E. I. Tyul’kova

The possible use of hypoxic preconditioning for the prophylaxis of post-stress depressive episodes.

The protective effects of hypoxic preconditioning on the development of depressive states in rat models were studied. Three episodes of intermittent preconditioning using hypobaric hypoxia (360 mmHg, 2 h) prevented the onset of depressive behavioral reactions, hyperfunction of the hypophyseal-adrenal system, and impairments in its suppression in the dexamethasone test in rats following unavoidable aversive stress in a model of endogenous depression. The anxiolytic and antidepressant actions of hypoxic preconditioning in experiments on rats were no less marked than those of the tetracyclic antidepressant ludiomil. The results obtained here provide evidence that preconditioning with intermittent hypobaric hypoxia increases resistance to psychoemotional stresses, has marked anxiolytic and antidepressant effects, and can be used for the prophylaxis of depressive episodes.

Thioredoxin-1 expression levels in rat hippocampal neurons in moderate hypobaric hypoxia

Previous studies have demonstrated that preconditioning (PC) with three sessions of moderate hypoxia significantly increases the expression of the antioxidant protein thioredoxin-1 (Trx-1) in the rat hippocampus by 3 h after subsequent acute severe hypoxia as compared with non-preconditioned animals. However, it remained unclear whether this increase in Trx-1 accumulation during PC is induced before severe hypoxia or is a modification of the response to severe hypoxia. This question was addressed in the present investigation using experiments on 12 adult male Wistar rats with studies of Trx-1 expression after PC without subsequent severe hypoxia. Immunocytochemical studies were performed 3 and 24 h after three episodes of moderate hypobaric hypoxia (three sessions of 2 h at 360 mmHg with 24-h intervals). Immunoreactivity to Trx-1 24 h after the last session was significantly decreased in neurons in all the areas of the hippocampus studied (CA1, CA2, CA3, and the dentate gyrus). Immunoreactivity in CA3 was also decreased 3 h after hypoxia. These results provide evidence that moderate preconditioning hypoxia itself not only does not increase, but even significantly decreases Trx-1 expression. Thus, increases in Trx-1 contents in the hippocampus of preconditioned animals after severe hypoxia are not associated with the accumulation of this protein during PC, but with a PC-induced modification of the reaction to severe hypoxia.

Effects of prenatal hypoxia on expression of thioredoxin-1 in the rat hippocampus at different stages of postnatal ontogeny

We studied the expression of the antioxidant protein thioredoxin-1 in the hippocampus of rat pups that were subjected to hypoxia at prenatal days 14–16, at the 3rd and 14th days after their birth, and at 80–90 days when the pups became mature. In spite of the specific features of certain hippocampal regions and the presence of exceptions related to them, 3 days after birth we observed a general trend to a decrease in thioredoxin-1 expression in rats subjected to hypoxia, as compared to the control animals of the same age. Then, thioredoxin-1 expression was substantially increased on the 14th day of postnatal life. In adult rats, thioredoxin-1 expression decreased again. These changes were very prominent in the CA1 field of the hippocampus. A decrease in the activity of the physiological antioxidant system is an important index of cell-membrane homeostasis, whose impairment under hypoxic conditions can result in the development of neurodegenerative diseases.

Threefold Exposure to Moderate Hypobaric Hypoxia Decreases the Expression of Cu,Zn-Superoxide Dismutase in Some Regions of Rat Hippocampus

The effect of moderate hypobaric hypoxia on the expression of a peptide antioxidant Cu,Zn-superoxide dismutase in rat hippocampal neurons was evaluated in an immunocytochemical study. The expression of Cu,Zn-superoxide dismutase decreased significantly in the dorsal hippocampus (CA1 and CA2) and tended to decrease in ventral regions (CA3 and dentate gyrus) by the 24th hour after 3-fold exposure to hypoxia.

A comparison of the effects of single and triple exposures to moderate hypobaric hypoxia on the expression of Cu, Zn-superoxide dismutase in the rat hippocampus

It was shown that preconditioning by three-time moderate hypobaric hypoxia improves and accelerates the expression of Cu, Zn-superoxide dismutase (SOD) in response to subsequent severe hypoxia in neurons of the rat hippocampus. However, preconditioning per se in the absence of subsequent exposure to severe hypoxia does not increase but even decreases Cu, Zn-SOD expression in some regions of the hippocampus. In the present study, we compared our previous immunocytochemical data on Cu, Zn-SOD expression 3 and 24 h after the last of three exposures to moderate hypobaric hypoxia with the data on the expression at the same time points after a single exposure to moderate hypobaric hypoxia. We found that a single exposure to hypoxia has similar effects on Cu, Zn-SOD expression as triple hypoxia. When we compared four time points during preconditioning, i.e., 3 and 24 h after single and triple exposures to hypoxia, respectively, we revealed wave-like changes in the levels of Cu, Zn-SOD expression, which may play an important role in modification of the response to subsequent severe hypoxia and, thus, in the mechanism of the formation of the tolerance of hippocampal neurons to hypoxia.

