Disturbance of nervous trophism. Neurodystrophic process

The review articles on cortisol and depression presented in this LiveJournal were completed by me while working at the International Scientific and Practical Center for Psychoneurology (formerly Solovyov Neurosis Clinic), but due to my emergency dismissal from this organization, I did not have time to publish them in the official medical press. These texts from the first to the last word were written by me. Their appearance anywhere in print without mentioning my authorship is theft.

Depression is one of the leading problems of modern medicine
Depression is recognized by the World Health Organization as one of the 10 most important problems of international concern. In addition to its negative impact on quality of life, depression is associated with the risk of developing a range of diseases and increased mortality. Thus, numerous studies have demonstrated a connection between depression and a high risk of coronary heart disease and myocardial infarction. In surgical outcome studies, depression is an independent adverse prognostic factor during the postoperative period in surgical patients, and is associated with a high risk of complications in such patients. Importantly, adequate treatment of depression results in reduced mortality and morbidity in patients with depression.

The risk of neurological diseases is also 2 to 3 times higher in patients with depression compared to the general population. A number of studies have shown that patients with depression are more likely to develop epilepsy, Parkinson's disease, strokes, traumatic brain injuries, and Alzheimer's disease. The increased risk of neurological diseases in patients with depression is consistent with the data of modern neuroimaging studies indicating a characteristic deficit in the volume of gray and white matter of the brain for such patients. At the same time, according to a study by J.L. Phillips et al. (2012), during treatment with antidepressants, brain volume in patients with depression increases, and this trend correlates with an improvement in mental status.

Symptoms of depression
Depression is characterized by persistent depressed mood, decreased interest in the world, inability to experience pleasure, and decreased activity. Characteristic manifestations depression are feelings of melancholy or emptiness, self-deprecation, indifference, tearfulness. In a whole range experimental research Depressed patients have been shown to have a tendency to negatively perceive neutral or even positive stimuli and/or situations. In particular, patients with depression are significantly more likely to perceive neutral facial expressions in portraits as an expression of sadness or anger.

At the same time, autonomic, somatic and psychomotor manifestations of depression can vary significantly. In the modern classification of depressive disorders, it is customary to distinguish two subtypes of depression. Melancholic depression is characterized by a classic symptom complex of vegetative-somatic disorders, including insomnia and decreased appetite with weight loss. Atypical depression is manifested by opposite disorders: hypersomnia and increased appetite with weight gain. Despite its name, atypical depression occurs at the same frequency (15-30%) as “pure” melancholic depression (25-30%), with most patients having a mixed pattern of depressive disorders. Moreover, the pattern of depressive disorders can change in the same patient throughout life. In general, the “atypical” pattern of depressive disorders is characteristic of more severe depressive disorders and is more common in women.

Although both types of depression are characterized by psychomotor retardation, in some cases depression may be accompanied by psychomotor agitation (agitated depression). It should also be noted that depressive disorders in substance abusers also have characteristics, in particular, such patients are not characterized by excessive feelings of guilt and self-deprecation. It is important that in the majority modern research subtypes of depression are not distinguished and, accordingly, the discrepancy between the results of studies with similar designs may be determined by differences in the proportions of depression of different types.

Depression is associated with overstrain of stress response systems
It is now generally accepted that Negative consequences depression is associated with overstrain of physiological stress response systems. In a stressful situation, all the necessary resources of the body are mobilized, and the main triggers of such mobilization are activation of the sympatho-adrenal autonomic system (fast component of the stress response) and activation of the hypothalamic-pituitary-adrenal axis (slow component of the stress response). Classic components of the stress response are an increase in blood pressure, an increase in heart rate, an increase in glucose concentrations and an increase in the rate of coagulation processes in the blood. The stress response also includes significant changes in the cellular and protein-lipid composition of peripheral blood. Thus, the mobilization of resources in response to acute stress leads to the body’s transition to special treatment functioning, designated in the relevant literature as a state of “allostasis” [Sudakov, Umryukhin, 2009; Dowd et al., 2009; Morris et al., 2012], contrasted with the “homeostasis” regime, in which restorative metabolic processes predominate.

Prolonged stress leads to adaptive and then pathological changes in the body, referred to as “allostatic load” [Sudakov, Umryukhin, 2009; Dowd et al., 2009; Morris et al., 2012]. The longer the chronic stress and, accordingly, the more intense the stress response systems, the more pronounced are such biological markers of allostatic load as increased systolic and diastolic blood pressure, abdominal obesity, increased concentrations of total cholesterol and decreased concentrations of high-density cholesterol, decreased glucose tolerance and increased level of glycosylated hemoglobin, increased daily cortisol, adrenaline and norepinephrine in the urine. Prolonged stay of the body in a state of “allostasis” is accompanied by damage to tissues and organs, including due to the insufficiency of metabolic processes aimed at maintaining homeostasis.

Negative emotions are an integral part of the response nervous system to stressful stimuli and events [Sudakov, Umryukhin, 2009]. Even against the backdrop of moderate everyday stress loads, natural changes occur in emotional sphere. So in a study by N. Jacobs et al. (2007) it was shown that against the background of an increase in the level of everyday stress (performing uninteresting and effortful work, etc.), the level of positive emotions decreases and the level of negative emotions and arousal increases. In a study by T. Isowa et al. (2004) stress loads also led to a significant increase in the level of situational anxiety and physical and mental fatigue in healthy subjects.

In recent years, much of the research into the adverse effects of acute and chronic stress, as well as depression, has focused on the role of the hypothalamic-pituitary-adrenal axis as one of the leading mediators of the stress response. Of all the hormones of this system, the effects of cortisol have been studied to the greatest extent, both due to the breadth of its regulatory influences on the structures and functions of the body, and because of the availability of its measurements. In this analytical review of the literature, we summarized the most important results of studies on the effect of cortisol on the functions and neurotrophic processes in the central nervous system, both under physiological conditions and under conditions of chronic stress and in patients with depression and/or anxiety disorders.

Features of the regulation of cortisol secretion in depression
Abnormalities in the functioning of the hypothalamic-pituitary-adrenal axis in patients with depression have been studied in numerous studies. In general, patients with depression are significantly more likely to show deviations in the daily rhythm of cortisol secretion, hyperactivity and/or reduced reactivity of the hypothalamic-pituitary-adrenal axis compared to normal controls. However, initial hopes for high specificity and sensitivity of tests assessing the functions of the hypothalamic-pituitary-adrenal axis as a method for diagnosing depression did not materialize. At this stage, there was also no unambiguous evidence of differences in the functioning of the hypothalamic-pituitary-adrenal system in melancholic and atypical types of depression.

Hypercortisolemia in the morning is characteristic of both patients with depression and healthy subjects predisposed to the development of depression. In approximately 50% of patients with depression, hypercortisolemia is also detected in the evening. A study of cortisol levels in hair also indicates that chronic hypercortisolemia is common in patients with depression.

According to various studies, the absence of an inhibitory effect of dexamethasone on cortisol concentrations is detected on average in 30-60% of patients with depressive disorder. The frequency of a positive dexamethasone test varies depending on the severity of depressive disorders. Thus, in a study that included outpatients with depression, the frequency of a positive result of the dexamethasone test was only 12%, while in populations of patients with psychotic forms of depression, the absence of the inhibitory effect of dexamethasone was recorded in 64–78% of cases. This test is not highly specific for depression, as previously thought, and may show similar results in the presence of fasting or other stressful events. The lack of an inhibitory effect of dexamethasone on cortisol secretion is interpreted by researchers as a manifestation of glucocorticoid receptor resistance.

Administration of corticoliberin is more likely to induce hyperproduction of ACTH with subsequent hypercortisolemia in patients with depression compared to healthy controls, which also indicates excessive activation of the hypothalamic-pituitary-adrenal axis in such patients. According to some studies, this tendency is more characteristic of atypical depression compared to melancholic depression. In recent years, a modified dexamethasone-corticoliberin test has begun to be actively used, when, after administering dexamethasone at 11 pm the day before, after determining the cortisol level the next day, corticoliberin is prescribed with the measurement of cortisol levels over the next few hours.

The hypothesis of a gradual modification of the functioning of the hypothalamic-pituitary-adrenal axis as the duration of depressive disorder increases is currently being explored. Experimental studies on animals indicate the predominant importance of corticoliberin as an inducer of ACTH secretion - cortisol in the acute phase of the disease, followed by a transition to predominantly vasopressin regulation of the activity of the hypothalamic-pituitary-adrenal system in the chronic stage of the disease. Thus, in patients with long-term depression and vasopressin-induced hypercortisolemia, the possibility of an acute stress response with a further increase in cortisol secretion against the background of acute activation of corticoliberin regulation of ACTH secretion remains.

The presence of two independent systems for regulating the secretion of ACTH - cortisol, according to researchers, explains the discrepancy between the results of studies in this area, which currently evaluate mainly the activity of the corticotropin-releasing hormone link. The authors recommend assessing the duration and severity of depressive disorder, the type of depression (melancholic, atypical), and individual characteristics patients as covariates of the functioning of the hypothalamic-pituitary-adrenal axis in patients with depression.

Given the evidence of the adverse effect of hypercortisolemia on the severity of depressive experiences, attempts have been made to evaluate the effectiveness of glucocorticoid receptor blockade as a method of treating depression. Preliminary data from such studies indicate the need to consider the state of the hypothalamic-pituitary-adrenal axis before treatment, since the individual effects of glucocorticoid receptor blockade vary significantly from significant improvement to significant worsening of emotional disorders.

A number of studies have identified dysfunction of the hypothalamic-pituitary-adrenal axis also in patients with anxiety disorders. However, the results of research in this area are contradictory: some studies have shown excessive hyperactivity of the hypothalamic-pituitary-adrenal axis in anxiety disorders, while other studies have revealed significantly lower cortisol concentrations or smaller changes in cortisol concentrations in response to stress load in patients with anxiety disorders compared to controls.
In particular, for populations of patients with post-traumatic stress disorder characterized by lower levels of cortisol concentrations in the blood compared to the control. According to a number of studies, the situation changes throughout the course of the disease; the acute period after a stressful event is characterized by hypercortisolemia; in the chronic phase of post-stress disorder, hypofunction of the hypothalamic-pituitary-adrenal axis is detected. Studies of hair cortisol concentrations in patients with anxiety disorders also indicate that chronically low cortisol levels are common in these patients.

Cortisol, neurotrophic factors and neurogenesis
The synthesis of neurotrophic factors in the structures of the hippocampus, primarily BDNF (brain-derived neurotrophic factor), decreases against the background of chronic stress. Data from experimental studies consistently indicate a strong negative effect of glucocorticoids on BDNF synthesis in the hippocampus, on the one hand, and an increase in BDNF synthesis during chronic administration of antidepressants.

Experimental studies have shown that chronic stress leads to pronounced changes in interneuronal synaptic connections in the hippocampus, amygdala, medial prefrontal cortex with a decrease in the length and number of dendritic processes by 16 - 20%. In addition, chronic stress under experimental conditions led to a decrease in neurogenesis (normally, 9 thousand neurons are born daily in the hippocampus of an adult rat and survive for a month). The activity of microglial cells also changes during chronic stress. Most researchers associate these neuromorphological changes with the adverse effects of hypercortisolemia.

Indeed, chronic administration of pharmacological glucocorticoids results in decreased proliferation and maturation of neurons, and the concentration of endogenous glucocorticoids under chronic stress correlates with morphological changes in oligodendrocytes of the corpus callosum. Shortening and decreased dendritic arborization in the hippocampus and prefrontal cortex have also been reported following administration of synthetic and natural corticosteroids in animal studies.

Hypercotisolemia accelerates the aging process in the nervous system, manifested by a decrease in the number of neurons and their axons, as well as a decrease in the density of corticosteroid receptors. In addition, glucocorticoids increase the accumulation of beta-amyloid in astrocytes, which may accelerate the formation of amyloid plaques characteristic of Alzheimer's disease.

At the same time, data from a number of studies indicate a positive effect of small doses of corticosteroids that activate mineralcorticoid receptors on neurogenesis. Similar beneficial effects of mineralocorticoid receptor stimulation have been demonstrated for BDNF synthesis. In addition, a number of experimental studies have demonstrated an increase in neurogenesis during a two-week course of antidepressants.

