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Objective. To study the use of combined therapy of poststroke depression using antidepressants and an antioxidant. Materials and methods. The dynamics of the clinical status of poststroke depression and parameters of oxidative stress were studied in 60 patients with poststroke depression before and after threemonth courses of treatment with fluvoxamine 100 mg/day and Cytoflavin 10 mg/day by i.v. infusion diluted in 200 ml of 5% glucose solution (or physiological saline in patients with diabetes mellitus) in the mornings for 10 days with subsequent transfer to the tableted form (two tablets in the morning and two in the evening for 90 days). Results. The data obtained here on the comparative efficacy of the treatment of poststroke depression with fluvoxamine monotherapy and with the combination of fluvoxamine and Cytoflavin confirmed the high efficacy of combined treatment, such that this should be regarded as an option in developing novel treatment regimes for poststroke depression and that the need to prescribe antidepressants and antioxidants must be determined on the basis of individual assessment of the severity of depressive disorder and measures of oxidative stress in terms of the activity of endogenous antioxidants in each individual poststroke patient.

A wide range of studies have demonstrated that hyperhomocysteinemia is associated with the risk of schizophrenia, but currently available assumptions about the direct involvement of homocysteine (Hcy) in the pathogenesis of schizophrenia are hypothetical. It is possible that in vivo Hcy is only a marker of folate metabolism disturbances (which are involved in methylation processes) and is not a pathogenetic factor per se. Only one study has been conducted in which associations of hyperhomocysteinemia with oxidative stress in schizophrenia (oxidative damage to protein and lipids) have been found, and it has been suggested that the oxidative stress may be induced by the elevated Hcy in schizophrenic patients. But the authors did not study the level of reduced glutathione (GSH), as well as possible causes of hyperhomocysteinemia—disturbances of folate metabolism. The aim of this work is to analyze the association of Hcy levels with the following: (1) redox markers in schizophrenia GSH, markers of oxidative damage of proteins and lipids, and the activity of antioxidant enzymes in blood serum; (2) with the level of folate and cobalamin (В12); and (3) with clinical features of schizophrenia measured using the Positive and Negative Syndrome Scale (PANSS). 50 patients with schizophrenia and 36 healthy volunteers, matched by sex and age, were examined. Hcy in patients is higher than in healthy subjects ( p = 0.0041 ), and this may be due to the lower folate level in patients ( p = 0.0072 ). In patients, negative correlation was found between the level of Hcy both with the level of folate ( ρ = − 0.38 , p = 0.0063 ) and with the level of B12 ( ρ = − 0.36 , p = 0.0082 ). At the same time, patients showed higher levels of oxidative modification of serum proteins ( p = 0.00046 ) and lower catalase (CAT) activity ( p = 0.014 ). However, Hcy is not associated with the studied markers of oxidative stress in patients. In the group of patients with an increased level of Hcy (>10 μmol/l, n = 42 ) compared with other patients ( n = 8 ), some negative symptoms (PANSS) were statistically significantly more pronounced: difficulty in abstract thinking (N5, p = 0.019 ), lack of spontaneity and flow in conversation (N6, p = 0.022 ), stereotyped thinking (N7, p = 0.013 ), and motor retardation (G7, p = 0.050 ). Thus, in patients with schizophrenia, hyperhomocysteinemia caused by deficiency of folate and B12 is confirmed and can be considered a marker of disturbances of vitamin metabolism. The redox imbalance is probably not directly related to hyperhomocysteinemia and is hypothetically caused by other pathological processes or by an indirect effect of Hcy, for example, on the enzymatic antioxidant defence system (CAT activity), which requires further exploration. Further study of the role of Hcy in the pathogenesis of schizophrenia is relevant, since the proportion of patients with hyperhomocysteinemia is high and correlations of its level with negative symptoms of schizophrenia are noted.

