Protein metabolism disorders. Metabolism is an epileptic seizure

(teaching aid for independent work of students)

coordinating methodological Council of Kazan State Medical University

PATHOLOGY OF PROTEIN METABOLISM (a teaching aid for independent work of students). Kazan 2006. - 20 p.

Compilers: prof. M.M.Minnebaev, F.I.Mukhutdinova, prof. Boychuk SV, Assoc. L.D. Zubairova, Assoc. A.Yu.Teplov.

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

Due to the variety of functions of proteins, their peculiar "omnipresence", 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 an important place in their pathogenesis and ultimately determine the degree of implementation of protective-adaptive reactions and adaptive mechanisms.

The methodological manual was compiled taking into account the relevant section of the program of pathological physiology.

Introduction

All proteins are in a state of continuous active metabolism - decay and synthesis. Protein metabolism provides the entire plastic side of the life of the organism. Depending on age, there is a positive and negative nitrogen balance. At a young age, a positive nitrogen balance prevails (increased growth), 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, prevails. In older age - the predominance of catabolic processes. The regenerative synthesis found in pathology is also an example of a positive nitrogen balance. Over a weekly period of time, up to 50% of nitrogen is updated in the liver, and only 2.5% is updated in the skeletal muscles during the same time.

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

An 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 proper).

General protein deficiency

It may be of alimentary origin, or due to a violation of neuroendocrine mechanisms of synthesis and decay, or cellular mechanisms of synthesis and decay. The occurrence of alimentary 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 is absorbed by an animal cell only in the form of amino groups, amino acids;

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

If the intake of energy materials does not meet the needs of the body, then proteins are used for energy needs. So, when only 25% of all the necessary energy material (glucose, fats) is received, all the protein received with food is used as an energy material. In this case, the anabolic value of proteins is zero. Hence, insufficient intake of fats, carbohydrates leads to a violation of protein metabolism. Vitamins B 6 , B 12 , C, A are coenzymes of enzymes that carry out biosynthetic processes. Hence - vitamin deficiency also causes disturbances in protein metabolism.

With insufficient intake of proteins or switching them to energy rails (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 decreases;

2. Redistribution of endogenous nitrogen in the body. These are adaptation factors for 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. At the same time, heterogeneity of disturbances in protein metabolism in different organs is revealed: the activity of gastrointestinal enzymes

is sharply limited, and the synthesis of catabolic processes is not disturbed. At the same time, the proteins of the heart muscle still suffer less. The activity of deamination enzymes decreases, and transamination enzymes retain their activity much longer. The formation of erythrocytes in the bone marrow is preserved for a long time, and the formation of globin in the structure of hemoglobin is disturbed 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 insufficiency) are: a) violation of the absorption of proteins; b) obstruction of the gastrointestinal tract; c) chronic diseases with decreased appetite. At the same time, protein metabolism is disturbed both as a result of their insufficient intake and the use of proteins as an energy material. Against this background, adaptive processes to some extent compensate for the 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 are disturbed (there is a loss of protein in the structures of the liver, skin, 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 impaired. The synthesis of plasma proteins, antibodies, enzymes is limited (including the digestive tract, which leads to a secondary violation of the absorption of proteins). As a result of a violation of the synthesis of enzymes of carbohydrate and fat metabolism, metabolic processes in the metabolism of fats and carbohydrates are disturbed. Adaptation to incomplete protein starvation is only relative (especially in growing organisms). In young organisms, adaptive decline

the intensity of protein metabolism (metabolic slowdown) is less perfect than in adults. Under conditions of regeneration and convalescence, a 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 starvation, pronounced protein depletion and death can occur. Incomplete protein starvation is often found with impaired absorption

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

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

2. Reserving role and portioned intake of food mass into the underlying sections of the gastrointestinal tract (this process is disrupted when peristalsis is accelerated). These two functions of the stomach are disturbed in achilic states, with a decrease in pepsin activity (or little secretion of pepsinogen): the swelling of food proteins decreases, and pepsinogen is poorly activated. Ultimately, there is a relative insufficiency of protein hydrolysis.

