THE ROLE OF OXIDATIVE STRESS AND ANTIOXIDANTS IN DIFFERENT DISADAPATION GENESIS

Abstract

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Adaptation (adaptatio) - is the body ability to adapt while having homeostatic disorders, this ability is based on alterations in the system of response to environmental changes and the preservation of stability system under some new conditions. During their lifespan organisms adapt to the constantly changing internal and external environmental conditions. Such adaptation occurs throughout a person's entire life regardless of whether they are healthy or not. While adjusting, the body moves to a new homeostatic level. The body ceases to maintain a state of dynamic equilibrium due to various “disturbing”, stressful impacts: emotional, physiological, physical, chemical. The same effects trigger a complex set of mechanisms, whose main task is the adaptation of the organism to changing con-ditions, and reducing the displacements occurring in internal environmental conditions of the living organism. The physiological adaptation is the process of reaching a sustainable level of mechanism operation activity of functional systems, organs and tissues, which provides animals and human beings with the possibility of vital activity under the changing environmental conditions and the ability to reproduce healthy offspring (Symposium «Adaptation of living systems», Moscow, 1975). Adaptation takes place in response to many different stimuli, in particular: the alterna-tion of day and night, and seasons; changes in atmospheric pressure; physical and mental stress; hypoxia and sharp fluctuations of oxygen concentration in the air; desynchronosis; exposure to heat, cold, light, darkness; lack of food and water; stressful situations, illnesses, injuries, effects of electric current, burns and frostbites, heavy blood loss, exogenous intoxications: chemicals, toxins, medications, radiation, shock, pain, collapse and others. Adaptation is connected to a constant strain of physiological and neurochemical mechanisms, the exhaustion of physiological reserves, and the condition of disadaptation, which can occur due to constantly strengthening disturbing stressful effects. Disadaptation (lat. dis - absence; adaptatio - adaptation) is a violation of adaptation, adjustment of the organism to the constantly changing conditions of the external or internal environment. Disadaptation is a discrepancy between the body and the environment, leading to the physiological functioning disruption, behavior change and the development of pathological processes. The degree of disadaptation is characterized by the disorganization level of the body functional systems. There is a body system disadaptation (cardiovascular, CNS, respiratory, gastrointestinal, and others.), professional disadaptation, social disadaptation and others. A complete disparity between the living organism and its environmental conditions is incompatible with life. Disadaptation is characterized by the same shifts observed in the initial phase of the adaptation when body systems come into a state of increased activity again and energy is spent wastefully. The disadaptation process is carried out when the action of excitatory stressing factors is enhanced and they are close to the extreme in power or when the functional activity is excessive under the new circumstances. There are two forms of disadaptation: non-pathological: the maintenance of homeostasis which is possible under the condition of increased, but "normal" physiological functioning; and pathological: maintaining homeostasis is possible only by the transition to the pathological functioning. Disadaptation launches a complex system of molecular changes, where free radical reactions, which lead to a degeneration of cells and DNA damage, take one of the key positions. For the first time the idea that free radical reactions are actively involved in the development of pathological conditions was stated by Academician N.M. Emanuel in 1960s, who showed that the excessive formation of free radicals are formed by the growth of tumors while having a radiation sickness and also by the aging process. Russian prominent scientists such as N.N. Semenov, N.M. Emanuel, B.N.Tarusov, U.V.Vladimirov, R.P. Evstigneeva, E.B.Burlakova and others pioneered in the scientific foundations of free radical oxidation theory and the role of these processes in cell pathology and antioxidants effects in the biological systems. Free-radical processes and lipid peroxidation play a crucial physiological role, they take part in a process of the biomembranes composition regeneration and maintenance of functional properties, energy processes, cell division, the synthesis of biologically active substances, intracellular signaling and other processes, which play a key role in the adaptation and disadaptation. During disadaptation and malfunction of biological regulation, free radical reactions go out of control and appear an universal cause of progressive accumulation of damage in living systems. Various disturbing, stressful endogenous and exogenous factors (emotional distress, trauma, hypoxia, physical and mental overexertion, inflammation, ischemia, and others) trigger complicated interrelated molecu-lar processes which are involved in the survival and cell death. A key place in this survival system is occupied by free radical processes that trigger the degeneration and