Hypercortisolemia, neurotrophic changes and cognitive impairment
Hypotrophic changes in the central nervous system under conditions of chronic stress have been studied in numerous experimental studies. The most studied adverse effects of chronic stress are on the hippocampal structures. Recently, the development of malnutrition against the background of chronic stressful stimulation in the structures of the prefrontal cortex and amygdala has been demonstrated.
Patients with Cushing's syndrome also showed decreased hippocampal volume and decreased performance on memory tests compared to healthy controls. Wherein successful treatment Cushing's syndrome results in enlarged hippocampal structures and improved performance on memory tests. In addition to memory impairment, patients with Cushing's syndrome are characterized by emotional instability, depression, anxiety, and impulsivity. It should be noted that adrenal hypertrophy with a tendency to chronic hypercortisolemia is a typical manifestation of chronic stress [Sudakov, Umryukhin, 2009].

An inverse correlation between the severity of hypercortisolemia and episodic memory capacity has been demonstrated in patients with depression, Alzheimer's disease, and in populations of relatively healthy elderly people. In a study by D.L. Mu et al. (2013) in cardiac surgery patients with hypercortisolemia on the first postoperative day, a greater severity of cognitive impairment was recorded a week after surgery compared to the control group with normal cortisol levels.
Progressive decline in episodic memory with parallel reduction in the volume of hippocampal structures in relatively healthy older adults with hypercortisolemia has been documented in longitudinal studies. In addition, hyperactivity of the hypothalamic-pituitary-adrenal system in the form of increased ACTH concentrations against the background of stressful events and increased pituitary gland volume in combination with reduced hippocampal volume is characteristic of populations at high risk of developing psychotic disorders.
Synthetic glucocorticoids in normal conditions they penetrate the blood-brain barrier worse than natural ones. However, significant neuropsychiatric problems occur in approximately 6% of patients receiving corticosteroids.
To be fair, it should be noted that Addison syndrome is also characterized by cognitive impairment. Thus, both increased and decreased activity of the glucocorticoid system are unfavorable.

Genetic and environmental factors modifying the effects of hypercortisolemia
Individual sensitivity to the effects of hypercortisolemia varies considerably, and this variability is determined by both genetic and environmental factors. It is important that genetic polymorphism of the genes for glucocorticoid and mineralocorticoid receptors, as well as the gene for the enzyme 11β-hydroxysteroid dehydrogenase-1, is relatively rare, especially in Asian populations, which indicates the very high importance of these genes for the normal functioning of the body. Several studies examining the association of glucocorticoid or mineralocorticoid receptor gene polymorphisms with psychiatric disorders, a higher incidence of depression has been demonstrated in carriers of a number of glucocorticoid and, less commonly, mineralocorticoid receptor alleles.

It is important that stress factors during development in childhood can influence the expression of glucocorticoid receptor genes through methylation (or acetylation) of the latter’s DNA, which subsequently significantly affects the expression of these genes. In particular, maternal care has been shown to increase the number of glucocorticoid receptors, which in turn increases sensitivity to feedback in the hypothalamic-pituitary-adrenal axis. Despite the fact that DNA methylation is a reversible process, inheritance of methylated DNA is possible, which ensures epigenetic transmission of the characteristics of the activity of the hypothalamic-pituitary-adrenal axis, at least to the next generation.

Polymorphism of the corticotropin-liberin receptor genes and polymorphism of the neurotrophic factor BDNF gene can also modify the risk of developing depression due to stressful events and, possibly, the effects of hypercortisolemia. Thus, approximately 30% of the population have the Val66Met allele, and these individuals are characterized by an increased risk of depression combined with lower hippocampal capacity and episodic memory.

The neurosteroid dehydroepiandrosterone (DHEA) also has a neuroprotective effect. DHEA has the highest blood concentration of any steroid and its concentration is reduced in patients with depression. According to J. Herbert (2013), it is not the absolute value of cortisol concentration that has a more important prognostic value regarding the adverse effects of hypercortisolemia, but the ratio of cortisol and DHEA, while the author points out the prospects of studying DHEA as a potential blocker of neurotrophic changes against the background of hypercortisolemia.

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Trophic processes maintain a certain level of metabolism in organs and tissues. These processes are regulated by the nervous system thanks to special compounds called “trophogens”. Among the trophogens there are polypeptides (nerve growth factor, neurotrophic factor synthesized in the brain, neurotrophins-3 and 4), gangliosides, neuropeptides (metenkephalin, substance P, β-endorphins, etc.), protein hormones (ACTH fragments, insulin-like factors growth), neurotransmitters (acetylcholine, catecholamines). Trophogens are synthesized not only by nerve cells, but also by target cells, which means the mutual regulatory influence of the nervous system and peripheral tissues. In addition, the synthesis of trophogens occurs in central and afferent neurons. For example, an afferent neuron has a trophic effect on the central neuron, and through it on the intercalary or efferent neuron.
According to A.D. Speransky, each nerve, regardless of its function, also performs a trophic function. The nervous system is a single neurotrophic network, in which neighboring and distant neurons exchange not only impulses, but also trophic signals. The mechanisms of the regulatory influence of trophogens on target cells are the direct participation of neurotrophic factors in metabolic intracellular processes and the effect of trophogens on the genetic apparatus of cells, which causes the expression or suppression of certain genes. Obviously, with the direct participation of trophogens in the metabolic processes of innervated cells, short-term ultrastructural changes occur. Changes in the genetic apparatus of the target cell under the influence of trophogens lead to stable structural and functional disorders properties of the innervated tissue.

Neurotrophic function can be disrupted by various pathological processes both in the nervous system itself and in peripheral organs and tissues. There are the following main causes of impaired neurotrophic function.

● Impaired metabolism of trophogens (both a decrease in the amount of substances produced and a change in the spectrum of synthesized neurotrophic factors, for example, with protein deficiency, damage to the genetic apparatus of a neuron).

● Impaired transport of synthesized trophogens to target cells (axon injury).

● Impaired release and entry of trophogens into target cells (autoimmune processes, disturbances in the regulatory function of neurotransmitters, etc.).

● Inadequate implementation of the action of trophogens, for example, during pathological processes in innervated tissues (inflammation, tumor, etc.).

Denervation syndrome occurs when innervation of a tissue or organ ceases as a result of destruction of nerve conductors (trauma, tumors, inflammation), damage nerve cells. In this case, functional, structural and metabolic disorders occur in denervated tissues. They are associated with a violation of the action of the corresponding neurotransmitter on target cells, deficiency of trophogens, changes in microcirculation and organ circulation, unresponsiveness of denervated tissue to endocrine influences, etc.

Denervation syndrome manifests itself most clearly in skeletal muscles when an axon is cut or a motor neuron body is destroyed. After denervation, neurogenic (neurotrophic, neurotic) atrophy occurs in striated muscles. A significant (100–1000 times) increase in muscle sensitivity to the neurotransmitter acetylcholine and other humoral influences (Cannon’s law of denervation), and an expansion of the reception zone around the myoneural plate are revealed. Loss of voluntary movements (paralysis) and the appearance of fibrillary muscle twitches associated with increased muscle excitability are also observed. At the same time, atrophied striated muscles are reduced in size, brownish in color (brown atrophy), and the amount of intermuscular connective and adipose tissue is increased. Microscopically, a decrease in the number of mitochondria and myofilaments is noted, the volume of the endoplasmic reticulum is reduced, and the number of autophagic vacuoles containing fragments of intracellular structures (mitochondria, endoplasmic reticulum, etc.) increases. Some of the cellular debris that is not broken down in autolysosomes is stored as residual bodies (for example, lipofuscin granules). With a large amount of lipofuscin, the tissue becomes brown in color. Biochemically, the process of neurotrophic atrophy is caused by an imbalance between the processes of synthesis and breakdown. In addition, neurotrophins, in particular nerve growth factor precursor, can trigger apoptosis of denervated cells. Changes in the genetic apparatus of cells and the appearance of antigenic properties of denervated tissue cause activation immune system(infiltration of tissue with lymphocytes, polymorphonuclear leukocytes, macrophages, i.e. development of a rejection reaction).

O.A. GROMOVA, Doctor of Medical Sciences, Professor Russian Collaborating Center "Neurobiology" of the UNESCO Institute of Trace Elements

In the mid-twentieth century, at the intersection of molecular biology and physical biochemistry, a direction of research into neurotrophicity arose. The direction is not just very relevant for neurology, but extremely important, giving rise to horizons of hope instead of the generally accepted point of view of that period that “nerve cells do not recover.”

The forerunner for the formation of such a revolutionary view was the work of the Spanish neuroanatomist and histologist of the late 19th century, Santiago Ramon y Cajal, who described the cytoarchitectonics of the brain. With the development of new staining techniques (the scientist prioritized the use of gold (Au) to stain brain tumors) and the comprehension of elements of the nervous system that had previously been overlooked by researchers, Ramón y Cajal obtained new data regarding the structure and function of the nervous system. By the time most neuroscientists believed that nerve fibers formed a network, Ramon y Cajal was able to trace the path of each fiber to a specific nerve cell and discovered that although fibers from different cells ran in close proximity to each other, they did not merge , but have free endings! This discovery allowed him to become a major proponent of the neural doctrine, the theory that the nervous system is composed of numerous individual cells. He also made the assumption that cells exchange signals (electrical, biochemical). Subsequently, Rita Levi-Montalcini (1952) suggested and then experimentally confirmed the existence of signaling factors, trophic molecules of the nervous system. Decoding the genome has not solved most of the problems of neurology, and therefore the determination of brain proteomes, which make up about 50% of all proteins in the human body, will make it possible to trace the biochemical routes of neurological pathology and identify target correctors. Some of these correctors are well known (peptides, growth factors nerve tissue, antioxidant enzymes, amino acids, unsaturated fatty acid, vitamins, macro- and microelements). Many of these substances were rejected because their effectiveness was not confirmed; the significance of others in the processes of brain trophism was not proven.

Neuroprotectors have a nootropic component of action. Classification proposed by T.A. Voronina and S.B. Seredenin (1998), shows how heterogeneous and significant the group of drugs with a nootropic component of action used in medicine is. Research into any neuroprotective agent, including those of synthetic origin, could potentially open up new pathways to control metal homeostasis in the brain. Microelement balance, in turn, can affect the pharmacokinetics and pharmacodynamics of neuroprotectors and have an independent neuroprotective effect.

Neuroprotection, considered as a means of protecting neurons in vascular pathology of the brain, is important aspect pharmacotherapy of neurodegenerative, cerebrovascular and other diseases of the central nervous system. However, a large number of clinical trials conducted to date suffer from a lack of satisfactory evidence of clinical effectiveness. Some "promising" drugs, such as gangliosides, some anti-calcium drugs (nimodipine) and most NMDA receptor antagonists, have now been rejected, either due to their lack of effectiveness or an unsatisfactory risk-benefit ratio. The supposed adverse effect of piracetam on mortality in the immediate period after ischemic stroke is discussed (S. Ricci, 2002).

New neuroprotective drugs, including GV150526, ebselen (a selenium-containing drug), glycine antagonists, Fos-phenytoin, gamma-aminobutyric acid (GABA) agonists, e.g. clomethiazole, aspartate receptor antagonists (AMPA), acidic fibroblast growth factor (bFGF) , NO synthase inhibitors and serotonin agonists (BAY3702), lithium preparations, are undergoing phase III clinical trials, and conotoxins, blockers of slow potassium channels, lazaroids, cytokines, regulatory peptides - mainly preclinical phase II trials. Many of the growth factors (nerve growth factor and neuroglial growth factor), as well as small-molecule drugs selected in screening studies by Western companies and shown to be effective in vitro, turned out to be completely ineffective during clinical trials. There is a point of view that the cause of ineffectiveness is the BBB. A priority direction of modern neuropharmacotherapy is the creation of new effective methods of drug delivery. "Biotech Australia" (Prof. Greg Russell-Jones' group) has patented several universal methods for transmembrane delivery of drugs using vitamin B12, low molecular weight peptides and lipid nanoparticles, ensuring penetration through the intestinal wall of those drugs that, in the absence of these systems, are not adsorbed at all. It is likely that similar systems can be used in the treatment of Cerebrolysin and other parenteral neurotrophics.