To study the use of combination therapy for post-stroke depression using antidepressants and antioxidants.The dynamics of the clinical status of post-stroke depression and parameters of oxidative stress were evaluated in 60 patients with post-stroke depression before and after a 3-month treatment with fluvoxamine in a daily dose of 100 mg per day and cytoflavin in a dose of 10 ml/day (200 ml of 5% glucose solution or physiological saline in patients with diabetes mellitus) intravenously in the morning for 10 days followed by transfer to tablet form (2 tabs in the morning and 2 tabs in the evening for 90 days).The results on the comparative effectiveness of the treatment of post-stroke depression with fluvoxamine monotherapy and the combination of fluvoxamine and cytoflavin confirmed the great effectiveness of the combination therapy, which should be taken into account when developing new treatment regimens for post-stroke depression, and the need for prescribing antidepressants and antioxidant drugs should be determined based on an individual assessment of the severity of depressive disorder and parameters of oxidative stress: endogenous antioxidant activities in each individual patient with ischemic stroke.Изучение применения комбинированной терапии постинсультной депрессии с использованием антидепрессантов и антиоксидантов.Оценивали динамику клинического статуса постинсультной депрессии и параметры окислительного стресса у 60 больных с постинсультной депрессией до и после 3-месячного курса лечения препаратами Флувоксамин 100 мг/сут и Цитофлавин 10 мл/сут утром внутривенно капельно с разведением в 200 мл 5% раствора глюкозы (или физиологического раствора у больных сахарным диабетом) в течение 10 дней с последующим переводом на таблетированную форму (по 2 таблетки утром и 2 таблетки вечером в течение 90 дней).Полученные данные о сравнительной эффективности лечения постинсультной депрессии монотерапией Флувоксамином и комбинацией Флувоксамина и Цитофлавина подтвердили большую эффективность сочетанной терапии, что следует учитывать при разработке новых схем лечения постинсультной депрессии, а необходимость назначения антидепрессантов и антиоксидантных препаратов должна определяться на основе индивидуальной оценки выраженности депрессивного расстройства и параметров окислительного стресса: активности эндогенных антиоксидантов у каждого конкретного больного, перенесшего ишемический инсульт.

The paper summarizes literature data on the importance of oxidative stress as one of the pathogenetic mechanisms in Alzheimer's disease. The paper describes the main specific and nonspecific ways of reactive oxygen species generation in the course of the disease development. The effect of reactive oxygen species generated by the functional activity of cells, i.e. apoptosis and mitotic cycle, is shown. The role of the regulatory system of nodal cells is performed by phosphorylation/dephosphorylation process which is associated with intense phosphorylation of tau protein and mitosis-specific proteins. In Alzheimer's disease, the regulating function of peptidyl-prolyl isomerases in particular of Pin1 associated with maintaining a balanced state of phosphorylation/dephosphorylation processes is disturbed. Taking into consideration the multifactorial impairment of the cell cycle control, this process should be considered from the standpoint of the general state of metabolic processes, and oxidative stress has one of the key positions in aging.Obobshcheny literaturnye dannye o znachimosti okislitel'nogo stressa v kachestve odnogo iz patogeneticheskikh zven'ev bolezni Al'tsgeĭmera. Otrazheny osnovnye spetsificheskie i nespetsificheskie puti generatsii aktivnykh form kisloroda pri razvitii bolezni. Pokazano vliianie generiruemykh aktivnykh form kisloroda na funktsional'nuiu aktivnost' kletok – apoptoz i mitoticheskiĭ tsikl. Rol' uzlovoĭ reguliatornoĭ sistemy kletok pri étom vypolniaiut protsessy fosforilirovaniia/defosforilirovaniia, chto sopriazheno s intensivnym fosforilirovaniem belka tau, belkov, uchastvuiushchikh v mitoze. Pri bolezni Al'tsgeĭmera narushaetsia reguliruiushchaia funktsiia peptidil-prolilizomeraz, v chastnosti, Pin1, sviazannaia s podderzhaniem sbalansirovannogo sostoianiia protsessov fosforilirovaniia/defosforilirovaniia. Uchityvaia mnogofaktornost' narusheniia kontrolia kletochnogo tsikla, sleduet rassmatrivat' étot protsessa s pozitsiĭ obshchego sostoianiia metabolicheskikh protsessov, odnu iz kliuchevykh pozitsiĭ kotorykh pri starenii organizma zanimaet okislitel'nyĭ stress.