death of cells. Reac-tive oxygen species (ROS) are produced in the organism as the products of biochemical reactions and produce multiple damaging effects and, first of all, the degradation and destruction of proteins, lipids, nucleic acids. Membranes, collagen, DNA, chromatin, structural proteins are damaged under the influence of the ROS; ROS participate in epigenetic regulation of expression of nuclear and mitochondrial genes affect intracellular calcium levels, trigger a cas-cade leading to apoptosis, etc. Pro-oxidant system confronts antioxidant system. Antioxidants are substances that have the ability to interact with a variety of reactogenic oxidants - reactive oxygen species and other free radicals and invoke them partial or complete in activation. Antioxidant is con-nected with free radicals and it blocks destructive action of the extra electron. With the help of the enzymatic defense system the organism converts the cell oxidant into water and oxygen (non-radical). The concentration of free radicals is reduced with a help of special antioxidants-"scavengers". During the disadaptation the prooxidant imbalance occurs and antioxidant systems lead to oxidative stress. Disadaptation endogenous system of antioxidant defense is inefficient and the reaction products of free radicals and macromolecules are constantly found in the organs and tissues of the body and the cells are subjected to oxidative stress. The oxidative stress occurs when the disadaptation with intervention of perturbing effects of endogenous and exogenous factors and dysfunction of the antioxidant system causes damaging of four main processes: acidification of DNA, proteins, lipids and glucooxidation. We have regarded more than 100 different conditions and illnesses where the pathogenic factor appears as free rad-icals firstly belonging to pathological conditions and brain illnesses including the disadaptation. Brain is the most vulnerable part of the body for the development of oxidative stress , as it has the highest speed of metabolic processes, the low rate of cell division, the high lipid content (more than 50% of the dry matter of the brain) , as well as containing high content of iron and copper in some parts of the brain. The brain in spite of its light weight consumes about 30% of oxygen and has an increased sensitivity to hypoxia, the malfunction of microcirculation, the alteration of energy balance and others. In recent years, especially abroad, the at-tention to the substances which have an antioxidant effect has increased dramatically. The number of endogenous and exogenous sub-stances relating to antioxidants constantly grows. The role of antioxidants in biology and in medicine is completely represented in the book written by Yunbo Li. [42]. Endogenous means like enzymes and vitamins come as antioxidant protection. They are: superoxide dismutase, glutathione peroxidase, catalase, beta-carotene, alpha-tocopherol, vitamin С, uric acid, melatonin, chelating agents and others. If the human is exposed by perturbing, stress and extreme factors in order to enhance antioxidant defense we use antioxidant action of alpha-tocopherol and its new analogues (raksofelast and MDL-74180DA), 2-amino chroman - U-78517F (the derivative of alpha-tocopherol), alphalipoic acid (an endogenous antioxidant), selezhelin, idebenone, ginkgo Biloba (EGb 761), neurostrol (herbal medicine), eksifon (Aldona), sabeluzol, chaleting agents, tenilsetam, deferiprone, lazabemide, meclofenoxate, fosfotidilserin, tirilazad mesylate, melatonin, selective blockers of NO, selenium organic compounds (ebselen), dibunol (ionol), probucol, mexidol and others. Synthetic antioxidants such as medicines have an advantage as they possess non protein structure and therefore they are stable. It is easy for them to penetrate into a cell and many of them are taken orally. In recent times in Russia the medicine with antioxidant and membranotropic actions such as mexidol (2-ethyl-6- .methyl-3-hydroxypyridine succinate) is widely used. The mexidol synthesis was carried out in the Institute of Pharmacology of Russian Academy of Medical Sciences in the middle of eighties by L.D.Smirnov and V.I.Kuzmin. They also implemented in-depth study of pharmacological effects of mexidol and how it acts (T.A.Voronina, A.V.Valdman, S.B.Seredinin, U.M. Tilekeeva, L.N.Nerobokova , T.L. Garibiva , L.D.Lukyanova, A.V.Eremenko, A.N.Aliev and others.) its safety (B.I.Lubimov, N.M.Smolnikova , A.S.Sorokina) and pharmacokinetics (A.K.Sariev, K.,, V.P. Zherdev). A trademark «mexidol» was created, and its registration was done in the USSR Min-istry of Health. The group of authors-developers (K.M.Dumaev, L.D.Smirnov, T.A.Voronina, E.B.Burlakova, T.L.Garibova, V.P.Zhestkov, L.N.Sernov, N.V.Vereshagin, Z.A.Suslina, N.V.Mironov, V.I.Shyrev, A.I.Phedin, B.A.Knyazev, E.A. Avakyan, E.Y. Lopatukhin) introduced mexidol into clinical practice. They were given an Award by the Government of the Russian Federation in the field of science and technology. «The creation and introduction of antioxidant medicines for the treatment and prevention of cerebrovascular disease into medical practice № 4861 2003. The effects and mechanisms of action of mexidol were studied in some theses [1, 17, 19, 30], and there a number of the relevant patents [24, 25, 26, 27]. In experimental studies it was found out that mexidol has a wide range of pharmacological effects such as neuroprotective, nootropic, anti-hypoxic, antistress, anxiolytic, anticonvulsant, antiaggressive, vegetotropic and others [2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 16]. Mexidol has high ability to go through the hematoencephalic barrier and high level of bioavailability. It was established that Mexidol is rapidly absorbed and eliminated from the organism by parenteral administration [25]. Mexidol is the drug with the polycomponent multi-target mechanism of action. The main components of its mechanism of action are antioxidant and membrane trophic effects, ability to reduce the glutamate exitotoxicity, to modulate the activities of receptors and membrane-bound enzymes, to restore the neurotransmitter balance, to raise the energy status of cells [10, 12, 15, 16, 18, 21, 22, 31, 36, 40]. 