One of the most promising areas for the use of neurotrophics is the synthesis of peptides with potential metal ligand properties. In particular, carnosine is one of the low molecular weight peptides that has the ability to bind Zn and Cu and transport them to the brain, especially when administered intranasally (Trombley et al., 2000). Carnosine can also prevent neuronal apoptosis caused by neurotoxic concentrations of Zn and Cu (Horning et al., 2000).

One potential route for administering neurotrophics is through convective delivery to peripheral nerves using microcannulas (Lonzer et al., 1998). The administration of neuropeptides in the form of aromatic compositions and solutions for intranasal drip administration is being studied.

Cerebrolysin (FPF-1070) has been used in neurological practice for more than 15 years and meets fairly stringent requirements for neuroprotection not only in therapeutic but also in pediatric practice. The drug has been tested in children, starting from the neonatal period (0–1 month of life). Many vasoactive and neuroprotective drugs (Cavinton, drugs based on Ginkgo biloba extract, Instenon) can be officially used in Russia and abroad in patients over 12–14 years of age. The multimodal neurospecific action of Cerebrolysin has been established by various experimental studies; clinical effectiveness The drug was confirmed in prospective, randomized, double-blind, placebo-controlled clinical trials conducted in accordance with international GCP requirements in a number of international centers. Two years ago, Cerebrolysin was registered in the US and Canada as a drug for the treatment of Alzheimer's disease. Cerebrolysin is a concentrate containing low molecular weight biologically active neuropeptides (leienkephalin, metenkephalin, neurotensin, substance P, β-endorphin, etc.) with a molecular weight not exceeding 10,000 daltons (15%) and free amino acids (85%). Until recently, all explanations for the effects of the drug were based on the content of amino acids in it as a specific nutritional substrate for the brain. New knowledge about neuropeptides and their high therapeutic activity has attracted significant interest from pharmacologists. At the same time, natural neurotrophic factors (neuron growth factor, neurotrophic ciliary factor, and others), when used in clinical trials, turned out to be unable to penetrate the BBB, which required the use of invasive methods such as intraventricular infusions of the tested peptides. The first attempts at intraventricular use of neuropeptides resulted in complications (hyperalgesia and weight loss) (Windisch et al., 1998). A low molecular weight fraction obtained from the pig brain cortex is able to penetrate the BBB and prevents the need to use such invasive techniques. Modern neurochemistry has proven that neuropeptides carry the main neurotrophic pharmacological load (Cerebrolysin EO21, enriched with peptides up to 25%, has a greater effect in experiments clinical effect than the clinically widely used Cerebrolysin with a 15% fraction of neuropeptides). The presence of a low-molecular peptide fraction allows the drug to relatively easily cross the BBB and reach directly nerve cells under conditions of peripheral administration. This is the difference between Cerebrolysin and nerve growth factor, large molecules of which have difficulty penetrating the central nervous system (Sugrra et al., 1993). Cerebrolysin is an indirect inhibitor of the Ca2+-dependent protease calpain and ensures activation of the synthesis of endogenous calpostatins. The effect of Cerebrolysin on the calpain-calpostatin system is multifaceted and mediated through the system of intracellular antioxidants. It depends on the presence in the preparation of neuropeptides and metal ligand complexes, which act as competitive antagonists of reversible Ca2+-dependent activation of calpain and stabilizers of the neuronal cytoskeleton (Wronski et al., 2000). Cerebrolysin has the ability to normalize plastic metabolism in presynaptic terminals and prevent disturbances in the production of amyloid precursor protein (Mallory et al., 1999). Cerebrolysin inhibits the activation of microglia in vivo and in vitro (Alvarez et al., 2000; Lombardi et al., 1999), which helps to inhibit immunoinflammatory disorders in the brain at the last stages of neurodegenerative remodulation through inhibition of the release of cytokines IL-1, IL-6, etc. Data from modern neurochemistry indicate that Cerebrolysin has membrane protector properties that can regulate calcium homeostasis and reduce the neurotoxic effect of increased concentrations of excitatory amino acids (glutamate). Cerebrolysin also optimizes the content of endogenous SOD in the brain and thereby increases the endogenous potential of nervous tissue (Gonzalez et al., 1998).

The increase in scientific and practical attention to Cerebrolysin is explained by the receipt of new information about the neurotrophic valencies of the drug in connection with the conduct of evidence-based experimental and clinical studies on the drug (V.I. Skvortsova et al., 2006).

Cerebrolysin improves glucose transport across the BBB (GLUT1 production) (Boado, 2000; Gschanes et al., 2000), thereby increasing the number of viable neurons and prolonging the survival time of the latter after ischemia and hypoxia.

Sugita et al. (1993) found that the drug is able to inhibit formation. OH radicals during experimental ischemia in mice. In addition, Cerebrolysin's ability to protect neuronal mitochondria from the damaging effects of lactic acidosis has been proven. Cerebrolysin has a high overall SOD activity (O.A. Gromova, O.I. Panasenko, 2000).

Cerebrolysin inhibits neuronal apoptosis and improves dendritic and axonal growth (Satou et al., 2000).

Cerebrolysin contains macroelements (MaE) and essential microelements (ME) (O. Gromova et al., 1997), exhibits vitamin activity of thiamine (vitamin B1), folic acid (O.A. Gromova, L.P. Krasnykh, 2005), zincobalamin, vitamin E, contains up to 100 short-chain peptides (V.A. Tretyakov et al., 2006), including glutathione and thyrotropin-releasing motifs (S.A. Mashkovsky, 2006; O.A. Gromova et al., 2006) .

In the experiment, Cerebrolysin increases the level of Li, B, Se in the hypothalamus, central cortex, and olfactory bulbs (O.A. Gromova, A.V. Kudrin, S.I. Kataev, 2003–2005).

The administration of Cerebrolysin led to a moderate accumulation of Se in the olfactory bulbs, hypothalamus and frontal cortex of the studied rats (A. Kudrin et al., 2004).

Administration of Cerebrolysin led to selective accumulation of Mn in the frontal cortex (A. Kudrin et al., 2004).

Cerebrolysin is an indirect calpain blocker and acts through a system of intracellular antioxidants, which depends on the presence of neuropeptides and metal ligand complexes in the drug, which act as competitive antagonists of Ca2+-dependent activation of calpain and degradation of the neuronal cytoskeleton in neurodegenerative and ischemic brain diseases (Wronski et al., 2000a ; 2000b).

Modulation of microelement homeostasis may be one of the essential components of the neuroprotective effect of Cerebrolysin.

There are two generally accepted routes of drug administration. Intramuscular Cerebrolysin is used from 1 to 5 ml. In the form of intravenous drip infusions: dilute 5 to 60 ml of the drug in 100–250 ml of saline and administer over 60–90 minutes. In neuropediatric practice, Cerebrolysin is prescribed 1–2 ml (up to 1 ml per 10 kg of body weight) intramuscularly. Research is being conducted on the effectiveness of Cerebrolysin administration per os, by metameric administration to biologically active points and using transorbital electrophoresis. A dose of 10–30 ml IV for at least 20 days has been proven to have a rehabilitative effect during the recovery period of a stroke (level of evidence A). In the absence of convulsive readiness in children with cerebral palsy, as well as in patients with consequences of traumatic brain injury, pharmacoacupuncture with Cerebrolysin is used. Cerebrolysin in a single oral dose (30 ml) caused potentiation of the α rhythm and memory parameters, as well as a decrease in the slow l rhythm of the cortex (M. Alvarez, 2000). These results show that oral administration of Cerebrolysin may also be an effective method of administration and use of the drug in neurodegenerative pathologies. The study needs to evaluate the bioavailability of Cerebrolysin when administered orally, since it is known that many neuropeptides undergo enzymatic degradation in the gastrointestinal tract.

Intranasal administration of element-containing drugs and neuropeptides, in particular Cerebrolysin, was proposed and tested by Professor L.B. Novikova (1986). This route of administration, in our opinion, may have much greater prospects. The absence of enzymes that break down neuropeptides on the nasal mucosa, good absorption of MaE and ME in combination with neuropeptides ensure rapid transport of the neurotrophic composition of Cerebrolysin to the brain. Intranasal administration of zinc sulfate (10-day course) followed by a 10-day course of intranasal administration of Cerebrolysin led to a 3-fold increase in zinc in the frontal cortex and hypothalamus and a 4.5-fold increase in zinc content in the olfactory bulb of rats (A. Kudrin et al. ., 2004). In neurological practice, the technique of transorbital electrophoresis with Cerebrolysin, proposed by Bourguignon (1984), is used, which makes it possible to economically and effectively use small doses (1–2 ml of the drug) per 1 physiotherapy session. M.R. Guseva et al. (2000) reported an improvement in visual function in patients with visual impairments with retrobulbar administration of Cerebrolysin. The range of pathologies for which the drug is prescribed has been sufficiently studied. The nootropic effects of Cerebrolysin are being clarified and the possibility of its use to improve memory in vascular diseases of the brain (E.I. Gusev, 2001; V.I. Skvortsova, 2004) and in children with learning difficulties and mental retardation (O.V. Badalyan, 1990) ; N.N. Zavadenko, 2003). A multicenter, double-blind, placebo-controlled study of Cerebrolysin in Alzheimer's disease (AD) (30 mL Cerebrolysin in 100 mL saline 0.9% NaCl once daily, 6 times weekly over a 4-week period) showed significant improvements in cognitive and general clinical parameters. brain functions (Bae et al., 2000). Ruther et al. (1994, 2000) demonstrated a stable improvement in cognitive parameters in patients with dementia of the Alzheimer's type 6 months after the end of Cerebrolysin therapy (30 ml once a day for 4 weeks). Such long-term retention of positive results of mental state modification in Alzheimer's disease has not been found for any drug proposed for the treatment of dementia, except for desferroxyamine (DFO). Using a transgenic animal model that reproduced Alzheimer's pathology, Masliah et al. (2000) found that Cerebrolysin significantly reduces the level of amyloidogenic peptides that trigger the process of neurodegeneration in AD. Cerebrolysin-induced reduction in the synthesis of amyloidogenic peptides is in direct correlation with a concomitant improvement in learning abilities and memory function in patients with AD, as well as an increase in the number of new synapses being formed. Three independent studies of Cerebrolysin were conducted at the Center for the Study of Aging, Montreal, Canada, on 192 patients with Alzheimer's disease (Gauthier et al., 2000, Panisset et al., 2000), in Ontario, Canada (Molloy & Standish, 2000) and in Germany on 149 patients with Alzheimer's disease (Ruther et al., 2000), showed that Cerebrolysin gives stable positive results that last up to 3-6 months after the end of therapy. Thus, most researchers note the ability of Cerebrolysin to provide optimal nutrition to the brain in cerebrovascular disorders (M. Windisch, 1996; E.I. Gusev, 2001; O.A. Gomazkov, 2004; V.I. Skvortsova, 2004). It is important that the neuroprotective effects of Cerebrolysin persist and develop after a course of treatment and that they persist for up to 4–6 months.

Macro- and microelements are an integral part of the neurotrophic system of the brain

In recent years, works have appeared in the field of neurochemistry devoted to the problem of the influence of metals on the nervous system. It becomes obvious that disturbances in the metabolism of elements are an important link in the pathogenesis of some diseases of the central nervous system. In turn, during various pathological processes in the nervous system, the metabolism of metals changes. With copper deficiency in preparations of brain synaptosomes, the binding of GABA to muscarinic receptors significantly increases and the binding of benzodiazepine decreases. Neuronal memory, realized through the voltage-dependent type of N-methyl-D-aspartate-sensitive receptors, is regulated by magnesium. According to recent data, at the mouth of the ion channel of glutamate receptors there is a site for zinc binding.

ME is a unique group of chemical elements that exist in the ionic concentration range of 10-8–10-10 mol × L-1 and are part of the vast majority of enzyme cofactors, transcription factors and DNA maintenance apparatus.

