[Clinical and biochemical heterogeneity of Parkinson's disease]. / Klinicheskaya i biokhimicheskaya geterogennost' bolezni Parkinsona.

OBJECTIVE: To study correlations between oxidative stress (OS) and clinical changes in patients with neurodegenerative Parkinson's and to identify clinical/biochemical subtypes of the disease. MATERIAL AND METHODS: One hundred and nine people were studied, including 91 patients with neurodegenerative Parkinson's (72 patients with Parkinson's disease (PD); 10 with multiple system atrophy (MSA); 9 with corticobasal degeneration (CBD), average age 61.1±7.2 years), and 18 clinically healthy people (average age 55.1±9.2). OS indexes were detected for scoring of redox state in peripheral blood of patients with PD and healthy people (control group). Detection of biochemical indexes was performed in erythrocytes and mononuclear fraction and blood. The activity of glutathione reductase (GR), myeloperoxidase (MPO) and content of reduced glutathione (GSH) was estimated. RESULTS AND CONCLUSIONS: OS is a universal mechanism and is observed in many neurodegenerative diseases. However it is possible to identify quite typical changes of redox state with group selection and their correlations with definite subtypes and PD progress, it gives opportunity, in particular, to make the differential diagnosis with atypical Parkinsonism.

[The role of myeloperoxidase, paraoxonase and nitric oxide system in blood and pericardial fluid in patients with IHD who underwent direct myocardial revascularization.]

76 patients with coronary artery disease who underwent aortocoronary bypass surgery were examined to study the role of paraoxonase, myeloperoxidase, arginase, asymmetric dimethylarginine and nitric oxide in the mechanisms of the pathogenesis of post-pericardiotomy syndrome (PPCS). Patients were divided into two groups: the 1st - patients with coronary artery disease, who did not have PPCS as a result of clinical studies; the 2nd- patients with ischemic heart disease (IHD who were diagnosed with PPCS. The results showed that the postoperative period after coronary artery bypass grafting is associated with inhibition of paraoxonase, activation of myeloperoxidase, increased activity of arginase, nitrite/nitrate level and asymmetric dimethylarginine, and may be accompanied by the development of endothelial dysfunction and increased systemic inflammatory response. In the present work, inverse correlation relationships between the arylesterase activity of paraoxonase and myeloperoxidase activity in plasma, as well as between the aryl esterase activity of paraoxonase in the blood plasma and the activity of arginase in erythrocytes of the patients of the two studied groups were established. tests were developed on basis of ratio of the enzymes activities to predict the development of post-pericardicotomy syndrome.

SkQ1 Controls CASP3 Gene Expression and Caspase-3-Like Activity in the Brain of Rats under Oxidative Stress.

Here, we studied the effect of the mitochondria-targeted antioxidant SkQ1 (plastoquinone cationic derivative) on the CASP3 gene expression and caspase-3 activity in rat cerebral cortex and brain mitochondria under normal conditions and in oxidative stress induced by hyperbaric oxygenation (HBO). Under physiological conditions, SkQ1 administration (50 nmol/kg, 5 days) did not affect the CASP3 gene expression and caspase-3-like activity in the cortical cells, as well as caspase-3-like activity in brain mitochondria, but caused a moderate decrease in the content of primary products of lipid peroxidation (LPO) and an increase in the reduced glutathione (GSH) level. HBO-induced oxidative stress (0.5 MPa, 90 min) was accompanied by significant upregulation of CASP3 mRNA and caspase-3-like activity in the cerebral cortex, activation of the mitochondrial enzyme with simultaneous decrease in the GSH content, increase in the glutathione reductase activity, and stimulation of LPO. Administration of SkQ1 before the HBO session maintained the basal levels of the CASP3 gene expression and enzyme activity in the cerebral cortex cells and led to the normalization of caspase-3-like activity and redox parameters in brain mitochondria. We hypothesize that SkQ1 protects brain cells from the HBO-induced oxidative stress due to its antioxidant activity and stimulation of antiapoptotic mechanisms.

SkQ1 Regulates Expression of Nrf2, ARE-Controlled Genes Encoding Antioxidant Enzymes, and Their Activity in Cerebral Cortex under Oxidative Stress.

