Abstract
The glutathione system in the mitochondria of the brain plays an important role in maintaining the redox balance and thiol–disulfide homeostasis, whose violations are the important component of the biochemical shifts in neurodegenerative diseases. Mitochondrial dysfunction is known to be accompanied by the activation of free radical processes, changes in energy metabolism, and is involved in the induction of apoptotic signals. The formation of disulfide bonds is a leading factor in the folding and maintenance of the three-dimensional conformation of many specific proteins that selectively accumulate in brain structures during neurodegenerative pathology. In this study, we estimated brain mitochondria redox status and functioning during induction of oxidative damage in vitro. We have shown that the development of oxidative stress in vitro is accompanied by inhibition of energy metabolism in the brain mitochondria, a shift in the redox potential of the glutathione system to the oxidized side, and activation of S-glutathionylation of proteins. Moreover, we studied the effects of pantothenic acid derivatives—precursors of coenzyme A (CoA), primarily D-panthenol, that exhibit high neuroprotective activity in experimental models of neurodegeneration. Panthenol contributes to the significant restoration of the activity of enzymes of mitochondrial energy metabolism, normalization of the redox potential of the glutathione system, and a decrease in the level of S-glutathionylated proteins in brain mitochondria. The addition of succinate and glutathione precursor N-acetylcysteine enhances the protective effects of the drug.
Highlights
An increase in the average life expectancy of people in modern society contributes to changes in the structure of morbidity and leads to a rise in the number of degenerative diseases, which are based on the mechanisms of cellular apoptosis
thiobarbituric acid-reactive substances (TBARS) (p < 0.05), while the content of protein-bound TBARS rose to 36.8% (p < 0.05) in mitochondria (Table 1), which is an index of the activation of lipid peroxidation
To test the possibility of enhancing the neuroprotective effect of panthenol, we studied the effect of the combination of PL with succinate on the redox balance in the mitochondria of the brain against the background of oxidative stress initiated by the addition of FeSO4
Summary
An increase in the average life expectancy of people in modern society contributes to changes in the structure of morbidity and leads to a rise in the number of degenerative diseases, which are based on the mechanisms of cellular apoptosis. Neurodegenerative diseases cause significant brain dysfunction and lead to a sharp decrease in the quality of life of elderly patients [1]. There is evidence that reactive oxygen species (ROS) are the primary cause of neuronal death; on the other hand, ROS are generated in response to the activation of certain signaling cascades, as was shown for tumor necrosis factor α-induced cell death or programmed necrotic cell death [5,6,7,8,9]. Activation of lipoperoxidation is one of the most striking manifestations of brain damage in neurodegenerative pathology [2,3,8].
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