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

With enterocolitis, accompanied by a decrease in sap secretion, accelerated motility and malabsorption of the small intestine mucosa, a complex insufficiency of protein absorption develops. Of particular importance is accelerated peristalsis, since the contact between 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, there are different transport systems for different groups of amino acids, since competitive relationships are created between amino acids during absorption). With enterocolitis, the edematous state of the mucosa, the acceleration of motility and the weakening of the energy supply of the absorption process disrupt absorption in the intestine. Thus, the qualitative balance of incoming amino acids is disturbed (uneven absorption of individual amino acids in time, violation of the ratio of amino acids in the blood - imbalance). The development of an imbalance between individual amino acids in the pathology of assimilation occurs because the absorption of individual amino acids occurs at different times in the process of digestion as amino acids are eliminated. For example, tyrosine and tryptophan are already split off in the stomach. The entire transition to 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 lengthened. From the blood, amino acids enter the cells, where they are either used for synthesis or deaminated. And for the passage of the synthesis, it is necessary that all partners of the amino acids be together at the same time and in certain ratios. If absorption processes are disturbed, this ratio is violated and amino acids do not go to protein synthesis, but along the path of deamination and degrade. There is an amino acid imbalance. This phenomenon also occurs when eating only one type of food protein (monotonous nutrition). The state of imbalance and impaired synthesis can manifest itself in the development of intoxication (when the body is overloaded with any individual types of amino acids, they have a toxic effect, or as a result of excessive deamination). Individual amino acids break down into toxic products. In the end, there is a general protein deficiency 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

insufficiency of individual amino acids (meaning, indispensable) and here protein synthesis is predominantly disrupted, in which this amino acid predominates. This is an amino acid deficiency. So, alimentary 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 combined in the concept of imbalance.

Violations of neurohumoral processes can also underlie the violation of the processes of protein synthesis and breakdown. In highly developed animals, the regulation of protein synthesis is carried out by the nervous system and hormones. Nervous regulation goes 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 types of protein synthesis and hormonal

Protein It has an important function in the body, as it is a plastic material from which the cells, tissues and organs of the human body are built. In addition, protein is the basis of hormones, enzymes and antibodies that perform the growth functions of organisms and protect it from negative environmental factors. With normal protein metabolism in the body, a person has high immunity, excellent memory and endurance. Proteins affect the full exchange of vitamins and mineral salts. The energy value 1 g of protein is 4 kcal (16.7 kJ).

With a lack of proteins in the body, serious disorders occur: a slowdown in the growth and development of children, changes in the liver of adults, the activity of the endocrine glands, blood composition, a weakening of mental activity, a decrease in working capacity and resistance to infectious diseases.

Protein metabolism plays an important role in the life of the organism. Violation of protein metabolism causes a decrease in activity, and resistance to infections also decreases. With an insufficient amount of proteins in the child's body, growth retardation occurs, as well as a decrease in concentration. It must be understood that violations are possible at different stages of 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 consider them in more detail.

Stage One: Absorption and Synthesis

The main amount of proteins a person receives from food. Therefore, when digestion and absorption are disturbed, protein deficiency develops. For normal protein synthesis, the proper functioning of the synthesis system is necessary. Disorders of this process can be acquired or hereditary. Also, a decrease in the amount of protein synthesized may be associated with problems in the immune system. It is important to know that disturbances in the process of protein absorption lead to nutritional insufficiency(dystrophy of intestinal tissues, starvation, unbalanced composition of food in terms of the amino acid component). Also, a violation of the processes of protein synthesis most often leads to a change in the amount of the 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.

Stage Two: Amino Acid Exchange

Amino acid metabolism disorders can also be associated with hereditary factors. Problems at this stage are most often manifested in a lack of tyrosine. This, in particular, provokes congenital albinism. A more terrible disease provoked by a lack of tyrosine in the body is hereditary tyrosenemia. The chronic form of the disease is accompanied by frequent vomiting, general weakness, painful thinness (up to the onset of anorexia). Treatment consists in following a special diet high in vitamin D. Amino acid metabolism disorders lead to an imbalance in the processes of transamination (formation) and oxidative degradation of amino acids. Starvation, 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 of the process of formation of nitrogenous products and their final excretion from the body may occur. Similar disorders are observed during hypoxia (oxygen starvation of the body). You should also pay attention to such a factor as the protein composition of the blood. A violation of the content of proteins in the blood plasma may indicate problems with the liver. Also, kidney problems, hypoxia, leukemia can be a catalyst for the development of the disease. The restoration of protein metabolism is carried out by a therapist, as well as a dietitian.