3-hydroxypyridine in the structure of Mexidol ensures its antioxidant and membrane trophic effects, ability to reduce the glutamate exitotoxicity, to modulate the activities of receptors. It is quite different than other drugs containing succinic acid. The presence of succinate in the structure of Mexidol marks it from emoxypine and other 3-oxypyridine derivatives, because succinate is functionally important for many processes in the organism. It is particularly a substrate for the increase of the energy exchange in cell. Mexidol is a direct-acting energizing antihypoxant. Its effect is connected with influence on the mitochondrial endogenic respiration, with activation of mitochondrial energysynthezing function, of compensatory metabolic flows. These flows supply energy substrates into the respiratory chain. In this case this is in reference to succinate. They also fulfil a function of adaptation mechanism in case of hypoxia [20, 21, 33]. Mexidol effect study on mitochondrial respiration rat brain cells estab-lished, that Mexidol at concentrations of 1 мМ - 5 мМ dose-dependently gathers speed of oxygen consumption by brain cells and consequently and promotes mitochondrial res-piration [32]. Mexidol influences different types of stress situations, for example, under stress, anxiety and fear conditioned, under previously obtained negative impacts, under waited for pain stress, in situations of desired and actual disagreement [2, 13]. The analysis of the anti-stress mechanism implementation of anxiolytic action of mexidol has shown that mexidol is not capable to bind to benzodiazepine and GABA receptors, however, it has the ability to enhance the binding of labeled diazepam to benzo-diazepine receptors [29, 40]. Consequently without having a direct affinity for the benzodiazepine and GABA receptors Mexidol provides modifying effect on them increasing their binding capacity. The unique action of Mexidol is its ability to increase the body's resistance to the action of various extreme factors, such as stress, conflict situations, electric shock, physical and mental overload, hypoxia, ischemia, sleep deprivation, trauma, various intoxication [8, 13, 14, 34, 35]. It is shown that Mexidol eliminates excessive activity of free radical oxidation processes in the dynamics of post-traumatic period and has a protective effect on bioenergetic processes in the brain by brain injury by changing the functional state of the mitochondrial respiratory chain [22]. Mexidol has high efficiency in different conditions involving neurodegeneration, impaired memory and sleep, dementia and Parkinson's symptoms [5, 37, 38, 39, 41]. Mexidol possesses high therapeutic effect in treating a variety of neurological, mental or cardiovascular diseases. Mexidol is used in the treatment of acute and chronic cere-brovascular disorder including stroke, vascular encephalopathy and vascular dystonia, as well as traumatic brain injuries, cardiovascular disorders, disorders of the brain during aging and atherosclerosis, epilepsy, treatment of neurotic and neurosis-like disorders and various violations in alcoholism including withdrawal symptoms of acute intoxications and other diseases. Mexidol is included (a grouping called emoxypine) in the List of Essential Drugs (VED) for 2015 year (Order of the Government of the Russian Federation of December 30, 2014 N 2782-p), in the list of medicines available on prescription (doctor's assistant ) in the provision of additional free medical care to certain categories of citizens entitled to receive state social assistance to complete the requirements for medicines and medical items and visiting team ambulance (№445n order of 11 June 2010.). Mexidol can be successfully used for the correction of violations observed during the disadaptation of various origins, which determines its complex mechanism of action and, above all, anti-oxidant (inhibition of both enzymatic and non-enzymatic lipid peroxidation processes, reduction of NO, increased activity of antioxidant enzymes) and membrane protective (reducing viscosity and increasing membrane fluidity, change the phospholipid composition) action, as well as its ability to attenuate glutamate excitotoxicity and restore the energy balance of the cell. Through the indicated mechanisms affecting the set of chemical and physical processes, and providing the necessary pairing of its main components (receptors, ion channels, enzymes, etc.), Mexidol is able to have a positive impact on the functioning of cellular structures associated with the transmission of information and the development of various pathological states, in-cluding a deadaptation.