The review summarizes literature data on the importance of oxidative stress as one of the pathogenetic mechanisms in Alzheimer’s disease. Special attention is paid to the main specific and nonspecific ways of reactive oxygen species (ROS) generation in the course of the disease development. Generated ROS influence functional activity of cells, particularly, apoptosis and the mitotic cycle. Phosphorylation/dephosphorylation processes associated with intense phosphorylation of tau protein and mitosis-specific proteins play the nodal regulatory role in the cell. Alzheimer’s disease is accompanied by impairments of the regulatory functions of peptidyl-prolyl isomerases, particularly, Pin1 involved in maintaining a balanced state of phosphorylation/dephosphorylation processes. Taking into consideration the multifactorial impairment of the cell cycle control, this process should be considered from the viewpoint of the general state of metabolic processes, and oxidative stress has one of the key positions in aging.

Literature data on the role of oxidative stress in aging have been summarized. There are certain links between parameters of free radical processes (intensity of generation of reactive oxygen species in mitochondria, oxidative modification of mitochondrial DNA, activity of desaturases, involved into biosynthesis of polyunsaturated C20 and C22 fatty acids) with life span. The review highlights the role of oxidative stress as on of pathogenic factors of numerous diseases including various neurodegenerative disorders. Special attention is paid to oxidative modification of proteins as one of early and reliable markers of tissue injury in free radical pathology. Oxidative destruction of proteins plays a major role in etiology of such neurodegenerative diseases as Alzheimer’s and Parkinson’s diseases. Oxidative stress and the stress related protein aggregation are considered as the pathogenic link in the development of familiar amyotrophic lateral sclerosis. Oxidative modification of proteins is associated with the development of cataract. The age-and pathology-related increases in the content of oxidized proteins in tissues is assessed as an early and specific parameter of oxidative stress.

The role of lipid peroxidation product 4-hydroxy-trans-2-nonenal (4-HNE) in functional activity of cells under normal and different pathological conditions is discussed. Different pathways of 4-HNE metabolism in tissues are analyzed, with particular focus on the role the glutathione system in this process. 4-HNE is implicated in regulation of cell growth, proliferation, differentiation, and apoptosis. 4-HNE and metabolic products of other antioxidants (carotenoids) resemble each other in chemical nature of the product and influence general pathways of signal transduction. Manifestation of 4-HNE toxicity under oxidative stress conditions is regarded as a link to many diseases whose pathogenesis is connected with modifications of proteins and nucleic acids.

Based on complex clinical-biochemical studies of 60 patients after ischemic stroke (on average 2,4+/-0,3 years from the disease-onset), we showed the disturbance of balance between anti- and prooxidant systems. The changes in the parameters of oxidative stress were revealed as follows: the reduction in the activity of antioxidant defense markers (superoxiddismutase, catalase, oxidized and reduced glutathione), as well as in the spontaneous and induced hemoluminescence, the increase of malonic dialdehyde, a final product of lipid peroxidation. The changes in biochemical parameters were correlated with the severity of ischemic stroke consequences, assessed by the Rankin scale and the Barthel index. This finding points out the necessity of including antioxidants in the rehabilitation treatment. The effect of antioxidant drugs on the consequences of ischemic stroke was studied using cytoflavin (10 ml in 200 ml of 5% glucose solution daily intravenous in drops during 10 days) and cortexin (10 mg in 2 ml of 5% novocaine solution daily intramuscular during 10 days). The results revealed a higher effect of cytoflavin that was supported by the data of clinical-biochemical blood analysis: the level of components of glutathione system and catalase was significantly (p0,05) increased in patients with sensory-motor disturbances and cognitive disorders thought did not reach the levels of control group.

Generalized literature data covering principal mechanisms of oxidative modification of protein and its role in various pathologies are presented in the paper. It is emphasized that due to peculiarities of protein structure organization the process of oxidative modification is of complicated and specific character, which is determined by amino acid composition of the protein. Oxidative modification of protein can be connected with impairment of not only a polypeptide chain itself, but also particular amino acid residues with formation of several types of radicals. Mechanisms of formation of long-life hydroperoxides and their role in oxidative stress are discussed. The role of electron-transfer (migratory) reactions in formation of radical centers on a protein molecule surface is elucidated. Oxidative modification of protein is considered as a process of regulation of their synthesis and degradation connected with activation of multicatalytic proteases. Oxidative destruction of protein is one of early and most reliable markers of tissue lesion in reactive species pathology.