It should be noted that nervous and glial tissues, from a physiological point of view, have unique properties, which determine the specifics of the ME functions in the central nervous system:

nervous tissue contains a very small compartment of stem cells, as a result of which the regenerative and restorative abilities of neurons are extremely low (in recent years, methods have been developed for the treatment of neurodegenerative diseases by introducing cultured stem cells into the damaged brain);

the life cycle of neurons is extremely stable and sometimes equal to the life expectancy of a person, due to which the level of natural apoptotic activity of nervous tissue is low and requires significant antioxidant resources;

energetic and plastic processes in nervous tissue occur extremely intensively, which requires a developed vascularization system, essential micronutrients, ME and oxygen. This determines the high sensitivity of nervous tissue to the products of oxidative stress;

the high sensitivity of the brain to various toxic products of endogenous and exogenous origin required, in the process of evolution, the formation of highly organized structures of the blood-brain barrier, limiting the central nervous system from the direct entry of most hydrophilic toxic products and drugs;

Nervous tissue consists of 96–98% water, the properties of which determine the extremely important processes of maintaining the volume of neurons, osmolar shifts and transport of various biologically active substances.

The accumulation of abnormal proteins inhibits the mitochondrial functions of neurons. Despite the evolutionarily provided features of the mitochondrial genome that provide its sufficiently capacious adaptive capabilities (multiple transcriptons, complex processing of pre-mRNA, extensive intronic and terminal non-coding sequences in mDNA and mRNA), the accumulation of congenital and acquired defects gradually leads to the occurrence of mitochondrial insufficiency. The range of diseases, especially in childhood, provoked by heavy metals and based on secondary mitochondrial dysfunction, is constantly expanding.

Optimizing the content of ME is a promising means of reducing apoptosis, which opens the way to the creation of pharmacotherapeutic approaches to the treatment of various chronic diseases and tumors of the nervous system. Microelements can become an important tool in strategies for promoting health and increasing life expectancy while maintaining intelligence.

The role of individual MEs in neurotrophic processes. The provision of MaE and ME, treatment with element-containing drugs is reflected in the mirror of evidence-based medicine.

Magnesium. At the molecular level, Mg participates in the formation of catalytic centers and in the stabilization of regulatory sites in numerous enzymes of nervous and glial tissues, is part of glutamine synthetase (conversion of glutamate into glutamine), γ-glutamine cysteine ​​synthetase (control of the first stage of glutathione synthesis), cholinesterase, etc. . Magnesium-containing enzymes and Mg2+ ions ensure the maintenance of energy (ATP cascade, glucose transport into cells) and plastic processes (ribosomal synthesis of neurospecific proteins and lipoprotein complexes) in nervous tissue. Mg is involved in the synthesis of neurotransmitters: norepinephrine, tyrosine, acetylcholine, neuropeptides in the brain. Mg levels play a role in regulating the balance of high- and low-density lipoprotein fractions and triglycerides. In a state of deep cerebral ischemia, the content of GluR2 subunits of glutamate receptors in the cortex decreases (in severe cases, by 90–100%). This causes overexcitation and death of neurons, leads to an increase in membrane permeability for Ca2+ and Na+, a decrease in the mitochondrial pool of Mg2+, and its movement first into the cytosol and then into the extracellular space, which leads to loss in the urine. At rest, the mouth of the AMPA receptor is blocked by magnesium ions. During hypoxia, the AMPA receptor loses Mg2+ from its mouth, a “shock” influx of Ca2+ is directed into the neuron (“hot spots” are formed in the brain), and the site for Zn2+ binding is deprived of the metal. A free pool of reactogenic, potentiating Zn2+ ions in the brain is formed. In the post-stroke period, the persistent Mg:Ca disproportion and magnesium deficiency (DM) potentiate the processes of sclerosis and subsequent fibrosis of the lesion; Calcification of the ASP, thickening of the intima of the vessels continues intensively, conditions are created for repeated strokes, GT (E.I. Gusev, 2005).

A series of large randomized statistical studies have confirmed the importance of hypomagnesemia preceding stroke (Bhudia, 2006), especially in women (Song, 2005). An analysis of 12 years of observations of 39,876 patients aged 39–89 years showed that women who consumed magnesium less than 255 mg/day were significantly more likely to have high blood pressure, cardiovascular disease, ischemic stroke (IS), and higher mortality (Song, 2005) . In a study of Mg levels in the blood of 16,000 German residents, the level was suboptimal (< 0,76 ммоль/л) обнаружен у 33,7 % обследованных, что превышало встречаемость дефицита Ca (23 %) и K (29 %) (Polderman, 2001). Уровень магния в периферической крови (ПК) ниже 0,76 ммоль/л рассматривается как дополнительный фактор риска возникновения инсульта. Мониторирование уровня Mg в ПК выявило, что гипотермия с целью нейропротекции, широко используемая у больных в постаноксической коме, перенесших хирургическое вмешательство на головном мозге, провоцирует снижение Mg в плазме крови от 0,98 ± 0,15 до 0,58 ± 0,13 ммоль/л в течение первых 6 ч холодового воздействия (K.H. Polderman с соавт., 2001). Ранее проведенные исследования R. Schmid-Elsaesser (1999) показали, что терапия магнием в острый период инсульта потенцирует защитное действие гипотермии. В острую фазу ИИ (A.A. Святов, 1999) дефицит магния в крови достигает critical values(below 60–70% of the norm), as well as with acute heart attack myocardium, the level of magnesium in the PC decreases to 0.455 ± 0.023 mmol/l with a norm of at least 0.82 ± 0.09 mmol/l, i.e. up to 55% of normal. Low level magnesium is a recognized risk factor for “final thrombus formation” in patients with stroke (Kumari KT, 1995). E.L. Ding, in the analytical review “Optimal Diet for Stroke Prevention” (2006), emphasizes that the Mg:Ca balance forms the basis of preventive work to combat stroke, especially in patients with arterial hypertension (AH). Mg deficiency, along with the intake of transgenic fats (TF), solid saturated fats (TSF), chronic deficiency of antioxidants, and antihomocysteine ​​vitamins (folate, pyridoxine, cyanocobalamin) are among the major dietary risk factors for stroke. With DM, not only fast metabolic changes (arrhythmia, convulsions, tics) develop, but also slow ones. The vessels of the heart and brain are the first to transform in DM. In hypomagnesium areas of the epithelium, conditions are created for excessive compartmentalization of calcium salts against the background of normal and even reduced intake of calcium into the body, but disproportionate with magnesium. Intake rate Mg: Ca - 2: 1; better 3: 1 - 5: 1. This is possible by including in the diet green-leaved plants (fresh herbs), algae, sea fish, nuts, orthomolecular magnesium salts of the second generation (magnesium lactate, orotate, aspartate, glycinate, citrate, pidolate, better in complex with the universal Mg carrier - pyridoxine).

Selenium. Physiological intake of the ultramicronutrient selenium (Se) has been recognized as a protective factor in the fight against stroke. Studies of the role of Se in the brain have led to a number of important discoveries. Se ions activate the redox enzymes of mitochondria and microsomes, glutathione reductase, glutathione peroxidase, cytochrome P450, participate in the synthesis of glycogen, ATP, in the transfer of electrons from hemoglobin to oxygen, support cysteine ​​metabolism, potentiate the work of α-tocopherol, and are an antidote against heavy metals in the brain (mercury, silver, cadmium, to a lesser extent - lead, nickel). In 1979, it was found that selenium is part of glutathione peroxidase (GPX), the main membrane antioxidant enzyme, in the form of a selenocysteine ​​residue (Se-Cys). Isoform-6 is expressed in the brain, especially in astroglia, and is dependent on selenium. In patients with selenium deficiency (DS), the level of Se in the blood decreases later than the activity of Se-GPX. Se is necessary for enzyme regeneration. Therefore, reduced enzymatic activity of Se-GPX is an early marker of poor selenium supply to the brain (I.V. Sanotsky, 2001). Other representatives of selenium-containing proteins and enzymes are also very important. Thioredoxin reductase, including three cytosolic and two mitochondrial forms, is maximally represented in oxygen-enriched organs (brain, heart, kidneys, etc.). For the brain, the concentration of Se-containing iodothyronine deiodinase type 2 (brain), type 3 (neuron), Se-methionine sulfoxide reductase (Se-protein-R, brain) is no less important. In general, selenium plays a critical role in the functioning of the central nervous system. The neuroprotective potential of Se is realized through the expression of Se proteins, which are primarily involved in the regulation of the redox state of neurons and glial cells under physiological conditions and oxidative stress. Insufficient levels of Se in the brain potentiate disturbances in the function and structure of neurons induced by endogenous and pathogenic influences, leading to apoptosis and death of neurons, and neurodegeneration. The determining, if not the only, mechanism for the deposition of Se in the central nervous system is the expression of the Se protein P. In 2005, R.F. Burk, A. Burk, H. Hill were the first to present the reference values ​​of biomarkers recommended for assessing the body's selenium supply: plasma Se - 122 ± 13 μg/l, Se-protein P - 5.3 ± 0.9 mg/l, GPX - 159 ± 32 U/l. Particularly important for the brain are Se-GPX and especially Se-protein P. More than 50 subtypes of Se-protein have been identified (R.F. Burk, 2005). Deviations in their metabolism turned out to be a clue to key points in the biochemical route of a number of diseases. A decrease in the activity of Se-BP1, or SELENBP1 (selenium-binding protein 1), is pathogmonic for schizophrenia; during exacerbation, it decreases to critical levels, and with replenishment, an improvement in the condition is observed (Glatt et al., 2005). Another Se protein, Se protein W, has been shown to be an important buffer against methylmercury brain poisoning (Kim et al., 2005). A decrease in Se protein 15 (SEP15) accompanies the development of mesothelioma, and when it is supplemented, tumor growth is suppressed.

Dietary DS leads to a significant decrease (from 40 to 80%) in the activity of Se-dependent enzymes in numerous tissues of epithelial, glandular and lymphoid origin. In the brain, the activity of Se-dependent enzymes remains at a relatively stable level even under conditions of severe selenium deficiency, due to the existence of a unique Se-transport system of the central nervous system (selenocysteine-depositing proteins, Se-transport protein of the Golgi apparatus, etc.). Obviously, this phenomenon should be considered as a protective reaction of the brain acquired during evolution in response to unstable consumption of this element in food (Allan et al., 1999; Gu et al., 1997, 2000; Hill et al., 1997; Romero- Ramos et al., 2000; A. Burk, 2005). When DS persists for a long time, Se concentrations remain subnormal only in the brain, and at a critical level - in the hypothalamic and pituitary regions of the brain. Selenium deficiency develops with age in most people. This is especially true in older people. Moderate selenium deficiency, which has some level of correlation with a decrease in cognitive parameters (data from a 4-year study on 1166 volunteers - EVA), was noted in the vast majority of elderly subjects (Berr et al., 1999). Selenium administration normalizes dopamine metabolism and prevents the effects of toxic substances that cause parkinsonism (Chen & Berry, 2003). Polymorphism of the Se-glutathione peroxidase genes (especially defects in the genes responsible for the synthesis of GPX-1, tRNK) for Se in estrogen-dependent breast cancer is a direct marker of tumor diseases (breast cancer gene 1): polymorphisms 185 delAG, C61G, T181G T>G, 4153 delA, 5382insC - markers for neurodegenerative and cerebrovascular diseases. This means that from the moment of birth, selenium metabolism is suppressed. In the future, early preventive, individually selected work to combat stroke, depending on the genotype variants, is relevant. SELECT study in 32,800 people treated with selenium (study duration 7–12 years) aims to examine the effect of combined vitamin E and selenium supplementation on long-term health parameters and the risk of developing Alzheimer's disease (results have not yet been published), but the S. Stranges study has now been completed et al (2006), published the results of a 7.6-year placebo-controlled observation of 1004 patients. A high correlation index (IC) of mortality was established in patients with myocardial infarction who received placebo and received 200 mcg/day. Se (IR = 0.61: 1.44), and ischemic stroke, placebo-treated and 200 μg/day. Se (IR = 0.76: 1.95).

