The study of the protective effect of mitochondrial uncouplers during acute toxicity of the fungicide difenoconazole in different organs of mice.

Pesticides represent a serious problem for agricultural workers due to their neurotoxic effects. The aim of this study was to evaluate the ability of pharmacological oxidative phosphorylation uncouplers to reduce the effect of the difenoconazole fungicide on mitochondrial DNA (mtDNA) of various organs in mice. Injections of difenoconazole caused cognitive deficits in mice, and the protonophore 2,4-dinitrophenol (2,4-DNP) and Azur I (AzI), a demethylated metabolite of methylene blue (MB), prevented the deterioration of cognitive abilities in mice induced by difenoconazole. Difenoconazole increased the rate of reactive oxygen species (ROS) production, likely through inhibition of complex I of the mitochondrial respiratory chain. After intraperitoneal administration of difenoconazole lungs, testes and midbrain were most sensitive to the accumulation of mtDNA damage. In contrast, the cerebral cortex and hippocampus were not tolerant to the effects of difenoconazole. The protonophore 2,4-DNP reduced the rate of ROS formation and significantly reduced the amount of mtDNA damage caused by difenoconazole in the midbrain, and partially, in the lungs and testes. MB, an alternative electron carrier capable of bypassing inhibited complex I, had no effect on the effect of difenoconazole on mtDNA, while its metabolite AzI, a demethylated metabolite of MB, was able to protect the mtDNA of the midbrain and testes. Thus, mitochondria-targeted therapy is a promising approach to reduce pesticide toxicity for agricultural workers.

The Effect of Methylene Blue and Its Metabolite-Azure I-on Bioenergetic Parameters of Intact Mouse Brain Mitochondria.

Methylene blue, a phenothiazine dye, that is widely used in medicine and is under clinical trials as an agent for treatment of Alzheimer's disease. One of the factors of the unique therapeutic effect of methylene blue is its redox properties, allowing implementation of alternative electron transport: the dye accepts electrons from reducing equivalents in mitochondria and transfer them to other components of the respiratory chain or molecular oxygen. Azure I, an N-dimethylated metabolite of methylene blue, is potentially a more effective compound than methylene blue, but its ability for alternative electron transport has not been studied yet. We have shown that in contrast to methylene blue, azure I is unable to restore the membrane potential in isolated mouse brain mitochondria, inhibited by rotenone and, therefore, is unable to perform bypass of the respiratory chain complex I. Moreover, addition of azure I does not affect the rate of mitochondrial respiration in contrast to methylene blue, which increases the rate of non-phosphorylation respiration. At the same time, both dyes stimulate an increase in H2O2 production. Thus, only methylene blue is capable of alternative electron transport, while azure I does not produce complex I bypass. This limits its therapeutic application only as a mitochondrial-targeted agent, but does not question its antidepressant effects.

[Effect of methylene blue and its metabolite - azure I - on bioenergetic parameters of intact mice brain mitochondria]. / Vliianie metilenovogo sinego i ego metabolita ­ azura I ­ na bioénergeticheskie parametry izolirovannykh mitokhondrii mozga myshei.

Methylene blue is a phenothiazine dye that is widely used in medicine and clinical trials for the treatment of Alzheimer's disease. One of the factors of the unique therapeutic effect of methylene blue is its redox properties, allowing implementation of alternative electron transport - the dye accepts electrons from reducing equivalents in the mitochondria and transfer it them to other components of the respiratory chain or molecular oxygen. Azure I, an N-dimethylated metabolite of methylene blue, is potentially a more effective compound than methylene blue, but its ability for alternative electron transport has not been studied. We have shown that azure I, unlike methylene blue, is unable to restore the membrane potential in isolated mouse brain mitochondria, inhibited by rotenone and, therefore, is unable to perform bypass of the respiratory chain Complex I. Moreover, the addition of azure I does not affect the rate of mitochondrial respiration in contrast to methylene blue, which increases the rate of non-phosphorylation respiration. At the same time, both dyes stimulate an increase in H2O2 production. As a consequence, only methylene blue is capable of alternative electron transport, while azure I does not produce complex I bypass. This limits its therapeutic application only as a mitochondrial-targeted drug, but not as a substance with a potentially powerful antidepressant effect.

[The influence of solar and geomagnetic activity on the risk of multiple sclerosis (results of correlation and regression analysis)]. / Vliianie solnechnoi i geomagnitnoi aktivnosti na risk razvitiia rasseiannogo skleroza (rezul'taty korreliatsionnogo i regressionnogo analiza).

AIM: Multiple sclerosis (MS) develops as a result of an interaction between genetic and environmental factors, among them solar (SA) and geomagnetic activity (GMA) attract the particular attention. An impact of SA and GMA on intrauterine and postnatal period in MS was studied. MATERIAL AND METHODS: The study included 358 patients with MS. Correlation (CA) and regression analysis (RA) were used to study the effects of SA and GMA during intrauterine period, the 1st year of life, a year of disease onset, a year before the onset. RESULTS AND CONCLUSIONS: CA revealed the association between the MS onset and mean values of kp-index in the onset year and the year before the onset year, number of days with kp≥4 and kp≥5 in the onset year and the year before the onset year, mean SFU in the onset year. RA revealed the association between the MS onset and mean kp in the year before the onset year and in the onset year, number of days with kp≥7 in the onset year and the year before the onset year, mean kp during pregnancy, number of days with kp≥7 in the 1st year of life and during pregnancy. The influence of high GMA during pregnancy and in the 1st year of life increases the MS risk in the future and the high GMA predisposes to the MS onset in adults. The practical value of the study is that predicting the GMA changes we can try to prevent the onset and relapses in the risk groups.

[The role of the solar and geomagnetic activity in the etiology of multiple sclerosis: a review of the literature and prospects of research]. / Rol' solnechnoi i geomagnitnoi aktivnosti v etiologii rasseyannogo skleroza: obzor dannykh literatury i perspektivy issledovaniya.

Despite the great progress in the study of multiple sclerosis (MS), its etiology remains unknown. It is proved that MS occurs in genetically predisposed people under the influence of environmental factors. Among these factors the solar activity (SA) and geomagnetic activity (GA) attract the particular attention. This article presents the review of studies concerning the influence of SA and GA on the incidence and course of MS.