We investigated the state of oxidative stress in aging people suffering from vascular dementia and Alzheimer's disease. We have examined the oxidative modification of plasma's proteins, the activity of enzyme antioxidative defense (superoxide dismutase and catalase) and the state of components of blood glutathione system. Aged patients with neurodegenerative diseases show decrease of metal-catalysed oxidative modification proteins, increase of superoxide dismutase and disrupt of balance enzymatic antioxidant and glutathione system in blood in comparison with aging people who have no psychoorganic disorders. The high activity of superoxide dismutase in patients with Alzheimer's disease has been discovered. We have shown the joint change of separate component oxidative stress with the degree of mental disorders. Oxidative stress is believed to play a role in the pathogenesis of different neurodegenerative diseases in aged patients.

Literature data on the role of oxidative stress in the aging of an organism have been summarized. The connection of some parameters of free radical processes (intensity of generation of reactive oxygen species in mitochondria, oxidative modification to the mitochondrial DNA, the activity of desaturases participating in biosynthesis of polyunsaturated C20 and C22 fatty acids) with life expectancy has been demonstrated. Oxidative stress is one of pathogenetical events in many diseases, including various neurodegenerative disorders. The special attention is paid to oxidatively modified proteins as one of early and reliable indicators of tissue injury in freeradical pathology. Oxidative protein destruction plays an important role in etiology of such neurodegenerative diseases, as Alzheimer's and Parkinson's diseases. Oxidative stress and the aggregation of proteins connected with it are considered to be a pathogenetical part in the development of familial amyotrophic lateral sclerosis. Oxidatively modified proteins are also associated with the development of cataract. The increase of the oxidatized protein ratio with the age and in various pathologies is assessed as an early and specific parameter of oxidative stress.

Specific features of metal-catalyzed oxidation (MCO) of purified proteins (human serum albumin and human erythrocyte superoxide dismutase) were analyzed by the oxidation level of tryptophan and tyrosine. The production of dityrosine cross-links and the oxidation of tryptophan residues were recorded by fluorescence. The degree of oxidative modification of the amino acid residues of the proteins depended on the concentration of the Fenton's medium components and on the incubation time. These changes were different in different proteins. By electrophoresis and gel-permeation chromatography, changes in the superoxide dismutase structure are shown to be caused by oxidative modification of the enzyme and to be accompanied by a decrease in its activity. Findings with OH* scavengers (mannitol and ethanol) suggest that oxidative modification of the proteins in Fenton's medium should be associated not only with hydroxyl radical but also with ferryl and perferryl ions and with the radical CO(-.)(3).

We examined the spontaneous and metal-ion-catalyzed oxidative modification plasma blood proteins in the group of healthy adults and elderly ones and patients with vascular dementia (mild and severe). We determined the spectrophotometric measurement of 2,4-dinitrophenylhydrazone derivatives formed by reactions with protein carbonyls. The level of metal-ion-catalyzed oxidation proteins in the aged patients both with and without dementia was high in comparison to the healthy adults. The patients with severe dementia showed lower amount of 2,4-dinitrophenylhydrazone deriviates. Low levels of metal-ion-catalysed protein oxidation strongly correlated with the degree of psychoorganic disturbances. The elderly persons with both and without dementia showed a high level of plasma nonenzymatic H2O2 scavenging in comparison with the healthy adult ones. We discovered an imbalance between enzymatic and nonenzymatic components of the antioxidant system. The latter indicates that the oxidative modification of brain tissue proteins probably plays an important role in aging and mental disorders.

The authors have found direct correlating between the enzymatic activity and the values of the total of circulation blood, erythrocytes, plasma and hematocrit. The highest activity of antioxidant-enzymes and values of hemodynamic was observed by the sixth hour of life of healthy newborns. Influenced by simultaneous effect of asphyxia and intrauterine chronic fetal hypoxia SOD, catalase, glucose-6-phosphate dehydrogenase activities in erythrocytes remain low during the first 24 hours of life. These newborns proved to have lower values of hemodynamics. The state of the antioxidant enzyme and hemodynamics at the moment of birth is discussed.

