In 1977, a group of Swiss scientists, studying one of the most mysterious phenomena of the human psyche - sleep, in experiments with cross-circulation of rabbits managed to isolate a bioactive substrate that influenced the formation of the delta phase of sleep.
Contrary to the then prevailing ideas, in vitro experiments showed that fragments of large bioactive protein molecules with the studied properties had completely independent effects. This fact could not be interpreted at that time. But the discovery gave rise to a wave of research work.
Many, many years of research and experimental work by scientists from different countries on the study of the biological activity of peptides and their fragments have led to a completely new understanding of the regulation of homeostasis maintenance systems in the body.
It has been established that bioactive peptides are mediators of most regulatory systems. Several thousand substances involved in signal transmission in the nervous, immune, endocrine, paraendocrine and other vital structures have been isolated and characterized.
As it turns out, many of these substances are produced in the body by trypsin-like enzymes and are then secreted by the cell. Most of them then react with specific receptors on the target cell, causing a cascade of reactions inside the cell.
In this series, the so-called neurotrophic factors (NTF) deserve special attention, both in connection with their role in the body and in connection with the subject of our discussion (DSIP).
In embryogenesis and the postnatal period, NTFs participate in the differentiation, maturation, and maintenance of survival of cells in the peripheral and central nervous systems. NTFs participate in the creation of the cytoarchitecture of nervous tissue, in the formation of the cell phenotype, and in the suppression of programmed neuronal death.
In an adult organism, NGFs are responsible for differentiation, plasticity, and survival of nervous tissue cells, and participate in the reparation of disorders caused by damage to the brain and peripheral nervous system, as well as neurodegenerative diseases. It has also been shown that the nerve growth factor plays an important role in the interaction of the immune and endocrine systems.
In these relationships, NTFs play the role of a “guard” molecule, capable of turning on both local and systemic protective processes in response to damaging effects.
NTFs modulate neuro-immune-endocrine functions vital for maintaining homeostasis. A number of substances have been found to induce and enhance the synthesis of NTF polypeptide chains.
At the same time, the peptidergic system is phylogenetically more ancient than the nervous or endocrine systems, since similar mechanisms apparently maintain homeostasis in unicellular organisms. At the level of a multicellular organism, their action can be cellular, tissue, or systemic, depending on the situation.
DSIP also belongs to a similar group of vital oligopeptides with an unclear molecular mechanism of action.
Intensive studies of this substance undertaken in subsequent years by various research groups have shown that DSIP in free and bound form is present in a number of CNS structures, as well as in various peripheral organs, tissues and body fluids. DSIP is capable of reducing locomotor activity, affects thermoregulation processes, circadian rhythms, and neuronal electrophysiological reactions in various parts of the brain.
It causes naloxone-dependent analgesia, reduces clinical manifestations of alcohol and opiate addiction, significantly increases resistance to various types of stress. Its effect on the release of pituitary hormones, as well as a powerful stimulating naloxone-dependent effect on the release of methionine enkephalins in the brain have been shown.
One of the most impressive features of its multifunctional physiological action is its pronounced stress-protective and adaptogenic activity.
Thus, when introduced into the peripheral blood at a dose of 100-200 μg/kg in an experiment, it significantly increases the survival rate of animals under acute stress and prevents cardiovascular disorders by influencing the transport of Ca ions in the sarcoplasmic reticulum. Its obvious antimetastatic, oncoprotective properties, and the ability to reduce the severity of side effects during chemotherapy and radiotherapy are also noted. Its antiepileptic activity is of great clinical interest, along with the ability to reduce the severity and duration of withdrawal syndrome of various etiologies, reduce the manifestations of "CRAVING" in the treatment of alcohol and drug addiction, and neutralize the manifestations of depression of various genesis.
<h3>Stress-protective activity of DSIP and mechanisms of its implementation</h3>
One of the most impressive features of its multifunctional physiological action is its pronounced stress-protective and adaptogenic activity.
Stress - a general adaptation syndrome - was identified more than 50 years ago as a universal reaction of the body to damage or the threat of such damage.
Being a necessary mechanism of adaptation and survival of the body, stress ensures the mobilization of a complex of reactions that ensure the survival of the body in extreme conditions. However, this physiological reaction entails a whole range of damage, which is a kind of payment for each act of resource mobilization.
Neuroendocrine, metabolic and immune disorders, cardiovascular and other disorders are described in detail in numerous publications on this topic (Meerson, Selye, Dilman, etc.).
Experimental and clinical data indicate the presence of direct damage to a number of subcortical nuclei of the brain due to stress.