Dynamics of lipid peroxidation of membranes in cells and mitochondrial fraction of neocortex in non- and preconditioned rats after severe hypobaric hypoxia

There was studied effect of severe hypobaric hypoxia and subsequent reoxygenation on level and dynamics of lipid peroxidation in membranes of neocortex cells and in mitochondriaenriched neocortex fraction of non-preconditioned rats and of rats preconditioned thrice with a moderate hypobaric hypoxia. The threefold hypoxic preconditioning increasing brain resistance has been shown to significantly prevent disturbance of lipid peroxidation processes in neocortex—one of the most hypoxia-sensitive brain structures—and to modify development of these processes in mitochondria.

Time course of lipid peroxidation in hippocampal membranes of preconditioned and nonpreconditioned rats subjected to severe hypobaric hypoxia

We studied the effects of severe hypobaric hypoxia and reoxygenation on the intensity and progression of lipid peroxidation in the cellular membranes of the hippocampi of rats subjected to moderate hypobaric hypoxic preconditioning. Hypoxic preconditioning, which increases brain resistance, substantially prevented changes in lipid peroxidation, which were induced by severe hypoxia in the hippocampus, one of the brain structures that is most sensitive to hypoxia.

Changes in Lipid Peroxidation in the Hippocampus and Neocortex after Severe Hypobaric Hypoxia in Rats

We studied the effects of severe hypobaric hypoxia followed by reoxygenation at the level and the time course of changes in free radical lipid oxidation in the hippocampus, neocortex, and mitochondriaenriched neocortical fraction of rats. We found that severe hypobaric hypoxia induced long-term changes in lipid peroxidation in the brain structures susceptible to hypoxia, the hippocampus and the neocortex.

The effects of prenatal hypobaric hypoxia on the level of lipid peroxidation in the neocortex and hippocampus of rats

We subjected rats to severe hypobaric hypoxia on days 14–16 or 17–19 of gestation and studied the effects of this treatment on the levels of the principal components of the lipid peroxidation (LPO) system in membranes of the neocortex and hippocampus of 14-(juvenile) and 90-day-old (adult) rats. We demonstrate that in the early postnatal ontogeny the formation of products of free-radical oxidation was enhanced in the rat brain. After the evaluation of LPO in the brain of juvenile and adult rats, the maximum differences were observed in the levels of triene conjugates and TBARS. We found that during the prenatal period on days 14–16 but not on days 17–19 of gestation, severe hypobaric hypoxia substantially modified the LPO levels in the neocortex and hippocampus of rats in postnatal ontogeny. The severity and direction of these alterations depend on the age of the animal that is subjected to testing. We also demonstrate that these alterations were different in the cortex and hippocampus of rats.

Modifications of the Expression of Thioredoxins and Superoxide Dismutases in the Rat Hippocampus that Were Induced by Prenatal Hypoxia Are Preserved in Mature Animals

Prenatal hypoxia induces structural and functional disturbances in the brain that develop during the following postnatal ontogeny. Some cognitive and behavioral disorders that are induced by prenatal hypoxia are preserved even in adults. Oxidative stress is a key factor of damage during hypoxia. Hence, the relationship between the pro- and antioxidant systems plays an important role in the development of both pathological and adaptive processes that were induced by hypoxia. Here, using immunocytochemistry we studied the expression of four endogenous protein antioxidants (Cu,Zn-superoxide dismutase, Mn-superoxide dismutase, thioredoxin-1, and thioredoxin-2) in hippocampal neurons of adult rats that were subjected to triple hypoxia at the 14th, 15th, and 16th days of their prenatal development. We found that in a number of cases prenatal hypoxia substantially modified the expression of endogenous antioxidants in hippocampal neurons of rats that achieved an adult age (80–90 days of postnatal ontogeny). The directions of these changes, however, are different for different antioxidants and areas of the hippocampus. It seems that this multidirectionality of changes in the expression of different antioxidants in different areas reflects an inextricable connection between the pathological consequences of prenatal hypoxia and adaptation processes that are induced by this hypoxia.