The administration of SkQ1 to rats at the dose of 50 nmol/kg for five days significantly increased the mRNA levels of transcription factor Nrf2 and of Nrf2-controlled genes encoding antioxidant enzymes SOD1, SOD2, CAT, and GPx4, whereas changes in the level of mRNA of SOD3 in the cerebral cortex of the rat brain were not significant. This was accompanied by activation of antioxidant enzymes (SOD, CAT, GPx, and GST) and increase in reduced glutathione concentration. Under oxidative stress induced by hyperoxia (0.5 MPa for 90 min), the mRNA level of transcription factor Nrf2 decreased, whereas changes in the transcriptional activity of Nrf2-induced genes (SOD1-3, CAT, GPx4) encoding antioxidant enzymes in the cortex of the rat brain hemispheres were insignificant. Under conditions of hyperoxia, lipid peroxidation intensity was increased, CAT was inhibited, and GST activity was moderately increased, whereas SOD and GPx activities in the rat brain cerebral cortex remained at the stationary level. Pretreatment with SkQ1 before the exposure to hyperbaric oxygenation led to an increase in mRNA level of transcription factor Nrf2 and of Nrf2-induced genes (SOD1-2, CAT, and GPx4) encoding antioxidant enzymes, whereas SOD3 expression in the cerebral cortex of the rat brain under oxidative stress was not changed. Concurrently, we observed an increase in activities of these antioxidant enzymes (SOD, CAT, GPx, and GST) and in level of reduced glutathione. We hypothesize that the protective effect of SkQ1 under hyperoxia-induced oxidative stress could be realized via direct antioxidant activity and through stimulation of the signaling defense system Keap1/Nrf2/ARE.

Influence of SkQ1 on Expression of Nrf2 Gene, ARE-Controlled Genes of Antioxidant Enzymes and Their Activity in Rat Blood Leukocytes under Oxidative Stress.

The study demonstrated that oxidative stress induced by hyperoxia (0.5 MPa for 90 min) resulted in reduction of mRNA levels of transcription factor Nrf2 and Nrf2-induced genes encoding antioxidant enzymes (SOD1, CAT, GPx4) in peripheral blood leukocytes of rats. The changes in gene expression profiles under hyperoxia were accompanied by disbalance of activity of antioxidant enzymes in the leukocytes, namely activation of superoxide dismutase and inhibition of catalase, glutathione peroxidase, and glutathione-S-transferase. Pretreatment of rats with SkQ1 (50 nmol/kg for five days) significantly increased mRNA levels of transcription factor Nrf2 and Nrf2-induced genes encoding antioxidant enzymes SOD2 and GPx4 and normalized the transcriptional activity of the SOD1 and CAT genes in the leukocytes in hyperoxia-induced oxidative stress. At the same time, the activity of catalase and glutathione peroxidase was increased, and the activity of superoxide dismutase and glutathione-S-transferase returned to the control level. It is hypothesized that protective effect of SkQ1 in hyperoxia-induced oxidative stress can be realized via a direct antioxidant property and the stimulation of the Keap1/Nrf2 redox-sensitive signaling system.

[FEATURES OF OXIDATIVE STRESS IN THE BLOOD AND THE SYNOVIAL FLUID ASSOCIATED WITH KNEE OSTEOARTHRITIS].

The features of regulation of free radical oxidation in the blood and the synovial fluid have been studied in patients with knee osteoarthritis. The data were obtained from 46 patients with primary knee osteoarthritis (II-III Kellgren-Lawrence grade, aged 63.26 ± 9.18) and 27 healthy controls. It was defined that the blood plasma was characterized by increased superoxide-eliminating activity and a tendency to the increasing of nitrite/nitrate concentration (nitrosative stress biomarkers). The erythrocytes were measured to have the increased concentration of malondialdehyde (secondary product of lipid peroxidation), activation of superoxide dismutase, gIutathione-S-transferase and reduced glutathione peroxidase activity and glutathione content. The peripheral blood mononuclear fraction of patients with osteoarthritis was characterized by significant activation of superoxide dismutase and glutathione-S- transferase, moderate catalase activation, non-significant glutathione peroxidase activity alterations and increased activity of xanthine oxidoreductase and myeloperoxidase. Finally redox-balance disturbance in the mononuclear cells leaded to oxidative stress development, which promoted lymphocytes apoptosis.