This fact seems extremely important, since in recent years our understanding of the mechanisms of realization of both stress reaction and distress has significantly deepened. Classical ideas about the role of the hypothalamic-pituitary-adrenal system have been supplemented by knowledge that glucocorticoid secretion is mainly regulated by a select population of neurosecretory neurons in the paraventricular nucleus of the hypothalamus. There is also indisputable data on the role of the amygdala in the implementation of the behavioral and cardiovascular response to stress. As it turned out, the nuclei of the striatum also affect the HPA axis, linking the amygdala, hippocampus with the brain systems that control vital homeostatic functions. Glutamate-containing neurons also play a certain role in regulation. All the above-described structures, as a rule, stimulate the HPA axis - the response to a stress stimulus.
Inhibitory influences (in addition to the direct inhibitory effect of secreted glucocorticoids) come from the hippocampus, prefrontal cortex, and lateral septum.
In this case, inhibitory neurons are most often GABA-containing.
Accordingly, it is clear that damage to regulatory structures entails inadequacy of the stress response: either its exhaustion, sometimes incompatible with survival, or transition to distress. Today, the basic idea is the role of stress-distress reactions in the pathogenesis of any, both acute and chronic diseases.
Why do neurons die during stress, since their normal functioning is so vital for the body? And what happens to the biochemical processes and membrane structures of cells, including neurons, in response to the action of a stress agent?
"Catecholamine excitation" leads to stimulation of tissue respiration in mitochondria.
It has been shown that hexokinase, a key enzyme of glucose utilization in the brain, has a characteristic feature: variable intracellular localization. Normally, 90% of the total cellular activity of GC is associated with mitochondria, while under stress, the proportion of mitochondrial GC decreases by 10% or more. Oxidation and phosphorylation are uncoupled, succinate dehydrogenase is activated, oxidizing succinic acid, and metabolic pathways that provide the influx of succinic acid into the tricarboxylic acid cycle are intensified. This increases the power of energy supply, but also causes a state of "hyperrecovery".
This creates conditions for the generation of excess amounts of superoxide radicals.
Activation of lipases by catecholamines leads to an increase in the pool of free fatty acids. These two circumstances, combined with increased entry of Ca+ into the cell, create conditions for the activation of lipid peroxidation.
Ca-dependent enzymes.
An increase in the number of free radicals can also occur due to changes in the distribution of MAO-A and MAO-B. MAO-A is normally contained in the mitochondria of brain cells; under stress, its activity decreases, it appears in the cytoplasm and its cytoplasmic component becomes approximately equal to the mitochondrial one, as a result of which the volume of reactions catalyzed by this enzyme increases sharply, which contributes to an increase in peroxide residues.
The source of activated oxygen in tissues can also be the process of oxidation of excess adrenaline present during stress into adrenochrome, as well as the formation of flavo and ubisemiquinones.
Since superoxide radicals are normal metabolites of a living cell utilizing oxygen in metabolic processes, there are protective enzymes of the superoxide dismutase (SOD) family to maintain a steady-state concentration of peroxide radicals. When studying the content of SOD in cells of different tissues under stress, a decrease in its content and activity was found at different but specific times after exposure to a stress factor, depending on both the type of tissue under study and the nature of the stress agent. Therefore, LPO, caused by an increase in the amount of peroxide radicals, free fatty acids and Ca-dependent enzymes, does not meet adequate restrictions.
Intensification of LPO processes inevitably leads to deformation and destruction of mitochondrial membranes, which results in changes in their ion permeability and deterioration of the connection with membrane-bound enzymes (MAO, GC, creatine phosphokinase, etc.). The membrane structure of the cells themselves also changes. Scavenger receptors of microglia react to changes in the membrane structure. Activation of microglia leads to the development of a classic cascade of inflammatory reactions, which, occurring in the most important brain structures, lead to various neurodegenerative changes, including direct death of neurons due to apoptosis.
The central nervous system affected by a stress reaction loses coordination in the implementation of a set of reactions necessary for the survival of the organism, which leads to difficult-to-correct disturbances of homeostasis, including multiple organ failure as a result of severe stress (trauma, infectious process, etc.).
The data accumulated in recent years indicate that stress-induced neurodegeneration is one of the main mechanisms for the formation of a complex of signs of aging of the body.
What is the role of DSIP in all these processes? As mentioned above, its stress-protective effects have been studied for many years.
The experiment revealed its effect in preventing cardiovascular disorders, improving adaptation to cold, hypokinetic stress, etc.
But at the expense of what?
The prevailing view in the literature is that it modulates, improving the coordination of all functional links.
The central nervous system influence is realized through classical neurotransmitter systems: adrenergic, serotonin and GABAergic.
Thus, in the work of Mendzheritsky, 1990, an increase in the content of GABA in brain structures was shown after systemic administration of DSIP.
Using radioimmunoassay, it was found that DSIP substances are contained intracellularly, mainly in mitochondria, and DSIP penetration through the blood-brain barrier was demonstrated.