Currently, a large controlled study is being conducted on the nitrite oxide synthase inhibitor glyceryl trinitrate (effect on NO synthesis) and the GPX simulant ebselen. Correction of native Se-GPX is not feasible, since the enzyme is very difficult to synthesize (since selencysteine, which is part of the active center of GPX, is encoded by a special stop codon), in addition, it is labile, unstable, and expensive. Therefore, GPX simulators are more promising. The most tested drugs for stroke are ebselen (2-phenyl-1,2-benzisoselenazole-3(2H)-OH) and its analogues. Ebselen regulates the level of reduced ascorbic acid in the brain, has an anti-inflammatory effect. Ebselen is already used in the complex treatment of acute IS in Japan. Fat-soluble carotenoid vitamers (lycopene, beta-carotene, etc.) potentiate the absorption of selenium in the brain. In the study by A.L. Ray (2006) in 632 women 70–79 years old in Baltimore, stroke mortality was higher in the group with a low supply of selenium and beta-carotene. Correction of Se balance in patients who have suffered a stroke or traumatic brain injury is becoming a mandatory rehabilitation strategy, without which it is impossible to achieve sustainable results in neuroprotection. The optimal dose of selenium for the prevention of IS and reduction of mortality from cerebro- and cardiovascular diseases should not exceed 200 mcg/day. Doses of selenium exceeding the maximum permissible intake threshold (more than 400 mcg/day), with long-term use, can stimulate melanoma-dependent skin cancer.

Lithium. Attempts to influence lithium (Li) preparations on the inflammatory component of IS and the level of prostaglandin PGA1 (a marker of excitotoxicity in nervous tissue in IS) have shown promise in experimental models of stroke (Xu, 2006). Previously (Xu, 2005) it was already proven that low doses of Li, both alone and in combination with captopril, were effective in preventing the rise in blood pressure and the occurrence of IS in spontaneously hypertensive rats. Lithium prolongs the effect of angiotensin-converting enzyme (ACE) inhibition. In arterial hypertension, hyperfunction of Na+-H+- and/or Na+-Li+ metabolism was detected, i.e. sodium accumulates intensively, and lithium is lost. Maddens et al. (2005), when examining patients over 80 years of age suffering from bipolar disorders and receiving lithium carbonate, drew attention to the hypotensive effect of Li in combination with low doses of thiazide diuretics, as well as a significant reduction in the frequency of IS compared with peers who did not receive lithium therapy. Lithium stimulates the production of nerve growth factor.

Zinc. The controversial effects of zinc on neurochemical processes are reflected in the reviews “The Two Faces of Zinc in the Brain” (Kudrine & Gromova, 2003) and “Zinc Supplementation: Neuroprotection and Neurointoxication?” (C. W. Levenson, 2005). The administration of zinc supplements, like iron supplements, is dualistic for brain biochemistry and can have negative consequences. IN acute period stroke zinc preparations release Zn2+ in high doses, which potentiates excitotoxicity, so they are not indicated. In contrast, Kitamara et al. (2006) demonstrates the neuroprotective effect of low doses of zinc in a model of middle cerebral artery occlusion in rats. Physiological doses of dietary zinc (5–15 mg/day) are necessary for the growing brain, since its adequate intake from food is a prerequisite for the formation and functioning of all parts of the immune system, the formation of cognitive function and normal functioning of the central nervous system.

Iron. Iron metabolism is under close attention of neurochemistry and neurology. Unique research in this direction was started by V.S. Reitses (1981), K. Saito, T. Saito (1991). It is known that both a deficiency and an excess of iron in nervous tissue leads to an escalation of pro-oxidant processes. Significantly reduced iron levels (corresponding to iron deficiency anemia) and its increased levels are predictors of increased FRO processes in the brain. Severe iron deficiency causes disruption of the production of neurotransmitters (serotonin, dopamine, norepinephrine), myelin, leads to the development of an energy crisis and can be combined with an increased risk of stroke. However, the latest achievements in molecular biology and neurochemistry of iron are summarized in the analytical review by M.H. Selim and R.R. Ratan (2004) "Role of iron neurotoxicity in ischemic stroke." What's the matter? The “criminal case” regarding iron concerns, to a greater extent, violations associated with the quality and quantity of its specific transporters in the brain - transferrin (TF), ferritin. The main transport protein for iron is TF. Normal human TF is represented by only one isoform. However, in neurological diseases, tumors, and in patients with chronic hepatitis, especially alcoholic etiology, modified or abnormal forms of TF may be secreted, in which there are no carbohydrate chains, due to a violation of the conjugative function of the liver. Our monograph (Kudrin A.V., Gromova O.A. Microelements in neurology, 2006) shows that iron neurotoxicity increases with age and with alcoholism; Using immunological methods, along with three TF isoforms (A, B and C), six subgroups (a1, b1, b2, b3, b4, c1) were identified. Twelve TF isoforms have been isolated from human cerebrospinal fluid. TF contains heavy (H) and light (L) chains. H-chain levels are higher in the 67–88 age group compared to younger individuals (in the frontal cortex, caudate, substantia nigra, globus pallidus). L-chains accumulate in elderly people in the substantia nigra and globus pallidus. Fe-binding centers of TF acquire the ability to bind not only Fe3+, but also Al3+, Ga3+, lanthanide and actinide ions. In cerebrospinal fluid, TF makes up about 7% of the total protein. About 75% of TF enters the brain from the outside, 25% of TF is synthesized by brain glia. It is important to note that under the influence of neuraminidase, glycan chains are separated and TF is converted into tau protein, the level of which increases during stroke and decreases during treatment. Free Fe2+ ions cause activation of CPO and oxidation of neuromelanin in the substantia nigra of the brain. Therefore, lazaroids and iron chelators may be promising in the pharmacotherapy of not only PD, but also IS. In addition to TF, ferritin plays a role in the deposition of the intracerebral Fe3+ pool. Ferritin carries out intracellular iron storage. This protein is formed from 24 subunits of two types: heavy (H) and light (L), with molecular masses of 22–24 kDa and 20–22 kDa, respectively. From 2 chains, ferritin forms a cavity capable of holding 4500 Fe3+ atoms. The maximum concentration of the transporter is in the liver, spleen, bone marrow, mainly in endothelial cells. The storage of iron in oxidized form prevents its involvement in oxidative processes and is intended to save the cells of the nervous system and vascular endothelium from excess FRO. Under physiological conditions, ferritin always remains an antioxidant (a trap of free Fe3+ ions). It is not yet clear what exact mechanisms trigger the release of iron and other trace elements from ferritin during stroke. In the most general outline This is global cerebral ischemia, as well as long-term excess intake of iron and/or poisoning with iron preparations. TF and ferritin are involved in the release of Al3+ and Fe3+, the triggering of FRO, the cross-linking of β-amyloid precursor molecules, which causes the formation of post-stroke senile plaques. Interest in studying ferritin as a risk factor for stroke concerns not only its increase in potential and existing patients. Abnormal forms of ferritin were detected. Mutations in its light chain lead to a sharp increase in the level of iron and manganese in the subcortical nuclei. In addition, the process of utilization of intracellular iron depends on the activity of mitochondrial cytochromes, aconitase and erythroid σ-aminolevulinate synthetase (σ-ALS). In general, an imbalance of iron in the body contributes to a joint increased accumulation of toxic metals in the central nervous system (Mn, Cu, Co, Cd, Al, Sc, etc.). Incomplete saturation of TF with Fe3+ or its reduced affinity for Fe3+ predisposes to the binding of other metals and their transport across the BBB, which may be associated with the pathogenesis of not only Alzheimer’s disease, but also post-stroke neurodegeneration and alcoholic dementia (L. Zecca, 2004).

Along with the achievements in the molecular biology of iron metabolism, it is important to complete experimental studies in the Netherlands (Van der A et al., 2005), France (E. Millerot, 2005), Turkey (J. Marniemi, 2005), which confirmed the direct correlation of increased levels ferritin levels with the risk of stroke, as well as negative effect iron supplements prescribed for “prophylactic purposes”. The only indication for iron therapy is Iron-deficiency anemia, confirmed by objective data (decrease in serum iron, ferritin and transferrin in the blood, and possibly hemoglobin). In an epidemiological study of 11,471 postmenopausal women aged 49 to 70 years, high serum levels of ferritin, transferrin, and iron corresponded to increased risk AI; ferritin level showed the highest informative value (Van der A, 2005). Therefore, it has been proposed to evaluate serum ferritin levels as a risk factor for stroke; it can be elevated, and in women more often than in men, in contrast to uric acid, more often elevated in men.

The use of metal chelators makes it possible to eliminate excess iron from brain tissue (the effectiveness of deoxyferroxamine DFO, desferal, cloquinol, VK-28 has been shown). Antioxidants such as melatonin, α-tocopherol, marine vitamin E, ebselen, lipoic acid, flavonoids, lycopene, epigalacatechins, algisorb (calcium alginate), artichoke extract (chophytol) showed moderate effectiveness in iron accumulation in the brain (Zecca et al., 2004; Gromova, 2006). To replenish vitamins and minerals in patients with stroke and at high risk of its occurrence, special iron-free IUDs have been produced (O.A. Gromova, 2007).

Fat metabolism and diet composition. The positive value of the provision of polyunsaturated fatty acids (PUFAs), especially omega-3, for the prevention of cardioembolic strokes has been objectively proven (J.J. O'Keefe, 2006). Standardized drugs for the level of PUFAs are omeganol, olisalvin, atheroblock, EPH-DHA, etc. He Ka et al. (2005) in a meta-analysis of 9 independent studies for the period 1966–2003 showed that the risk of IS begins to decrease even when consuming fish 1–3 times a month.Consumption of fatty fish varieties by people over 55 years of age, especially cold-water ones containing easily digestible form of Se, 2 times a week reduces the risk of IS by 4 times.

Genetic passport. To normalize the exchange of ME and targeted assistance to a potential stroke patient, it is desirable to determine a complete genetic passport. A person’s genotype, as a set of data on the status of all his genes, does not change throughout life and can be determined in childhood. Certain genotype variants - polymorphisms - are constant internal risk factors, including ME-dependent diseases, in contrast to external factors such as environmental conditions, food, water composition, stress, infectious diseases, smoking, alcohol, taking ME-removing drugs. In recent years, new modern technologies have been introduced in Russia genetic testing, corresponding to the best world standards in this area (E.V. Generozov, V.E. Tretyakov, 2006, www.pynny.ru). The heat-labile variant A223V (677 C->T) of methylenetetrahydrofolate reductase (MTHFR) may reduce genomic stability due to DNA hypomethylation. 10% of the risk of developing coronary atherosclerosis is due to an increase in homocysteine ​​levels in the blood plasma. The presence of the 677T mutation in the MTHFR gene in patients with antiphospholipid syndrome correlates with the recurrent course of thrombosis. In the system of counteracting negative polymorphisms of lipid metabolism, the role of eliminating transgenic, excess saturated solid fats and sugars in the diet, introducing PUFAs, Se, Mg, I, Mn, bioflavonoids, a complex of antioxidants from dry red wine, green tea, α-tocomonoenol, the so-called marine tocopherol.

Thus, it is important to note that the nutritional system, the provision of MaE, ME, and vitamins is the main modifying factor for the clinical implementation of the genetic program. To date, it has already been established that the subsidy of increased doses of folates (in active vitamers, up to 800–2500 mcg/day), pyridoxine (25 mg/day), magnesium (350 mg/day) and cyanocobalamin (15 mg/day .), containing 4% cobalt, can disable the program of polymorphisms in the MTHFR gene, restore methylation, reduce homocysteine ​​levels and prevent dependent cerebrovascular pathology.

New directions. In terms of the neuroprotective effect, substances with potential effects on different parts of the ischemic cascade are being studied: beta-interferon, magnesium preparations, iron chelators (DFO, desferal, a new iron chelator codenamed DP-b99), AMPA receptor antagonists (zonanpanel), serotonin agonists (repinotan, piclozotan) membrane modulators (citicoline), lithium preparations, selenium (ebselen), etc. (Ferro, 2006). A new target for neuroprotection is the impact on the chain of reactions dependent on SOD (superoxide dismutase) activity. Thus, the drug phosphatidylinositol 3-kinase (PI3-K)/Akt (protein kinase B) is aimed at the survival of neurons. Activation of PI3-K/Akt, an increase in the amount of the proline-rich substrate Akt and phosphorylated protein Bad in neurons that survived after ischemia, which were also characterized by an increase in the activity of Cu-Zn superoxide dismutase, were shown (P.H. Chan, 2005). Calcium antagonists and Mg ions block slow calcium channels and reduce the proportion of patients with adverse outcomes and neurological deficits due to hemorrhagic stroke in the MCA caused by ruptured aneurysm.