Symptoms of a protein metabolism disorder

With a large amount of protein in the body, there may be an overabundance of it. This is primarily due to malnutrition, when the patient's diet consists almost entirely of protein products. Doctors identify the following symptoms:

Decreased appetite;
Development of renal failure;
Salt deposits;
Chair disorders.

Too much protein can also lead to gout and obesity. A risk factor for gout may be excessive consumption of 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;
a significant increase in body weight;
fragility of bones;
hypertension (increased hydrostatic pressure in the vessels).

In the presence of the above problems, it is necessary to reduce the consumption of protein products, drink more clean water, play sports. If, on the contrary, the body does not have enough proteins for synthesis, it reacts to the situation in the following way: there is general drowsiness, sudden weight loss, general muscle weakness and a decrease in intelligence. Note that the “risk group” includes vegetarians and vegans who, for ethical reasons, do not consume animal protein. People who adhere to this style of eating need to additionally take vitamin complexes inside. Pay special attention to vitamin B12 and D3.

Hereditary disorders of amino acid metabolism

It is important to know that with a hereditary violation of the synthesis of enzymes, the corresponding amino acid is not included in the metabolism, but accumulates in the body and appears in biological media: urine, feces, sweat, cerebrospinal fluid. If you look at the clinical picture of the manifestation of this disease, then 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 a substance that should have been formed.

Tyrosine metabolism disorders

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

Blood protein disorders

It is also worth mentioning violations of the protein composition in the blood. Changes in the quantitative and qualitative ratio of blood proteins are observed in almost all pathological conditions that affect the body as a whole, as well as with congenital anomalies protein synthesis. Violation of 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 a normal total protein content.

Hypoproteinemia occurs due to a decrease in the amount of albumin and can be acquired (during starvation, liver disease, protein malabsorption) and hereditary. The release of proteins from the bloodstream (blood loss, plasma loss) and the loss of proteins in the urine can also lead to hypoproteinemia.

Scientists have found that increasing the production of a protein that is involved in the mechanism of long-term memory formation prevents epileptic attacks. In the course of the study, scientists managed to significantly increase protein synthesis using genetic engineering. eEF2 in laboratory mice. The relationship between the action of this protein and epilepsy has not been 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 Milan and a number of other European universities. Professor Kobi Rosenblum, scientific director of the study, says: "By changing the genetic code, we were able to prevent the development of epilepsy in mice that were supposed to be born with this disease, as well as cure mice that already suffered from this disease."

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

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

In order to test how the production of this protein affects the development of epileptic seizures, mice were divided into two groups. The first group had a gene mutation and, accordingly, intensively produced protein eEF2, and the second control group of mice was without any genetic changes. The mice of both groups were injected with a solution that causes epileptic seizures. This led to epileptic seizures in mice from the control group, and mice with the 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, mice with a protein mutation did not experience epileptic seizures. Throughout the study, the mice were exposed to various texts defining motor, cognitive, and behavioral functions. All of them remained normal in mice that had a mutation of this protein.

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

Heat shock in the developing brain and the genes that determine epilepsy

N. E. Chepurnova

Moscow State University 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 the human population in 2-4%, it poses the greatest danger in childhood. Febrile seizures (FS) account for up to 85% of all seizures observed in children. The total number of children aged 6 months to 6 years with FS is 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 a peak incidence between 18 and 22 months of age. Convulsions can be provoked by diseases that occur 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. Assumptions have been made about autosomal dominant inheritance, autosomal recessive inheritance of FS, but polygenic or multifactorial inheritance is not excluded. The genetic heterogeneity of epilepsy manifests itself at different levels. It is revealed in a variety of clinical features of the phenotype, inherited traits (patterns), primary gene products, among which there may be factors for the development and differentiation of neurons, enzymes, receptor proteins, channel proteins, and finally, products of another gene. Violations of the genetic code are also not the same, and several loci in different chromosomes may be involved.

