Homocysteine in Schizophrenia: Independent Pathogenetic Factor with Prooxidant Activity or Integral Marker of Other Biochemical Disturbances?

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.

[Oxidative stress and post-stroke depression]. / Okislitel'nyi stress i postinsul'tnaya depressiya.

OBJECTIVE: To study the use of combination therapy for post-stroke depression using antidepressants and antioxidants. MATERIAL AND METHODS: 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). RESULTS AND CONCLUSION: 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.

[Comparative analysis of unsaturated indicators fatty acids in elderly patients in initial stages of Alzheimer's disease and vascular dementia.]

A decrease in cognitive functions up to the development of dementia in the elderly is associated with a decrease in the blood level of polyunsaturated fatty acids, especially Omega-3, which occurs against the background of oxidative stress. The paper presents a comparative analysis of the spectrum of polyunsaturated fatty acids and the activity of individual components of the enzymatic antioxidant system in the blood of elderly people with impaired cognitive performance to the level of «mild cognitive decline¼ (MCI AD, prodromal Alzheimer's disease) or vascular etiology (MCI VaD, prodromal vascular dementia) compared with older people without signs of cognitive impairment. A decrease in the concentration of Omega-3 polyunsaturated fatty acids in the blood of both groups of the examined patients was revealed compared with the control group. In patients with AD MCI, a sharp decrease in the concentration of arachidonic acid (Omega-6) was detected compared with patients with MCI VaD and the control group. The decrease in the activity of the antioxidant enzymatic system and the decrease in polyunsaturated fatty acids due to their peroxidation revealed in this study indicate an intensification of the OS processes in patients with impaired cognitive functions. The question of the pathogenetic role of arachidonic acid in patients predisposed in the future to the development of AD is discussed.

[Oxidative stress and its effect on cells functional activity of alzheimer's disease].

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.

Role of 4-hydroxy-trans-2-nonenal in cell functions.

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.

[Perspectives of treatment of patients with ischemic stroke: the place and the role of cytoflavin].

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 (p<0,05) increased in patients with sensory-motor disturbances and cognitive disorders thought did not reach the levels of control group.

[Oxidative modification of proteins, its role in pathologic states].

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.

[Free radical processes in aging, neurodegenerative diseases and other pathological states].

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.

[The factors of oxidative stress in neurodegenerative diseases (vascular dementia, Alzheimer disease)].

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.

Oxidative modification of proteins: oxidation of tryptophan and production of dityrosine in purified proteins using Fenton's system.

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).

[Oxidative modification of blood plasma proteins in elderly people with vascular dementia]. / Okislitel'naia modifikatsiia belkov plazmy krovi u pozhilykh liudei s sosudistoi dementsiei.

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 role of reactive oxygen species as signal molecules in tissue metabolism in oxidative stress]. / Rol' aktivnykh form kisloroda v kachestve signal'nykh molekul v metabolizme tkanei pri sostoianiiakh okislitel'nogo stressa.

This review deals with literature data on the functioning of the reactive oxygen species (ROS) as second messengers. ROS induce various biological processes such as stimulation of protein phosphorylation, Ca(2+)-signaling, phospholipid hydrolysis and transcription factor activation. Physiological significance of the role of biological oxidants in the regulation of signal transduction and the mechanisms of the adaptation of organism to extremital conditions are discussed. Oxidative stress is a common step for the development of many diseases characterized by the intensive ROS generation.

[Oxidative modification of blood proteins in patients with psychiatric disorders (depression, depersonalization)]. / Okislitel'naia modifikatsiia belkov plazmy krovi bol'nykh psikhicheskimi rasstroistvami (depressiia, depersonalizatsiia).