General indications for the use of neurotrophic drugs and drugs containing MaE and ME are:

Alzheimer's disease, vascular dementia, cerebral ischemia ( acute stage and rehabilitation period), traumatic brain injury (acute stage and rehabilitation period), dementia caused by alcohol and drug abuse;

coma, delirium, overcoming drug and alcohol addiction;

consequences of perinatal encephalopathy, intellectual disability in children suffering from mild or moderate mental retardation, learning difficulties, cerebral palsy.

Thus, trophic therapy in neurology has much wider boundaries than is commonly thought. Neurotrophic therapy is the use of innovative achievements in the synthesis of new drugs, the use of drugs that have proven their effectiveness and safety (Cerebrolysin, cytoflavin, ebselen, etc.), and the integration of correction of microelement metabolism into treatment protocols. Restoring the elemental and ligand balance in patients who have suffered a stroke or traumatic brain injury is becoming a mandatory rehabilitation strategy, without which it is impossible to achieve sustainable results in neuroprotection.

LOCAL FACTORS

From the complex of local factors influencing the condition of periodontal tissues, the following should be highlighted: dental plaque, dental plaque microflora, uneven loads on periodontal tissue, malocclusion, traumatic occlusion, unsanitized oral cavity, defective fillings (supracontact, overhanging edge of a filling or artificial crown), defects in prosthetics, orthodontic appliances, bad habits, incorrect positioning of the frenulum of the lips and tongue, physical effects (burns, ionizing radiation), chemicals (acids, alkalis).

Dental deposits. The development of inflammatory changes in the periodontium is a consequence of the damaging effects of dental plaque.

There are soft non-mineralized– pellicle, dental plaque, white matter (soft plaque, food debris), dental plaque and hard mineralized- dental supra- and subgingival calculus, dental deposits.

Pellicle- This is an acquired thin organic film that replaces the cuticle. The pellicle is free of bacteria and is a derivative of salivary glycoproteins that selectively adsorb on the enamel surface. The pellicle is a membrane that gives the enamel selective permeability. The mechanism of pellicle formation is facilitated by electrostatic forces (van der Waals forces), which ensure strong bonding of the surface of hydroxyapatites of tooth enamel with positively charged components of saliva or gingival fluid.

Dental plaque It is a soft amorphous granular formation that accumulates on teeth, fillings, and dentures. It adheres tightly to their surface and is separated only by mechanical cleaning.

In small quantities the plaque is not visible, but when a lot of it accumulates, it takes on the appearance of a gray or yellow-gray mass. The plaque forms equally on the upper and lower jaws, more on the vestibular surfaces of the lateral teeth and the lingual surfaces of the lower frontal teeth.

Dental plaque consists mainly of proliferating microorganisms, epithelial cells, leukocytes and macrophages. It consists of 70% water, the dry residue is 70% microorganisms, the rest is the intercellular matrix. The matrix, in turn, consists of a complex of glycosaminoglycans, in which the main components are carbohydrates and proteins (about 30% each), lipids (15%), and the rest consists of waste products of plaque bacteria, remnants of their cytoplasm and cell membrane, food and salivary derivatives glycoproteins. The main inorganic components of the plaque matrix are calcium, phosphorus, magnesium, potassium and, in small quantities, sodium.

Dental plaque is basically a highly ordered bacterial formation, which is characterized by progressive growth and is quite firmly attached to the hard tissues of the teeth. Dental plaque begins to form within 2 hours after brushing your teeth. It forms and ripens within a short time - up to three weeks.

In the process of dental plaque formation, there are three main phases:

1st phase – formation of a pellicle that covers the surface of the tooth.

2nd phase – primary microbial contamination.

3rd phase – secondary microbial contamination and plaque preservation.

Primary microbial contamination occurs already in the first hours of pelicule formation. The primary layer covering the pellicle is Act. viscosus and Str. sanguis, due to the presence of special adhesive molecules, with the help of which these microorganisms selectively attach to similar adhesive foci on the pellicle. At Str. sanguis such adhesive sites are dextran molecules, in Act. viscosus are protein fimbriae that attach to proline proteins on the pellicle. First, microorganisms attach and adhere to the surface of the pellicle, then they begin to multiply and form colonies. With secondary microbial colonization, new periodontopathogenic microorganisms appear: Prevotella intermedia, Fusobacteria nucleatum, Porphyromonas gingivalis, Capnocytophaga saprofytum. Within a few days, there is an increase in cocci (their populations) and an increase in the number of gram-negative strains: cocci, rods, spindle-shaped bacteria (spirillum and spirochetes). Streptococci make up approximately 50% of the bacterial flora of the plaque. An important role in the occurrence of dental plaque is played by microorganisms that are capable of fermenting (synthesizing) carbohydrates with the formation of polysaccharides, dextrans, levans, characterized by adhesion to the hard tissues of teeth. These products form a mesh structure of dental plaque.

As dental plaque develops, its composition also changes. At first, aerobic microorganisms predominate, later, as the plaque matures, anaerobic microorganisms predominate.

In recent years, many scientists have considered dental plaque as a biofilm. The essence of the new approach is as follows: in accordance with the order of introduction of microorganisms into the plaque, the last to populate it are filamentous and spindle-shaped forms that secrete exopolysaccharides that form a viscous substance. Thus, all microbes included in the plaque are isolated from other microbial associations. In this state, this biofilm (or plaque) has direct access to nutrition, and therefore to reproduction and the realization of its damaging potential on adjacent soft tissue formations (in particular, on connective epithelial cells). Moreover, being part of biofilms, bacteria acquire new properties due to the exchange of genetic information between colonies, in particular, they acquire greater virulence and, at the same time, resistance to antibacterial influences.

The composition of dental plaque varies greatly among individuals. One of the reasons is the different intake of carbohydrates from food, which contribute to the accumulation of organic acids in the plaque.

As the plaque grows and organizes, the number of microorganisms in it increases to approximately 70-80% of its mass.

Mature plaque has a fairly organized structure and comprises: 1) acquired pellicle, which provides connection between the plaque and the enamel; 2) a layer of front garden-like fibrous microorganisms that settle on the pellicle; 3) a dense network of fibrous microorganisms in which there are colonies of other types of microbes; 4) the surface layer of coccus-like microorganisms. Depending on the location in relation to the gingival margin, supragingival (coronal and marginal) and subgingival plaques are distinguished. Subgingival plaque is divided into 2 parts: associated with the tooth and associated with the epithelium. Bacteria from subgingival plaque associated with the epithelium can easily penetrate the connective tissue of the gums and alveolar bone.

Plaque bacteria use nutrients (easily digestible carbohydrates - sucrose, glucose, and, to a lesser extent, starch) to form matrix components, consisting mainly of a polysaccharide-protein complex. The plaque contains inorganic substances in very small quantities, mainly calcium and phosphorus, traces of magnesium, potassium and sodium. The rate of plaque formation depends on the nature of the diet, the hygienic state of the oral cavity, the properties of saliva, but on average it takes about 30 days for the plaque to mature . As the plaque grows, it spreads under the gum, causing irritation of periodontal tissue, damage to the epithelium and the development of inflammation of the underlying tissues . Endo- and exotoxins secreted by plaque microorganisms have a toxic effect on periodontal tissue, disrupt cellular metabolism, cause vasomotor disorders, and sensitization of periodontal tissue and the body as a whole.

Plaque microorganisms, as a result of the active release of various enzymes (hyaluronidase, chondroitin sulfatase, proteases, glucuronidase, collagenase), have pronounced proteolytic activity). These enzymes cause depolymerization of glycosaminoglycans, periodontal tissue proteins, and primarily collagen, contributing to the development of microcirculatory disorders in the periodontium.

Increased formation of dental plaques is promoted by mouth breathing, smoking, soft food consistency, excessive consumption of easily digestible carbohydrates, and poor oral hygiene.

White substance (soft plaque)- this is a superficial acquired formation on the teeth, covering the pellicle. It does not have a constant internal structure, which is observed in the plaque. Its irritating effect on the gums is associated with bacteria and their waste products. It is a yellow or grayish-white soft and sticky deposit that adheres less tightly to the tooth surface than plaque. The largest amount of plaque is located at the necks of the teeth, in the interdental spaces, on the contact surfaces and on the cheek surfaces of the molars. Plaque is quite easily removed with a cotton swab, a stream of water, a toothbrush, and is erased by chewing solid food.

Basically, plaque consists of a conglomerate of food debris (food debris), microorganisms, constantly exfoliating epithelial cells, leukocytes and a mixture of salivary proteins and lipids. Dental plaque contains inorganic substances - calcium, phosphorus, sodium, potassium, trace elements - iron, fluorine, zinc and organic components - proteins, carbohydrates, proteolytic enzymes. The bulk of dental plaque consists of microorganisms: 1 mg of plaque can contain up to several billion of them.

The intensity of formation and the amount of plaque depend on many factors: the quantity and quality of food, the viscosity of saliva, the nature of the microflora, the degree of tooth cleansing, and the condition of periodontal tissues. With increased carbohydrate consumption, the rate of plaque formation and its amount increase.

Mechanism of plaque formation:

1. stage – formation of a pellicle (thickness from 1 to 10 microns);

2. stage - adsorption of proteins, microorganisms and epithelial cells on the surface of the pellicle;

3. stage - mature dental plaque (thickness up to 200 microns);

Stage 4 - transition of soft plaque into tartar. This occurs when conditions of anaerobiosis are created in mature dental plaque, a change in the composition of microorganisms occurs (replacement of aerobes by anaerobes), a decrease in acid production and an increase in pH, accumulation of Ca and its deposition in the form of phosphate salts.

Food leftovers- This is the fourth layer of non-mineralized dental plaque. Food particles are located at retention points. When eating soft food, its remains undergo fermentation and rotting, and the resulting products contribute to the metabolic activity of dental plaque microorganisms.

Tartar. Over time, the concentration of inorganic substances in the dental plaque increases, and it becomes a matrix for the formation of tartar. The predominant calcium phosphate in the plaque impregnates its colloidal base, changing the ratio between glycosaminoglycans, microorganisms, desquamated epithelium, and leukocytes.

Tartar is predominantly localized in the cervical area of ​​the teeth (vestibular, lingual surface), retention points, on the surface of the teeth adjacent to the excretory ducts of the salivary glands, under the marginal edge of the gums.

Depending on the location relative to the gingival margin, there are supragingival And subgingival tartar. They differ in the mechanism of formation, localization, hardness and influence on the development of pathological processes in the oral cavity. Mineral components (calcium, phosphorus, magnesium, carbonates, microelements) penetrate into the supragingival tartar from the oral fluid, and into the subgingival tartar from the blood serum. About 75% of these are calcium phosphate, 3% calcium carbonate, the rest are magnesium phosphate and traces of various metals. The mostly inorganic part of tartar has a crystalline structure and is represented by hydroxyapatite. Depending on quantity minerals The consistency of tartar changes, with 50-60% of mineral compounds - soft, 70-80% - medium, more than 80% - hard.

The organic basis of tartar is a conglomerate of protein-polysaccharide complex, desquamated epithelial cells, leukocytes and various types of microorganisms. A significant part consists of carbohydrates, represented by galactose, glucose, glucuronic acid, proteins and amino acids.

In the structure of dental stone there are a superficial zone of bacterial plaque without signs of mineralization, an intermediate zone with crystallization centers and a zone of dental calculus itself. The presence of a large number of bacteria (their enzymatic properties) in dental calculus explains its pronounced sensitizing, proteolytic and toxic effect, which contributes to the development of microcirculatory disorders in the periodontium and causes destruction of connective tissue.

Based on their structural characteristics, hard dental deposits are divided into into: crystalline-granular, concentric-shell-shaped and collomorphic.