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

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

The study of families with FS inheritance determined the genetic component and autosomal dominant inheritance. In the works of Japanese geneticists, when examining 6706 children aged three years in Fuchu Province of Tokyo with a population of about 182,000 people, it was shown 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 the synthesis of the Na+ channel protein. Features of the immune status in Egyptian children who underwent FS suggested that genetically determined FS were observed in children with the HLA-B5 antigen, low levels of IgA immunoglobulin, and low T-lymphocyte counts. All this allows us to speak about the feedback: the children had not only a predisposition to FS, but also an increased sensitivity to acute infections that occur with fever, which becomes the physiological cause of convulsions. The combination of syndromes of intrauterine encephalopathy with hereditary family history of epilepsy only exacerbates the outcome of FS. Since the main condition for the occurrence of FS in a child is fever, hyperthermia should be considered as a factor in epileptogenesis.

The role of the hypothalamic thermoregulatory center in the initiation of febrile convulsions

Why is a prolonged rise in temperature so dangerous for the developing brain of a child? Facilitation of the onset of FS is determined by a 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 ATP level in the brain for one reason or another, especially under the influence of hypoxia. The level of products of lipid peroxidation increases in a child, microcirculation of the brain is disturbed, hyperthermia of the brain is accompanied by edema. All neurochemical systems of neuronal inhibition, and especially the hypothalamic ones, are immature. In the brain, connections are still being established between the brain cells responsible for the constancy of body temperature.

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

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 a child that are also immature and cannot stop the growing hyperthermia.

Simulation of febrile seizures in newborn animals

The developed models of PS on newborn animals - rat pups - helped to identify vulnerable, critical periods of brain development, temperature thresholds at which PS occurs, to study the long-term effects of PS, and to study the effect of anticonvulsant drugs. Working 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 a unique opportunity to prevent or reduce the severity of FS in rat pups. Of all the methods developed by physiologists: endogenous hyperthermia, external heating with air, microwave, infrared rays, we chose simple heating with an incandescent lamp. As the body temperature rises, there is a gradual development of external signs of motor convulsions, the severity of which was determined according to the generally recognized scale of P. Maresh and G. Kubova. Hyperthermia was stopped when tonic-clonic convulsions appeared in rat pups with loss of posture, and in the absence of PS, after 15 min. To measure infrared radiation from the intact surface of the skin of an animal, a thermovision method was used - an infrared detector Inframetrics 522L.

Neuroendocrine regulation of febrile seizures

The neurohormone arginine-vasopressin (AVP) is involved in the brain's response to hyperthermia. The following facts speak in favor of this hypothesis of K. Pitman: 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 synthesizing AVP contributes to the cessation of fever. On the one hand, clinical data indicate an increase in the level of AVP in 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 in elevated body temperature. The hypothesis allows us to talk about the discovery of an endogenous antipyretic (from the Greek. pyretos - fever, fever, pyretica - a drug that causes fever). Paradoxically, it turned out that the function of the antipyretic is combined in the neurohormone AVP with a proconvulsant effect.

In our experiments performed with the Soros student A.A. Ponomarenko, new facts were obtained about the proepileptic effect of AVP on the example of PS in the early postnatal ontogenesis of the brain of rat pups. AVP indeed significantly shortens the time of occurrence of generalized, hyperthermally induced 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 administration of AVP in the experimental group, febrile status epilepticus lasting more than 2 hours ended in the death of all rat pups treated with AVP. Such lethal events cannot but be controlled at the hormonal and neurochemical levels. It was necessary to find out which regulators exacerbated 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 a recently discovered peptide that activates pituitary adenylyl cyclase (abbreviated in the first Latin letters - PACAP). The effect of the latter does not depend on the 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 nuclei of the hypothalamus 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 AVP secretion at the time of hyperthermia (see Fig. 2). Multidirectional changes in experimental febrile seizures in rat pups were found after the use 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.