Plasma and erythrocytes of cord blood were incubated with bilirubin (40-400 mkMol/l) for 30 min. This incubation resulted in reduction of lipid peroxidation both in plasma and erythrocytes. The antioxidant activity increased in erythrocytes after incubation, but decreased in plasma. It concluded that high concentration of protein-bound bilirubin and about its effect exerted an antioxidant effect and could influence the stability of blood cells.

It has been shown that human blood plasma displays a low activity of superoxide dismutase, a key enzyme of antioxidative protection. This enzyme was isolated and purified from human blood plasma by using a novel procedure based on gel filtration on Ultrogels AcA-34 and AcA-44. Data from gel filtration and disc electrophoresis in the presence of sodium dodecyl sulfate and beta-mercaptoethanol suggest that the molecular mass of the enzyme decreased with time and a simultaneous change in activity. Purification of superoxide dismutase from blood plasma revealed the presence of low molecular mass peptides (1000 and 5000 Da) which inhibited the enzyme activity. A possibility was considered for superoxide dismutase transition into an active, conformationally labile state after a split-off of the inhibiting fragment under conditions of oxidative stress.

A procedure for purification of superoxide dismutase (SOD) from human blood plasma has been developed, which includes gel filtration on Ultrogels AcA-34 and AcA-44 (LKB, Sweden). The protein purified from blood plasma is a glycoprotein which is thermostable at 70-80 degrees C. The molecular mass of the protein determined immediately after gel filtration is approximately 147,000 daltons. A comparative analysis of effects on the SOD activity of plasma and erythrocytes of compounds capable of forming chelating complexes with metals within the enzyme active center has been carried out. The purified enzyme differs by its physico-chemical characteristics from cytosolic Cu,Zn-SOD and pertains to a new class of SOD, the so-called extracellular SOD, detected in some biological fluids.

Recent data available in literature and the author's data about the state of the antioxidant protection of the blood plasma have been generalized. The role of superoxide dismutase as the basic compound of the antioxidant system is discussed. The character of individual macromolecules (transferrin, ceruloplasmin, albumin) which have shown nonenzymatic specific antioxidant properties is presented. Possible mechanisms of biological activity of some antioxidants have been examined.

The paper is concerned with the measurement of the relative and absolute counts of lymphocytes, T and B lymphocytes (106 patients) and superoxide dismutase (SOD) activity of red blood cells (237 patients) in acute and chronic viral hepatitis (VH). In addition, a study was made of SOD activity of red blood cells in guinea-pigs immunized with bovine serum albumin (BSA). It is shown that SOD activation in red blood cells related to the enzyme induction with superoxide anionic radical was seen both in patients with acute and chronic VH and in guinea-pigs immunized with BSA. The patients with acute and chronic VH demonstrated the reduction of the absolute count of T lymphocytes and the increase of the B lymphocyte count in the peripheral blood together with SOD activation in red blood cells, more remarkable in acute than in chronic VH. The immunological response in VH patients manifested since days 14-20 from the disease onset or its exacerbation which was evidenced by changes in the cooperative interaction of cellular immunity and SOD activity.

In healthy newborn babies, superoxide dismutase activity and MetHb content of the erythrocytes are higher than those in adult subjects. It was also demonstrated that low activity of superoxide dismutase in guinea pigs, albino mice and teleost fish Coregonus autumnalis (in autumn period) is paralleled by a higher level of MetHb. On the contrary, high enzymic activity in albino rats and C. autumnalis (spring period) accounts of a lower level of MetHb. Seasonal changes in the activity of superoxide dismutase were found in guinea pigs and fish.

Activity of superoxide dismutase (SOD), myeloperoxidase, glucose-6-phosphate dehydrogenase (G6PD) and the rate of lipid peroxidation were studied in blood of children within first weeks of life, when a change-over to lung respiration occurred. Two groups of newborn children were found with dissimilar alterations in the SOD activity within the first week. Independently of the SOD activity alterations, an increase in the rate of lipid peroxidation and in G6PD activity as well as a distinct decrease of myeloperoxidase activity were detected in blood of newborn children as compared with adults. The state of the blood antioxidation system at the moment of birth is discussed.