Supragingival calculus(salivary) is more common and is formed due to the mineralization of soft dental deposits. It is usually white or whitish-yellow in color, hard or clay-like in consistency, and is easily detected upon inspection. The color is often affected by smoking or food pigments. There are several theories for the formation of supragingival tartar: salivary, colloid, microbial.

Subgingival calculus located under the marginal gum, in the gingival periodontal pockets, on the root cement. It is usually not visible during visual examination. Probing is necessary to detect it. It is dense and hard, dark brown in color and tightly attached to the surface of the tooth. Subgingival tartar is formed as a result of coagulation of protein and mineral substances of blood serum and inflammatory exudate in the periodontium.

Tartar (especially subgingival calculus) has a pronounced mechanical damaging effect on the periodontium and contributes to the development of local C-hypovitaminosis. It contains metal oxides (vanadium, lead, copper), which have a pronounced toxic effect on the periodontium. On the surface of tartar there is always a certain amount of non-mineralized plaques, which are the most important irritants of periodontal tissue and largely determine the nature of the pathogenic effect of tartar. The mechanism of the damaging effect of tartar on the periodontium is largely related to the action of the microflora contained in it.

Microflora. About 400 strains of various microorganisms constantly live in the oral cavity, but only about 30 of them can be considered opportunistic for periodontal tissues.

Microorganisms vary greatly in their ability to attach to different surfaces in the mouth. Thus, Streptococcus mutans, S. sanguis, Lastobacillus strains, Actinomyces viscosus readily attach to tooth enamel. Streptococcus salivarius, Actinomyces naeslundii inhabit the dorsum of the tongue, while Bacteroides and spirochetes are found in the gingival sulci and periodontal pockets. Such types of microorganisms as Streptococcus mutans, S.sanguis, S.mitis, S.salivarius, Lactobacillus strains have the ability to form extracellular polymers from dietary carbohydrates. These extracellular polysaccharides are insoluble in water and significantly enhance the adhesion of microorganisms, and therefore dental plaque, to the surface of the teeth. They stick to the surface of the pellicle and subsequently to each other, ensuring the growth of the plaque.

In addition to plaques tightly attached to the tooth, there are loose microbial accumulations on the walls inside the pocket. The role of dental plaque and loose microorganisms in the development of the pathological process is not the same: the influence of plaque dominates, but in some cases it is loosely attached microorganisms that play a significant role in the course of aggressive forms of periodontitis and in the onset of the exacerbation phase.

There are a significant number of different factors in the oral cavity that suppress the growth of microflora. First of all, this is saliva, which contains substances such as lysozyme, lactoperoxidase, lactoferrin. Immune components, such as IgA, are secreted by the salivary glands and enter the oral cavity, preventing the attachment of microorganisms to the surface of hard dental tissues and cell membranes.

The basement membrane is also considered as a fairly powerful barrier to the penetration of microorganisms, but if its integrity is damaged, bacteria relatively easily penetrate deep into the periodontal tissues. The entrance gate for microflora is a violation of the integrity (ulceration) of the attachment of the sulcus epithelium to the hard tissues of the teeth.

Periodontal tissues function fully when there is a balance between the resistance of the human body and the virulence of bacteria. Some types of microorganisms have the ability to overcome the host's defenses and penetrate the periodontal pocket and even the connective tissue of the gums. Bacteria can damage host tissues through the direct action of their toxins, enzymes, toxic metabolic products, or indirectly by stimulating host responses that cause damage to its own periodontal tissues.

The microbial population that forms on the surface of the teeth in the form of plaques is significantly different from the microorganisms found on the surface of the oral mucosa. Microorganisms entering the oral cavity first come into contact with saliva or saliva-coated surfaces. Therefore, they are easily washed off if they do not have the ability to adhere to the surface of the teeth. Consequently, adhesiveness is considered as an important property and the main factor in the opportunistic microflora of the oral cavity. If any changes occur in the host’s body or in the microorganisms themselves that are in symbiosis, this leads to a significant disruption of the habitat of microbes in the oral cavity. New conditions that have arisen require adaptation of the host organism and microbes, so the oral cavity is usually populated with new strains of microorganisms that are more adapted to the current conditions. This phenomenon is called bacterial heredity and occupies an important place in the pathogenesis of gingivitis and periodontitis.

There are a sufficient number of observations confirming the specificity of the complex of microorganisms that are associated with this disease or are most often isolated in various types of human periodontal diseases, various courses of generalized periodontitis. This occurs despite the rather different causes of the diseases and, apparently, reflects certain, more or less identical conditions that arise at this time in the periodontium

Microbiological research in this case, the complex of microorganisms most often sown from periodontal pockets is determined.

This made it possible to create a kind of classification of periodontal microbial complexes.

There are: red, green, yellow, purple, orange microbial complexes.

Red complex(P. gingivalis, B. forsitus, T. denticole). The combination of these microorganisms has a particularly aggressive effect on the periodontium.

The presence of this complex causes severe bleeding of the gums and the rapid course of destructive processes in the periodontium.

Green complex(E. corrodent, Capnocytophaga spp., A. actinomycetemcomitans). The main virulence factor of A. actinomycetemcomitans is a leukotoxin that causes neutrophil lysis. This combination of microbes can cause both periodontal diseases and other lesions of the oral mucosa and hard dental tissues.

Yellow complex(S. mitis, S. israilis, S. sanguis).

Purple complex(V. parvula, A. odontolyticus).

Orange complex(P. nigrescen, Prevotella intermedia, P. micros, C. rectus + Campylobacter spp.). Prevotella intermedia produces phospholipase A, disrupts the integrity of epithelial cell membranes, is an active producer of hydrolytic proteases that break down proteins of periodontal tissues and tissue fluid into polypeptides, produces proteolytic enzymes, and therefore plays main role in the formation of periodontal abscesses.

These three complexes are also capable of causing periodontal lesions and other oral diseases.

The identification of these complexes does not mean that they include only the listed species of microorganisms, but these communities of species are the most stable.

A possible reason for the stability of just such microbial combinations is their existence in the form of viscous biofilms according to the principle of the above-mentioned “convenience” of their metabolism, when the products secreted by some are nutrient sources for other microbes or provide them with increased resistance and virulence.

The listed microbial associations are part of stable dental plaques attached to the surface of the tooth or to the walls of the periodontal pocket. Moreover, the composition free The location of microbial accumulations inside the periodontal pocket may be completely different.

Periodontal microorganisms identify a number of different pathogenic factors that cause the destruction of periodontal tissue, namely: leukotoxins, endotoxins (lipopolysaccharides), lipoic acid, resorbing factor, capsular material, various short-chain fatty acids. These bacteria also secrete enzymes: collagenase, trypsin proteases, keratinase, neuraminase, arylsulfatase. These enzymes are capable of lysing various components of periodontal tissue cells. Their effect is enhanced when combined with enzymes that release leukocytes accumulated on periodontal cells.

The primary reaction of the gums to the combined effect of these factors and, first of all, inflammatory mediators, is the development of gingivitis. Pathological changes in gingivitis are reversible, however, prolonged maintenance of inflammation leads to increased permeability of histohematic barriers, a significant increase in the migration of leukocytes and their infiltration of periodontal tissues, the interaction of bacterial antigens with antibodies, and increased secretion of lysosomal enzymes by leukocytes. Subsequent blast transformation of lymphocytes, leading to the formation of plasma cells and tissue basophils, stimulation of the secretion of lymphokines and activation of osteoclasts, determines the development of destructive processes in soft and hard periodontal tissues.

The development of periodontitis is directly dependent on the amount of plaque and general microbial contamination of the oral cavity and inversely on the effectiveness of hygiene measures.

Traumatic occlusion. Conditions in which the periodontium is exposed to loads that exceed its reserve compensatory capabilities and lead to its damage are called “functional traumatic overload”, “occlusal injury”, “trauma as a result of occlusion”, “traumatic occlusion”. There are various possible causes and mechanisms of development of traumatic occlusion. If excessive damaging chewing pressure acts on teeth with healthy periodontal disease not affected by the pathological process, then such traumatic occlusion is defined as primary. Primary traumatic occlusion can occur with traumatic overload of teeth due to increased bite (filling, crown, mouthguard, orthodontic appliance), malocclusion and individual teeth, loss of many teeth, pathological abrasion. Quite often, primary traumatic occlusion occurs as a result of parafunctions: bruxism, tonic reflexes of the masticatory muscles, compression of the tongue between the teeth. Traumatic overload occurs when the lower jaw is displaced due to loss of teeth or improper prosthetics. Thus, primary traumatic occlusion occurs as a result of the action of excessive (compared to normal, physiological) chewing load on the teeth or a change in its direction. It should be noted that primary traumatic occlusion is reversible pathological process.

On the other hand, against the background of a pathological process in periodontal tissues, the usual normal chewing load may exceed the reserve forces of the periodontium. As a result of resorption of alveolar bone and periodontal fibers, the tooth cannot resist the normal chewing pressure that it could withstand with intact periodontium. This habitual occlusal load begins to exceed the tolerance of its structures and turns from a physiological load into a factor that injures and destroys periodontal tissue. Wherein. the relationship between the height of the clinical crown and the length of the root changes, which causes significant overload of the bone walls of the alveoli. This leads to overload of the periodontium and accelerates resorption bone tissue holes. Such traumatic occlusion is defined as secondary. It most often occurs in generalized periodontitis. A vicious circle of pathological changes is formed: traumatic occlusion occurs against the background of periodontal changes and subsequently it contributes to the further progression of destruction of the alveolar bone and other periodontal tissues. Typically, with secondary traumatic occlusion, resorption of periodontal tissue (periodontium, alveolar bone) and hard dental tissue (cement, dentin) occurs.

The adverse effects of traumatic occlusion increase with tooth extraction. When teeth are lost or removed, resistance from neighboring teeth disappears, which compensates for a certain horizontal component of the chewing load. Such teeth begin to take the load in isolation, and the dentition ceases to act as a single system. The resulting overload of such teeth leads to their inclination towards the defect in the dentition. This leads to atrophy of the alveolar bone at the site of application of excessive chewing pressure.

When a pathological situation exists for a long time, the reflex activity of the masticatory muscles changes, and this reflex is consolidated. Incorrect movements of the lower jaw, in which some areas of the dentition are not exposed to chewing load, while others, on the contrary, are overloaded, lead to changes in the temporomandibular joints.

Characterizing this pathological condition in general, it should be noted that traumatic occlusion is understood as such occlusal relationships of individual groups of teeth or dentitions, which are characterized by premature and unstable closure, uneven distribution of chewing pressure with subsequent migration of overloaded teeth, pathological changes in the periodontium, dysfunction of the chewing teeth muscles and temporomandibular joints.

Sometimes combined traumatic occlusion is identified as a separate form. In this case, signs of both primary and secondary traumatic occlusion are revealed.

Anomalies of bite and position of individual teeth have a significant damaging effect on periodontal tissue. Pronounced changes develop with a deep bite in the frontal area of ​​the dentition, since these areas are overloaded during vertical and horizontal movements of the lower jaw. With a distal bite, this is aggravated by the resulting significant horizontal overload of the teeth, which subsequently manifests itself in a fan-shaped divergence of the upper frontal teeth. With medial, on the contrary, their displacement occurs to the palatal side. In the frontal area of ​​the lower jaw, displacement of the teeth and their crowding are noted. In these areas there is a significant accumulation of food debris, microorganisms, and the formation of dental plaque and tartar.

The development of inflammatory processes in the periodontium with anomalies in the position of the teeth and occlusion pathology is associated with a disruption of the normal functioning of the periodontium - overload of some of its areas and underload of others.

The severity of these pathological changes in the periodontium depends on the severity of the malocclusion and individual teeth.

Unsanitized oral cavity, in which there are many teeth affected by caries, represents a whole complex of periodontal damaging factors. Food debris accumulates in carious cavities, and the formation of a significant amount of dental plaque is observed in the area of ​​​​these teeth.

Especially adverse effect The tissue is affected by carious cavities located in the cervical region and on the contact surfaces of the lateral teeth. The damaging effect of the latter is enhanced by the absence of a contact point in these areas: food debris is pushed deeper during chewing, injuring the gums and other periodontal tissues. Approximately the same adverse effect on periodontal tissue is caused by improperly filled carious cavities on the contact surfaces of teeth, especially with edges overhanging the gingival papilla. Under them, food debris accumulates, dental deposits form and, thus, conditions are created for the emergence and progression of the pathological process in the periodontium.