Thus, AVP combines the functions of an endogenous antipyretic agent and an inducer of a convulsive motor reaction during a rapid increase in body temperature, and one of the regulators of its secretion, PACAP, can accelerate these processes. It seems probable that AVP and PACAP directly act on the membranes of nerve cells through their receptors (Fig. 3). But other ways of regulation cannot be excluded, for example, through the releasing factor of the hypothalamus - corticoliberin. Cells synthesizing PACAR 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 convulsions are no exception. Significant excess of body temperature leads to the expression of the genes of a huge number of proteins, called "heat shock proteins" (HSPs). HSP transcription begins a few minutes after heating. This reaction has always been regarded as protective against lethal outcome due to heat shock. The latest confirmation of this theory comes from the Cancer Institute in Copenhagen. It has been shown in tissue culture that severe heat stress causes apoptosis (from the Greek apoptosis - falling leaves or petals from a flower - genetically

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

HSP synthesis is a nonspecific stress reaction. 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, impaired levels of Ca2 + and pH. Dutch physiologists in Nijmegen have recently shown that protective 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 in hippocampal lesions.

Thus, HSP genes are expressed in FS, but such nonspecific protection is not always sufficient to preserve inhibitory cells, especially in the hippocampus. Therefore, there is a threat of long-term consequences in the form of mesial hippocampal sclerosis, which causes temporal lobe epilepsy. If, at the same time, the genetic predisposition to temporal lobe epilepsy is combined with a predisposition for 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 unfolded on the question of whether cells die as a result of FS, or they die for other reasons (for example, as a result of a violation of the protective synthesis of HSP, the development of apoptosis). Molecular biological studies in the laboratory of C. Waterline in Los Angeles showed that convulsive processes in the developing brain retard its development, and in particular the growth of axons, since convulsions disrupt the expression of the axon growth cone marker gene, the GAP-43 protein.

Temporal surgeons for temporal lobe epilepsy note that many of their patients had episodes of FS in childhood. However, this is a retrospective estimate. The latest 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 convulsions covered the child's brain and the more nerve cells died. No matter how small the percentage of such children (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. A channel is a single protein molecule, it is characterized by strict selectivity with respect to the type of ion to be passed through, it has a gate device, which is controlled by the potential on the membrane (Fig. 4, a). The occurrence and conduction of nerve impulses depends on the state of the ion channels. For the past ten years, hereditary diseases of the nervous system have been studied, which received a new name - "channelopathy". Violations are associated with the localization of genes in chromosomes: 19q13.1 (Na+ channel), 12p13, 20q13.3, 8q24 (K+ channel), 7q (Cl channel). Uncovering the molecular structure of the channels helped to understand the inheritance of epilepsy.

A nerve impulse is a consequence of the movement of Na + into the cell through the membrane channels, and K + from the cell. Positively charged Na+ ions entering along the ionic gradient create a membrane-depolarizing current that reduces the membrane potential to zero and then recharges 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. Violations of Na+ channels lead to a change in cell depolarization, and violations of K+ channels lead to a violation 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 predisposition to epilepsy. M-currents change the excitability of the cell and prevent the occurrence of epileptic activity of the neuron. Violation of the genes KCNQ2/KCNQ3-potassium channels leads to the disease "familial neonatal convulsions", which occurs in a child on the 2-3rd day after birth. The recently synthesized drug retigabine helps patients with epilepsy by opening KCNQ2/KCNQ3 channels in neuronal membranes. This is an example of how the fundamental study of channels helps to synthesize new drugs against channelopathies.

