.
An increase in the synthesis of immunoglobulins occurs during allergic and autoallergic processes.
In some cases, it is possible to distort protein synthesis and form proteins that are not normally found in the blood. This phenomenon is called paraproteinemia. Paraproteinemia is observed in myeloma, Waldenström's disease, and some gammopathies.
For rheumatism, severe inflammatory processes, myocardial infarction, hepatitis, a new, so-called C-reactive protein is synthesized. It is not an immunoglobulin, although its appearance is due to the body's reaction to the products of cell damage.

Increased protein breakdown.

With protein starvation, an isolated increase in the formation of thyroxine and glucocorticoids (hyperthyroidism, syndrome and Cushing's disease), tissue cathepsins and protein breakdown are activated, primarily in the cells of striated muscles, lymphoid nodes, and the gastrointestinal tract. The resulting amino acids are excreted in excess in the urine, which contributes to the formation of a negative nitrogen balance. Excessive production of thyroxine and glucocorticoids also manifests itself in impaired immunity and an increased susceptibility to infectious processes, dystrophy of various organs (striated muscles, heart, lymphoid nodes, gastrointestinal tract).

Observations show that in three weeks in the body of an adult, proteins are renewed by half through the use of amino acids received from food and through breakdown and resynthesis. According to McMurray (1980), at nitrogen equilibrium, 500 g of proteins are synthesized daily, i.e., 5 times more than what comes from food. This can be achieved through the reuse of amino acids, including those formed during the breakdown of proteins in the body.

The processes of enhancing protein synthesis and breakdown and their consequences in the body are presented in Schemes 9 and 10.

Scheme 10. Nitrogen imbalance
	Positive nitrogen balance	Negative nitrogen balance
Reasons	An increase in synthesis and, as a consequence, a decrease in the excretion of nitrogen from the body (tumor of the pituitary gland, reticular zone of the adrenal cortex).	The predominance of protein breakdown in the body and, as a result, the release of nitrogen in larger quantities compared to intake.
Mechanisms	Strengthening the production and secretion of hormones that provide protein synthesis (insulin, somatotropin, androgenic hormones).	Increased production of hormones that stimulate protein catabolism by activating tissue cathepeins (thyroxine, glucocorticoids).
Consequences	Acceleration of growth processes, premature puberty.	Dystrophy, including the gastrointestinal tract, impaired immunity.

Disturbances in the transformation of amino acids.
During interstitial metabolism, amino acids undergo transamination, deamination, and decarboxylation. Transamination is aimed at the formation of new amino acids by transferring an amino group to a keto acid. The acceptor of amino groups of most amino acids is alpha-ketoglutaric acid, which is converted into glutamic acid. The latter can again donate an amino group. This process is controlled by transaminases, the coenzyme of which is pyridoxal phosphate, a derivative of vitamin B 6 (pyridoxine). Transaminases are found in the cytoplasm and mitochondria. The donor of amino groups is glutamic acid, located in the cytoplasm. From the cytoplasm, glutamic acid enters the mitochondria.
Inhibition of transamination reactions occurs during hypoxia, vitamin B6 deficiency, including suppression of intestinal microflora by sulfonamides and ftivazide, which partially synthesizes vitamin B6, as well as during toxic-infectious liver lesions.
In case of severe damage to cells with symptoms of necrosis (infarction, hepatitis, pancreatitis), transaminases from the cytoplasm enter large quantities into the blood. Yes, when acute hepatitis, according to McMurray (1980), the activity of glutamate-allanine transferase in blood serum increases 100 times.
The main process leading to the destruction of amino acids (their degradation) is non-amination, in which, under the influence of amino oxidase enzymes, ammonia and keto acid are formed, which undergo further conversion in the tricarboxylic acid cycle to C0 2 and H 2 0. Hypoxia, hypovitaminosis C, PP, B 2 , B 6 blocks the breakdown of amino acids along this pathway, which contributes to their increase in the blood (aminoacidemia) and excretion in the urine (aminoaciduria). Usually, when deamination is blocked, some amino acids undergo decarboxylation with the formation of a number of biologically active amines - histamine, serotonin, gama-amino-butyric acid, tyramine, DOPA, etc. Decarboxylation is inhibited by hyperthyroidism and excess glucocorticoids.

As a result of deamination of amino acids, ammonia is formed, which has a strong cytotoxic effect, especially for cells of the nervous system. The body has formed a series compensatory processes, ensuring the binding of ammonia. The liver synthesizes urea from ammonia, which is a relatively harmless product. Ammonia binds in the cytoplasm of cells glutamic acid with the formation of glutamine. This process is called amidation. In the kidneys, ammonia combines with a hydrogen ion and is excreted in the urine in the form of ammonium salts. This process, called ammoniogenesis, is also important physiological mechanism aimed at maintaining acid-base balance.

Thus, as a result of deamination and synthetic processes in the liver, such end products of nitrogen metabolism as ammonia and urea are formed. During the transformation in the tricarboxylic acid cycle of the products of interstitial protein metabolism - acetyl coenzyme-A, alpha-ketoglutarate, succinyl coenzyme-A, fumarate and oxaloacetate - ATP, water and CO 2 are formed.

The end products of nitrogen metabolism are excreted from the body in different ways: urea and ammonia - mainly with urine; water in urine, through the lungs and by sweating; CO 2 - mainly through the lungs and in the form of salts in urine and sweat. These non-protein substances containing nitrogen constitute residual nitrogen. Normally, its content in the blood is 20-40 mg% (14.3-28.6 mmol/l).

The main phenomenon of disturbances in the formation and excretion of end products of protein metabolism is an increase in non-protein nitrogen in the blood (hyperazotemia). Depending on the origin, hyperazotemia is divided into production (hepatic) and retention (renal).

Productive hyperazotemia is caused by liver damage (inflammation, intoxication, cirrhosis, circulatory disorders), hypoproteinemia. In this case, the synthesis of urea is disrupted, and ammonia accumulates in the body, producing a cytotoxic effect.

Retention hyperazotemia occurs when the kidneys are damaged (inflammation, circulatory disorders, hypoxia), or impaired urine outflow. This leads to a delay and increase in residual nitrogen in the blood. This process is combined with the activation of alternative pathways for the release of nitrogenous products (through the skin, gastrointestinal tract, lungs). With retention hyperazotemia, the increase in residual nitrogen occurs mainly due to the accumulation of urea.

Disturbances in the formation of urea and the release of nitrogenous products are accompanied by disorders of water and electrolyte balance, dysfunction of organs and body systems, especially the nervous system. The development of hepatic or uremic coma is possible.

The causes of hyperazotemia, mechanisms and changes in the body are presented in Diagram 11.

Scheme 11. Disturbances in the formation and excretion of end products of protein metabolism
HYPERAZOTEMIA
	Hepatic (productive)	Renal (retention)
Reasons	Liver damage (intoxication, cirrhosis, circulatory disorders), protein starvation	Impaired urea formation in the liver
Mechanisms	Inflammation of the kidneys, circulatory disorders, disturbances in the outflow of urine	Insufficient excretion of nitrogenous products in urine
Changes in the body	Consequences- Dysfunction of organs and systems, especially the nervous system. The development of hepatic or uremic coma is possible. Compensation Mechanisms- Amidation in cells, ammoniogenesis in the kidneys, release of nitrogenous products by alternative routes (through the skin, mucous membranes, gastrointestinal tract)

Source: Ovsyannikov V.G. Pathological physiology, typical pathological processes. Tutorial. Ed. Rostov University, 1987. - 192 p.