Incorrectly manufactured artificial crowns, bridges and removable dentures have a similar effect on the periodontium. Fillings and fixed dentures that increase the bite additionally cause overload of the teeth during chewing movements of the lower jaw. This leads to the development of traumatic occlusion and the appearance of traumatic nodes in these areas.

Anomalies of the anatomical structure of gum tissue, mucous membrane and oral cavity as a whole also have an adverse effect on periodontal tissue. Thus, the high attachment of the frenulum of the lips or tongue leads to the fact that when they move, the gums are torn away from the necks of the teeth. In this case, a constant tension arises in the area of ​​attachment of the gums to the necks of the teeth, or more precisely, the attachment of the epithelium of the gingival sulcus to the hard tissues of the teeth. Subsequently, in these areas the integrity of the epithelial attachment is disrupted, first a gap is formed, and then a periodontal pocket. Approximately the same mechanism of damaging action on the periodontium with a small vestibule of the oral cavity.

With prolonged mechanical overload of the teeth, swelling and destruction of collagen fibers occur, the mineralization of bone structures decreases, and then their resorption occurs.

The effect of microorganisms is significantly enhanced against the background of impaired trophism of periodontal tissue. This occurs when the structure of the soft tissues of the vestibule of the oral cavity is disrupted or when there are “pulling” strands of the mucous membrane.

Bad habits sucking or biting the tongue, soft tissues of the oral cavity, or any foreign objects have a damaging effect on periodontal tissue. Habitual biting of foreign objects creates a small but constant traumatic overload of the teeth in this area. Biting soft tissues, such as the cheek, causes additional tension on its tissues. Through the mucous membrane of the transitional fold, it is transmitted to the gum tissue and promotes its separation from the hard tissues of the teeth. This further leads to the accumulation of food residues in such areas and the formation of dental plaque.

Local irritants.

In addition to dental plaque, there are a number of different factors in the oral cavity that can cause mechanical trauma, chemical and physical damage to periodontal tissue.

Mechanical irritants may be different foreign bodies, which (especially in children) can easily injure the gums. Acute injury is possible due to careless use of hard objects (hard parts of food, toothpicks, toothbrushes, in children - parts of toys), injuries (bruise, blow) to the maxillofacial area.

Common cause Inflammatory periodontal diseases are chronic trauma from sharp edges of carious cavities (especially localized in the cervical area or on contact surfaces), overhanging edges of defective fillings, defective dentures.

Adolescents often experience acute periodontal trauma due to dental trauma, their dislocation or subluxation, or jaw contusion. In such cases, localized periodontitis usually develops.

Chemical damaging factors associated with the effect of various acids, bases (alkalis), chemical medications, and components of filling materials on the periodontium. Due to the expansion of the arsenal of means household chemicals Chemical burns of the mucous membrane and periodontal tissue are observed, especially in children. Depending on the character chemical substances, their concentration and duration of contact with the oral mucosa, either catarrhal inflammation or gum necrosis develops, and in severe cases, deep periodontal lesions with necrosis of the alveolar bone. Typically, more severe lesions occur with burns caused by bases, which, unlike acids, cause the development of liquefaction necrosis of tissue.

Physical factors . These include damage to the periodontium when exposed to high or very low temperatures, electric current, ionizing radiation. In domestic conditions, periodontal burns are possible with hot water and food. Depending on the temperature, duration of action of the kogut irritant, the age of the victim, the severity of changes in the periodontium can be different: from catarrhal inflammation to deep destructive damage (ulcers, tissue necrosis).

In case of tissue damage electric shock Usually there is a violation of the integrity of the gum tissue, in severe cases - necrosis of the superficial and deep periodontal tissues. The cause of inflammatory changes in the gums may be microcurrents that occur between parts of dentures (metal fillings) made of different metals. In the latter case, a combination of electrothermal and electrochemical effects on periodontal tissue is possible.

The influence of ionizing radiation is possible when radioactive substances are incorporated into the oral cavity, accidental exposure of victims to areas of increased radiation, when radiation therapy neoplasms of the maxillofacial region. Depending on the type of ionizing radiation and its dose, various options for the clinical course of the lesion are possible: from catarrhal inflammation to extensive erosive and ulcerative lesions and necrosis of periodontal tissue.

General factors:

Periodontal lesions are associated with a number of common factors: genetic predisposition, immunodeficiency, age-related changes, pregnancy, diabetes. The final result of their action is the strengthening of destruction processes and the weakening and slowing down of repair processes. Systemic diseases are more legitimately considered as aggravating the development of periodontal diseases or influencing their pathogenesis.

Neurotrophic disorders.

Periodontal disease as a neuro-dystrophic process was substantiated in his works in the 30-60s of the last century by D.A. Entin, E.E. Platonov, I.O. Novik, E.D. Bromberg, M.G. Bugaiova and modern scientists – N.F. Danilevsky, L.M. Tarasenko, L.A. Khomenko, T.A. Petrushanko.

In a number of works, D.A. Entin experimentally confirmed the role of the central nervous system in the occurrence of generalized periodontitis. By irritating the area of ​​the gray tubercle, he for the first time received degenerative changes in the periodontal tissues, similar to generalized periodontitis in humans. These changes are based on organic and functional disorders of the central nervous system, which intensify under unfavorable environmental conditions (for example, hypovitaminosis C).

N.F. In experiments on monkeys, Danilevsky used a physiological stimulus - experimental neurosis caused by a violation of the sexual and herd reflexes.

Disturbance of nervous trophism. Neurodystrophic process

Cell trophism and dystrophic process. Cell trophism is a complex of processes that ensure its vital activity and maintain its genetically inherent properties. Trophic disorder is dystrophy, developing dystrophic changes constitute dystrophic process.

Neurodystrophic process. This is a developing trophic disorder, which is caused by a loss or change in nervous influences. It can occur both in peripheral tissues and in the nervous system itself. Loss of nerve influences consists of: 1) cessation of stimulation of the innervated structure due to a violation of the release or action of the neurotransmitter; 2) in violation of the secretion or action of comediators - substances that are released together with neurotransmitters and play the role of neuromodulators that provide regulation of receptor, membrane and metabolic processes; 3) in violation of the release and action of trophogens. Trophogens (trophins) are substances of various, mainly protein nature, which carry out the actual trophic effects of maintaining the vital functions and genetically inherent properties of the cell. The source of trophogens are: 1) neurons, from which trophogens enter with an anterograde (orthograde) axoplasmic current into recipient cells (other neurons or innervated tissues in the periphery); 2) cells of peripheral tissues, from which trophogens enter the nerves with a retrograde axoplasmic current into neurons (Fig. 21-3); 3) glial and Schwann cells, which exchange trophic substances with neurons and their processes. Substances that play the role of trophogens are also formed from serum and immune proteins. Some hormones can have a trophic effect. Peptides, gangliosides, and some neurotransmitters take part in the regulation of trophic processes.

TO normotrophogens include various types of proteins that promote the growth, differentiation and survival of neurons and somatic cells, maintaining their structural homeostasis (for example, nerve growth factor).

Under pathological conditions, trophic substances are produced in the nervous system, causing persistent pathological

Rice. 21-3. Trophic connections between motor neuron and muscle. Substances from the body of the motor neuron (MN), its membrane 1, perikaryon 2, nucleus 3 are transported with anterograde axoplasmic current 4 to terminal 5. From here they, as well as substances synthesized in terminal 6 itself, enter transsynaptically through the synaptic cleft (SC) to the terminal plate (LP) and into muscle fiber (MF). Some of the unused material flows back from the terminal to the neuron body with a retrograde axoplasmic current

7. Substances formed in the muscle fiber and end plate enter transsynaptically in the opposite direction to the terminal and then with a retrograde axoplasmic current 7 into the body of the neuron - to the nucleus

8, into the perikaryon 9, to the membrane of the dendrites 10. Some of these substances can come from the dendrites (D) transsynaptically to another neuron through its presynaptic ending (PO) and from this neuron further to other neurons. Between the neuron and the muscle there is a constant exchange of substances that maintain trophism, structural integrity and normal activity of both formations. Glial cells (G) take part in this exchange. All of these formations create a regional trophic system (or trophic circuit)

changes in recipient cells (pathotrophogens, according to G.N. Kryzhanovsky). Such substances are synthesized, for example, in epileptic neurons - entering with axoplasmic current into other neurons, they can induce epileptic properties in these recipient neurons. Pathotrophogens can spread throughout the nervous system, as through a trophic network, which is one of the mechanisms for the spread of the pathological process. Pathotrophogens are also formed in other tissues.

Dystrophic process in denervated muscle. Substances synthesized in the neuron body and transported to the terminal with an axoplasmic current are released by the nerve ending and enter the muscle fibers (see Fig. 21-3), performing the function of trophogens. The effects of neurotrophogens are visible from experiments with transection of the motor nerve: the higher the transection is made, i.e. The more trophogens are preserved in the peripheral segment of the nerve, the later denervation syndrome occurs. The neuron, together with the structure it innervates (for example, muscle fiber), forms a regional trophic circuit, or regional trophic system (see Fig. 21-3). If cross-reinnervation of muscles with different initial structural and functional characteristics is carried out (reinnervation of “slow” muscles with fibers from neurons that innervated “fast” muscles, and vice versa), then the reinnervated muscle acquires significantly new dynamic characteristics: “slow” becomes “fast” , “fast” - “slow”.

New trophogens appear in denervated muscle fibers, which activate the proliferation of nerve fibers (sprouting). These phenomena disappear after reinnervation.

Neurodystrophic process in other tissues. Mutual trophic influences exist between each tissue and its nervous system. When afferent nerves are cut, dystrophic changes in the skin occur. Transection of the sciatic nerve, which is mixed (sensory and motor), causes the formation of a dystrophic ulcer in the hock joint (Fig. 21-4). Over time, the ulcer may increase in size and cover the entire foot.

The classic experiment of F. Magendie (1824), which served as the beginning of the development of the entire problem of nervous trophism, consists of cutting the first branch of a rabbit trigeminal nerve. As a result-

After such an operation, ulcerative keratitis develops, inflammation occurs around the ulcer, and vessels that are normally absent in it grow into the cornea from the limbus. Ingrowth of blood vessels is an expression of pathological disinhibition of vascular elements - in a dystrophically altered cornea, the factor that normally inhibits the growth of blood vessels into it disappears, and a factor appears that activates this growth.

Additional factors of the neurodystrophic process. The factors involved in the development of the neurodystrophic process include: vascular changes in tissues, disorders of hemo- and lymph microcirculation, pathological permeability of the vascular wall, impaired transport of nutrients and plastic substances into the cell. An important pathogenetic link is the emergence of new antigens in dystrophic tissue as a result of changes in the genetic apparatus and protein synthesis, antibodies to tissue antigens are formed, and autoimmune and inflammatory processes occur. This complex of pathological processes also includes secondary infection of the ulcer, the development of infectious lesions and inflammation. In general, neurodystrophic tissue lesions have a complex multifactorial pathogenesis (N.N. Zaiko).

Generalized neurodystrophic process. When the nervous system is damaged, generalized forms of the neurodystrophic process can occur. One of them manifests itself in the form of gum damage (ulcers, aphthous stomatitis), tooth loss, hemorrhages in the lungs, erosion of the mucous membrane and hemorrhages in the stomach (usually in the pylorus area), in the intestines, especially in

area of ​​the boisguin valve, in the rectum. Since such changes occur relatively regularly and can occur in various chronic nerve injuries, they are called standard form of nervous dystrophy(A.D. Speransky). Often these changes occur when higher vegetative centers are damaged, in particular the hypothalamus (due to injuries, tumors), in an experiment when a glass ball is placed on the sella turcica.

All nerves (motor, sensory, autonomic), no matter what function they perform, are simultaneously trophic (A.D. Speransky). Disorders of nervous trophism constitute an important pathogenetic link in diseases of the nervous system and nervous regulation of somatic organs, therefore, correction of trophic changes is a necessary part of complex pathogenetic therapy.

NEURON PATHOLOGY