We have already mentioned two loci responsible for FS. New studies have shown the involvement of another region 19q13.1 responsible for the synthesis of the b1 subunit of the Na+ channel. Mutations in this region determine the occurrence of febrile seizures in combination with generalized epilepsy. The Na+ channel consists of one a- (forming a pore) and two b-subunits, the latter modulating the process of channel inactivation, that is, the operation of the a-subunit (see Fig. 4a). The effect of the a-subunit on the portal 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 a 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 the mutation occurs, leading to its destruction and changes in the structure of the extracellular domain b1 (Fig. 4b). The transfer of the gene into the Xenopus laevis oocyte and the induction of the synthesis of the defective channel made it possible to study the mutant channel electrophysiologically and prove that it is inactivated more slowly (see Fig. 4b). 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 neuronal isoform of Na+ channels. This mutation was identified as a result of research by Australian geneticists. Six generations of families (378 people) were studied, mainly living in Tasmania and having family histories of FS in combination with generalized epilepsy. These works have opened a new avenue for studying idiopathic forms of epilepsy, which may be the result of as yet unknown forms of channelopathies.

No less important are disturbances in the synthesis of receptor proteins for mediators. Autosomal dominant inheritance of nocturnal frontal 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, undergoes a change. Disturbances in the regulation of the expression of the gene of the b-subunit of the NMDA receptor protein to the excitatory mediator glutamate, the release of which by brain cells initiates an epileptic seizure, were also found. If, during mRNA editing, glutamine is replaced by arginine in the membrane domain, the resulting violation 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 on the head of an immobile rat until a severe epileptic seizure occurred. An unbiased study of this report showed that the torment created by the rat is caused by the desire to understand a serious illness, which in populous India covers almost 7% of all patients with epilepsy and amounts to 60 cases per 100 thousand diseases. This phenomenon is close to the hyperthermally induced convulsions discussed above.

The case of an epileptic seizure when washing the head with hot water was first described in New Zealand in 1945. A sick person, when washing his head (and in the traditions of the Hindus this procedure is repeated 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 most closely by inserting a special electrothermometer inside the auditory canal close to the eardrum. It turned out that in patients, the temperature of the brain at the beginning of washing the head rises very quickly (every 2 minutes by 2-3 ° C) and very slowly

decreases after cessation of washing. Their brain slowly (10-12 min) "cools down", whereas 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 genetically determined? The true cause was revealed by twin studies and family analysis data. It turned out that in India, up to 23% of all cases of "hot water epilepsy" recur in the next generations.

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

Conclusion

The neurogenetic approach made it possible to finally establish the genetic predisposition to febrile convulsions. That is why not every child who is at a very high temperature (40-41 ° C) for a long time has motor convulsions. The main PS gene is associated with the membrane mechanisms of neuron excitability, with the control of the synthesis of a protein channel through which Na+ ions pass. A depolarization excitation of the neuron is created. Not surprisingly, the "genes" of these disorders related to FS are somewhat "stand apart" from the specific genes responsible for other forms of epilepsy. An external cause of FS is overheating, which occurs either under the influence of endogenous pyretics (for example, in an infectious disease), or actually under the influence of an increase in the temperature of the environment. In response to hyperthermia, physiological defense is the first to turn on - a functional system for maintaining temperature in the optimal range. It is aimed at lowering body temperature. Nerve signals go to the vegetative centers - commands aimed at the release of heat and the reduction of heat production. The cells of the hypothalamus, having the ability to measure the temperature of the blood, themselves follow the results of these commands through feedback mechanisms. Since they are neurosecretory and secrete liberins and statins, they can simultaneously trigger complex biochemical changes by regulating the secretion of pituitary hormones. Endocrine mechanisms and behavioral defense reactions are almost simultaneously connected to autonomic regulation. 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 the pituitary cells. Unfortunately, this defensive attempt to lower body temperature ends up provoking seizures. Genetic predisposition, low convulsive threshold lead to irreversible development of events. There is a paroxysmal pathological convulsive activity of neurons, first in the hippocampus, amygdala, associative sections of the cortex, and then in the motor cortex. In all types of seizures, the main cause is a violation of the ratio of the release of excitatory (glutamate) and inhibitory (GABA) mediators. This violation is a trigger mechanism. Unrestricted excitation in the nerve networks covers the parts of the brain responsible for tone and movement, and leads to convulsions. Before this, there is a loss of consciousness, since pathological excitation covers the structures of the brain stem and thalamus. Of course, the brain also has other defense mechanisms, such as compensatory expression of early oncogenes (c-fos, c-jun), accumulation of cAMP, secretion of thyroliberin, and prolonged release of the inhibitory mediator. However, the question of why these mechanisms are ineffective in the case of a genetic predisposition to FS requires further study.