Low activity of catalase, superoxide dismutase, alterations in metabolism of glutathione as well as activation of lipid peroxidation and increase in Na+, K+-ATPase activity were found in erythrocytes of newborns funic blood under conditions of chronic hypoxia and simultaneous effects of acute and chronic hypoxia. Acute hypoxia during labor caused increase in activity of superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, Na+, K+-ATPase as well as in the rate of lipid peroxidation. These alterations, observed in the enzymatic activity and in the rate of lipid peroxidation, which were detected in funic blood erythrocytes under conditions of hypoxia, may be responsible for some diseases during postnatal period of children ontogenesis.

Seasoned variations in the activity of Mg++-ATPase and Mg++-DNP-ATPase have been revealed in studies on ATPase system of mitochondria of skeletal muscles of newborn, 7-, 10-day and adult rabbits. The degree of activation of ATPase by 2-4-DNP did not depend on the age of animals and the season of year. Absolute values for DHPATPhase were lower in young animals in spring. The activity of Mg++- and Mg++-DNP-ATPases and the extent of activation of the enzymes by Mg++ increased with the increase in the age of animals.

The superoxide-dismutase (EC 1.15.1.1) activity was revealed in blood plasma after its successive treatment with alcohol, chloroform and one- or two-substituted phosphate. Its value is the highest when treating plasma with KH2PO4. The boiling of the supernatant liquid obtained after addition of K2HPO4 leads to a complete loss of the activity. The treatment of plasma with KH2PO4 provides higher stability of the enzyme to thermal actions. The analysis of EPR-spectra has shown the presence of different complex compounds of copper ions in the supernatant liquid. Certain experiments with the use of aqueous solutions of CuCl2 and histidine have shown that Cu2+ inhibits the superoxide-dismutase activity in samples treated with KH2PO4 and increases it in samples treated with K2HPO4.

A study was made of the effect of thyroxine in vitro on the activity of antioxidant enzymes: superoxide dismutase (SOD) and catalase, and on the methemoglobin content in the erythrocytes of 23 healthy persons aged 17-25. Erythrocyte incubation was performed in different media: in their own plasma, a weak solution of NaOH, tris-HCl buffer solution (pH 7.4) with thyroxine in the physiological concentration and without it. The enzyme activity was compared in the native and incubated erythrocytes. After the incubation of erythrocytes with thyroxine in their own plasma the SOD and catalase activity showed a statistically significant rise, and the methemoglobin content decreased. This effect was undetectable in the incubation of erythrocytes with thyroxine in tris-buffer solution. Direct incubation of SOD with thyroxine isolated from the erythrocytes did not cause any changes in enzyme activity. Probably the interaction of thyroxine with erythrocyte membrane components is important for the implementation of the hormonal effect. Some unidentified factors contained in the blood plasma may play a role in the SOD activation. The authors discuss thyroxine ab to cause rapid regulation of the activity antioxidant enzymes.

ATPase activity from freshly prepared, "aged" and "heparin" mitochondria was studied in adult, newborn and 7 day old rabbits. Heparin, incubated with the mitochondria within 2-2.5 hrs at 20 degrees C, increased the activity of endogenous ATPase in the newborn rabbits. Activities of Mg-2++-ATPase and Mg-2+-DNP-ATPase were decreased under effect of heparin in both adult and new born rabbits. In 7 day old rabbits, to the contrary, increased activity of Mg-2+-ATPase and its activation by 2,4-DNP were observed.

One- and two-substituted potassium-salts of phosphoric acid are studied for their effect on the value of superoxide dismutase (SOD) activity in the plasma and erythrocytes of healthy adults and newborn children. It is shown that the superoxide dismutase activity of plasma depends on the phosphoric acid salts which are used during its treatment. Single direction of changes in the activity of superoxide dismutase obtained after the plasma treatment by KH2PO4 and K2HPO4 depending on the pH incubation medium, the results of separation of protein fractions obtained by the method of disc-electrophoresis testify that the superoxide dismutase activity is connected with the same protein. Different absolute values of the plasma SOD activity and different influence on it of azide sodium are, probably, determined by spatial orientation of copper ions in the active centre, which changes depending on pH of the medium. Superoxide dismutase plasma and erythrocytes in newborn children have higher activity than is adults.