We determined the oxidative modification of proteins (spontaneous and metal-catalysing oxidation, MKO) and the level of corticosteroids in patients with the depersonalization and depression. For detecting oxidative modification of plasma proteins we measured the concentration of protein carbonyl groups formed with 2,4dinitrophenylhydrazine 2,4dinitrophenylhydrazone derivatives; the formation of dityrosine by fluorescence method; protein aggregation and fragmentation. Polyacrylamide gel electrophoresis with sodium dodecyl sulfate (SDS)-PAGE in the presence beta-mercaptoethanol was used to determine the aggregation or fragmentation of proteins by oxygen radicals (OH). Acid-soluble peptides were analised as products of the fragmentation oxidative modification proteins. The level of the corticosteroids was determined using HPLS. The increase of the concentration of protein carbonyl groups in blood plasma of patients with mental disorders. In patients with depersonalization we determined the increase of the bityrosyl cross-link, and different degrees of fragmentation compared with depressive patients. The cortisol level was decreased and corticosterone was increased in the blood plasma of patients with depersonalization. In depressive patients the cortisol level was increased and corticosterone was decreased is discussed. We discussed the role oxidative modification proteins in the disturbance of the corticosteroid and opioid receptors functions in the patients with mental disorders.

[High performance liquid chromatography of corticosteroids in patients with depression and depersonalization]. / Vysokoéffektivnaia zhidkostnaia khromatografiia kortikosteroidov u bol'nykh s depressiei i depersonalizatsiei.

Six corticosteroids were measured by high performance microcolumn reverse-phase liquid chromatography in patients with the depressive syndrome and depersonalization. Changes in the blood concentrations of hydrocortisone, cortisone, and corticosterone were revealed. The method is recommended as an additional tool for the differential diagnosis of depressions and depersonalization.

[Antioxidant enzymes activity of erythrocytes and indicators of blood hemodynamics of normal and hypoxic newborns in their first day of life]. / Fermenty antioksidantnoi sistemy éritrotsitov i nekotorye pokazateli gemodinamiki krovi v pervye sutki zhizni novorozhdennykh detei v norme i pri gipoksicheskikh sostoianiiakh.

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.

[Oxidative modification of human serum proteins. A method of determining it]. / Okislitel'naia modifikatsiia belkov syvorotki krovi cheloveka, metod ee opredeleniia.

A rate of protein oxidative destruction may be estimated from the reaction of the resultant carbonyl derivatives of amino acids reaction with 2,4-dinitrophenyl hydrazine. The procedure for estimation of 2,4-dinitrophenyl hydrazones was modified for clinical application. The initiating effect of nonenzymatic components (Fe(3+)-ascorbic acid, Fe(2+)-O2, Fe(2+)-H2O2) was in the metal-catalyzing oxidation of proteins. Estimation of derivatives of 2,4-dinitrophenyl hydrazones in tissues may serve as a pattern of protein oxidative modification during oxidative stress in the body.

Characteristics of low molecular weight substances regulating plasma superoxide dismutase activity.

Low molecular weight peptides which inhibit both plasma and red cell superoxide dismutase (SOD) activity have been isolated from human plasma. Several fractions of the substance were isolated chromatographically. The most active peptides have molecular weight about 1000 and 5000 D. The peptide lowering the SOD activity accelerates the hemoglobin oxidation reaction by NaNO2 and diminishes the laboratory animals' period of life in the process of intoxication by NaNO2. Another peptide was also isolated from human plasma and increased the SOD activity. The work is in progress on purification of this substance and investigation of its physical properties.

[The action of bilirubin in vitro on the antioxidant activity and lipid peroxidation of the plasma and erythrocytes of cord blood]. / Deistvie bilirubina in vitro na antioksidantnuiu aktivnost' i perekisnoe okislenie lipidov plazmy i éritrotsitov pupovinnoi krovi.

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.

[Certain functional characteristics of enzymatic antioxidant defense in human blood plasma]. / Nekotorye osobennosti funktsionirovaniia fermentativnoi antioksidantnoi zashchity plazmy krovi cheloveka.

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.