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 protein cleavage in its middle part to albumose and peptones. Exopeptidases (carbopeptidase, aminopeptidase and dipeptidase), which are formed in the pancreas and small intestine, ensure the cleavage of the terminal sections of protein molecules and their decay products to amino acids, the absorption of which occurs in the small intestine with the participation of ATP.

Violations 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 causes lead to a deficiency of hydrolytic enzymes or an acceleration of peristalsis, when peptidases do not have time to ensure the breakdown of proteins.

Unsplit proteins enter the large intestine, where, under the influence of microflora, putrefaction 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. Under conditions of a sharp increase in the processes of decay, intoxication of the body is possible.

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

Violations of the breakdown and absorption of proteins, as well as insufficient intake of proteins in the body, lead to protein starvation, impaired protein synthesis, anemia, hypoproteinemia, a tendency to edema, and immunity deficiency. As a result of the activation of the hypothalamus-pituitary-adrenal cortex and the hypothalamic-pituitary-thyroid system, the formation of glucocorticoids and thyroxin 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 exacerbates the breakdown and absorption of proteins.

With the absorption of unsplit protein, allergization of the body is possible. So, artificial feeding of children often leads to allergization of the body in relation to cow's milk protein and other protein products. Causes, mechanisms and consequences of violations of the breakdown and absorption of proteins are presented in Scheme 8.

Scheme 8. Violations of hydrolysis and absorption of proteins
	Hydrolysis disorders	Malabsorption
The reasons	Inflammation, tumors, resections of the stomach and intestines, increased peristalsis (nervous influences, decreased acidity of the stomach, eating 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)
Effects	Protein starvation -> hypoproteinemia edema, anemia; impaired immunity -> susceptibility to infectious processes; diarrhea, disruption of hormone transport. Activation of protein catabolism -> atrophy of muscles, lymph nodes, gastrointestinal tract, followed by aggravation of violations of 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 unsplit proteins enter the large intestine, the processes of bacterial cleavage (decay) 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 protein breakdown, and disturbances in the conversion of amino acids in the body.

Violation of protein synthesis.
Biosynthesis of proteins occurs on ribosomes. With the participation of transfer RNA and ATP, a primary polypeptide is formed on ribosomes, in which the amino acid inclusion sequence is determined by DNA. The synthesis of albumins, fibrinogen, prothrombin, alpha and beta globulins occurs in the liver; gamma globulins are produced in the cells of the reticuloendothelial system. Protein synthesis disorders 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 the hereditary damage to the B-system of immunity, in which the formation of gamma globulins in boys is blocked (hereditary agammaglobulinemia).
Lack of protein synthesis leads to hypoproteinemia, impaired immunity, dystrophic processes in cells, possibly slowing down blood clotting due to a decrease in fibrinogen and prothrombin.
The increase in protein synthesis is due to excessive production of insulin, androgens, somatotropin. So, with a pituitary tumor involving eosinophilic cells, an excess of somatotropin is formed, which leads to the 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 is enhanced, manifested in the form of gigantism and macrosomia. If an increase in somatotropin secretion occurs in adults, then an increase in protein synthesis leads to the growth of protruding parts of the body (hands, feet, nose, ears, superciliary arches, 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, a congenital defect in the formation of hydrocortisone, as well as a tumor of the testes, the formation of androgens increases and protein synthesis is activated, which is manifested in an increase in muscle volume and early formation of secondary sexual characteristics. An increase in protein synthesis is the cause of a positive nitrogen balance.
An increase in the synthesis of immunoglobulins occurs during allergic and autoallergic processes.
In some cases, a perversion of protein synthesis and the formation of proteins that are not normally found in the blood are possible. This phenomenon is called paraproteinemia. Paraproteinemia is observed in multiple myeloma, Waldenström's disease, some gammopathy.
With 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, Itsenko-Cushing's syndrome and 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 is also manifested in impaired immunity and an increased tendency 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 from food, and due to decay and resynthesis. According to McMurray (1980), with nitrogen balance, 500 g of proteins are synthesized daily, that is, 5 times more than is supplied with 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 the synthesis and breakdown of proteins and their consequences in the body are presented in Schemes 9 and 10.