Changes in the indices of oxidative phosphorylation in mitochondria during hypoxic stress are significantly manifested in a decrease in the rate of ADR phosphorylation and some decrease in the rate of phosphorylating respiration. Preliminary administration of DSIP completely prevents changes in these indices.
Under conditions of hypoxic stress, a significant change in the level of adenine nucleotides was revealed.
The concentration of ADR and ATP is significantly reduced with a simultaneous increase in the content of AMP. In the guanine nucleotide system, a sharp decrease in the concentration of GTR (by 79%) is noted with a simultaneous increase in the amount of GDR. After preliminary administration of DSIP, the concentration of ADR and ATP in hypoxic animals levels out and approaches the initial level, while the amount of AMP changes little. Noticeable changes occur in the content of GTR, its amount increases, although the final level still remains lower than in intact animals.
The study of GC activity showed that DSIP prevents stress-induced changes in GC distribution and activity. Administration of DSIP under stress completely prevents GC release from mitochondria.
If under stress the ability of the mitochondrial membrane to bind GC decreases threefold, then against the background of preliminary administration of DSIP it remains at the normal level.
These data indicate a direct protective effect of the administered DSIP on the mitochondria of brain tissue.
In the same work, changes in serotonin content in the brain were studied under stress, in intact animals and after administration.
DSIP. It turned out that during hypoxic stress the level of serotonin in the brain increases by 1.5 times; the introduction of DSIP reduces its content during stress almost to normal.
It also turned out that under conditions of hypoxic stress, the introduction of DSIP prevents an increase in blood glucose levels (increases 2-fold in animals subjected to stress), bringing it almost to normal, and does not affect the glucose content in the blood of intact animals.
The details of the biochemical action of DSIP attract such close attention, since the understanding of its place and role in the endogenous regulation of the body's stress response in all the diversity of mechanisms and relationships lies in the concept of its possible clinical use in a whole spectrum of pathological processes and simply in conditions of both physical and psycho-emotional, intellectual overstrain.
At the same time, I would like to emphasize once again that DSIP is an exclusively endogenous substance. Therefore, the drug "Deltalitsin", which is its structural analogue in its biological and biochemical sense, is not a substance foreign to the human body. This structure, which is present in the body of each of us, as well as in the bodies of vertebrates and other animals. The molecule is phylogenetically conservative, non-species-specific, and, due to this, cannot carry allergenic information.
By adding DSIP to the body from the outside, we are simply (!!!) replenishing the deficit, absolute or functional, of this substrate, allowing the control neurons to work as adequately as possible under stress conditions of any genesis.
"DELLIN" does not tone the nervous system, it only (!!!) optimizes the functioning of the central nervous system in difficult conditions of stress or overstrain.
<h2>Use of a drug based on the delta sleep peptide in children with functional and organic disorders of the central nervous system</h2>
Objective of the study. To study the reorganization of the bioelectrical activity of the brain upon administration of a drug based on the delta sleep peptide in children with various types of CNS pathology.
Objectives of the study: To group patients based on a comparison of clinical and physiological data.
To describe the nature of the initial background bioelectrical activity of the brain in the selected groups with an assessment of the nature of the involvement of brain structures in the pathological process.
In each group, describe the dynamics of the restructuring of the biorhythms of the brain after a course of treatment based on the main EEG rhythms.
To assess the dynamics of changes in bioelectrical activity
depending on the initial EEG.
To conduct a comparative analysis of the dynamics of neurophysiological indicators in groups of patients with organic and functional disorders of the central nervous system.
To identify possible patterns in the dynamics of indicators of bioelectrical activity of the brain induced by the use of factors of a neuropeptide nature.
<h3>Material and methods of the study.</h3>
A total of 19 children were examined, including 14 boys and 5 girls aged 3 to 14 years (mean age 9.3-3.5 years) before and after treatment with a neuropeptide preparation in the form of nasal drops. According to the etiology of the disease, all patients were divided as follows. 9 children were diagnosed with cerebral palsy, 2 people - the consequences of severe traumatic brain injury, 1 patient - with the consequences of mild or moderate concussion, 4 people - instability of the cervical spine with vertebrobasilar insufficiency, a patient - a congenital malformation of the brain - Sturge-Weber syndrome.
Of the 19 people, 2 had a delay in psychomotor development.
Based on the data on the nature of the disorders of the central nervous system functions in combination with the clinical neurological picture of the disease, all patients were combined into two groups. The first group included children with severe organic damage to the central nervous system against the background of congenital or early acquired pathology, clinically combined with pronounced neurological symptoms.
This group was represented by 12 patients aged from 3 to 14 years (average age 8.1 + 1.2 years).
Clinically, spastic lower diplegia was observed in 5 cases, hemiparesis occurred in two patients, tetraparesis in one case, and a combination of pyramidal and extrapyramidal disorders occurred in one patient.