Scheme 10. Violation of nitrogen balance
	positive nitrogen balance	Negative nitrogen balance
The reasons	An increase in synthesis and, as a result, a decrease in the excretion of nitrogen from the body (tumors 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 a larger amount compared to intake.
Mechanisms	Increased production and secretion of hormones that provide protein synthesis (insulin, somatotropin, androgenic hormones).	An increase in the production of hormones that stimulate protein catabolism by activating tissue catheins (thyroxine, glucocorticoids).
Effects	Acceleration of growth processes, premature puberty.	Dystrophy, including the gastrointestinal tract, impaired immunity.

Violations of the transformation of amino acids.
During the intermediate exchange, amino acids undergo transamination, deamination, decarboxylation. Transamination is aimed at the formation of new amino acids by transferring an amino group to a keto acid. The acceptor of the amino groups of most amino acids is alpha-ketoglutaric acid, which is converted to 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, which is 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, which partially synthesizes vitamin B6, with sulfonamides, ftivazid, as well as with toxic-infectious liver lesions.
With severe cell damage with necrosis (heart attack, hepatitis, pancreatitis), transaminases from the cytoplasm enter the blood in large quantities. So, in acute hepatitis, according to McMurray (1980), the activity of glutamate-allanine transferase in the 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 are further converted in the tricarboxylic acid cycle to CO 2 and H 2 0. Hypoxia, hypovitaminosis C, PP, B 2 , B 6 block 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, part of the amino acids undergoes decarboxylation with the formation of a number of biologically active amines - histamine, serotonin, gamma-aminobutyric acid, tyramine, DOPA, etc. Decarboxylation is inhibited in hyperthyroidism and an excess of glucocorticoids.

As a result of deamination of amino acids, ammonia is formed, which has a pronounced cytotoxic effect, especially for cells of the nervous system. A number of compensatory processes have been formed in the body that ensure the binding of ammonia. In the liver, urea is synthesized from ammonia, which is a relatively harmless product. In the cytoplasm of cells, ammonia binds with glutamic acid to form glutamine. This process is called amidation. In the kidneys, ammonia combines with a hydrogen ion and is excreted in the form of ammonium salts in the urine. This process, called ammoniogenesis, is also an 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 the intermediary metabolism of proteins - acetylcoenzyme-A, alpha-ketoglutarate, succinylcoenzyme-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 with urine, through the lungs and sweating; CO 2 - mainly through the lungs and in the form of salts with urine and sweat. These non-protein substances containing nitrogen make up the residual nitrogen. Normally, its content in the blood is 20-40 mg% (14.3-28.6 mmol / l).

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

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

Retention hyperazotemia occurs with kidney damage (inflammation, circulatory disorders, hypoxia), impaired urine outflow. This leads to retention and an increase in residual nitrogen in the blood. This process is combined with the activation of alternative pathways for the excretion of nitrogenous products (through the skin, gastrointestinal tract, lungs). With retention hyperazotemia, an increase in residual nitrogen occurs mainly due to the accumulation of urea.

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

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

Scheme 11. Violations of the formation and excretion of the end products of protein metabolism
HYPERAZOTEMIA
	Hepatic (productive)	Renal (retention)
The reasons	Liver damage (intoxication, cirrhosis, circulatory disorders), protein starvation	Violation of the formation of urea in the liver
Mechanisms	Inflammation of the kidneys, circulatory disorders, urinary outflow disorders	Insufficient excretion of nitrogenous products in the urine
Changes in the body	Effects- Dysfunction of organs and systems, especially the nervous system. Perhaps the development of hepatic or uremic coma. Compensation mechanisms- Amidation in cells, ammoniogenesis in the kidneys, excretion of nitrogenous products in alternative ways (through the skin, mucous membranes, gastrointestinal tract)

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