[The effect of ethylmethylhydroxypyridine succinate on the parameters of chronic neuroinflammation and plastic processes in the brain of old rats during course of dexamethasone administration].

Objective: To study was to evaluate the potential modulatory impact of succinate/SUCNR1 signaling on the non-genomic immunosuppressive and gene-mediated inflammatory-degenerative effects of glucocorticoid receptor (GR) activation in the cerebral cortex (CC) of aging rats.

Material And Methods: Using Western blot analysis, we assessed the expression level of pro-inflammatory (TNF-α, IL-1β), anti-inflammatory cytokines (IL-10, TGF-β1), mitochondriogenesis markers (PGC-1α, NDUFV2, SDHA, cyt c1, COX2, ATP5A), angiogenesis marker VEGF, neurotrophin BDNF, GR, succinate receptor SUCNR1 in the CC of 18-month-old rats with isolated administration of the highly specific GR ligand dexamethasone (1 mg/kg, i.p.

[The effect of Mexidol on cerebral mitochondriogenesis at a young age and during aging].

Aim: To study the ability of mexidol to induce cerebral mitochondriogenesis in the brain of young and aging rats.

Material And Methods: Expression level of marker proteins of cerebral mitochondriogenesis was evaluated during treatment with mexidol (20, 40, 100 mg/kg; 20 days; intraperitoneally) in the cerebral cortex of young (3 month) and aging (6, 9, 12, and 15 month) outbred male rats, using the Western blot analysis.

Results: It has been shown for the first time that the course injections of mexidol in doses of 40 and 100 mg/kg is accompanied by dose-dependent induction of the succinate receptor SUCNR1 and protein markers of mitochondrial biogenesis: transcription coactivator PGC-1α, transcription factors (NRF1, TFAM), catalytic subunits of respiratory enzymes (NDUV2, NDUV2,cytb, COX2) and ATP synthase (ATP5A) in the cerebral cortex of young and aging outbred male rats.

Peculiarities of Immediate Response of Respiratory Chain Enzymes in Rat Cerebral Cortex to Hypoxia.

We performed a complex study of the dependence of immediate reaction of catalytic subunits in mitochondrial enzymes (NDUFV2, SDHA, Cyt b, COX1, and ATP5A) in rat cerebral cortex (the most hypoxia-sensitive tissue) on the severity and duration of hypoxia in vivo and the role of individual resistance of rats to oxygen deficiency in this process. Three types of responses to hypoxia were revealed. The immediate response of mitochondria to oxygen deficiency appeared after its drop by 30-33% relatively to normal atmosphere level.

Specific Features of Immediate Ultrastructural Changes in Brain Cortex Mitochondria of Rats with Different Tolerance to Hypoxia under Various Modes of Hypoxic Exposures.

We performed ultrastructural study of cerebral cortex mitochondria in rats with different tolerance to oxygen deficiency (low resistant and highly resistant specimens). Low resistant rats were characterized by the prevalence of mitochondria with lightened matrix due to the nondense packing of cristae. By contrast, mitochondria of highly resistant animals had the dense packing of cristae.

The Role of Succinate in Regulation of Immediate HIF-1α Expression in Hypoxia.

Hypoxia-induced immediate expression of transcription factor HIF-1α in the brain cortex is regulated by succinate produced in both the tricarbonic acid cycle and GABA shunt reactions and is induced by succinate-containing drugs. These facts prove the existence of succinate-dependent signalling regulation involved in immediate and delayed molecular adaptation and increased body resistance to oxygen deficiency, where succinate acts as a signal molecule. The intensity of this process differs in animals with low and high resistance to hypoxia.

Specific Features of Immediate Expression of Succinate-Dependent Receptor GPR91 in Tissues during Hypoxia.

Under normoxic conditions, succinate-dependent receptor GPR91 was found in varying amounts in all analyzed aerobic tissues except erythrocytes. The maximum density of the receptor was observed in the myocardium: by 2.3 and 1.

[Role of the glutathione system in regulation of redox status in the rat cerebral cortex under hypoxia].

The study compared effects of different hypobaric hypoxia regimens (14% O2, 10.5% O2, and 8% O2; 1 hour; 15 days) on parameters of the glutathione system, intensity of free radical oxidation, and intensity of lipid peroxidation in cerebral cortex (CC) of rats with different, genetically predetermined resistance to acute hypoxia. In normoxia, baseline concentrations of oxidized glutathione (0.

[Urgent changes in the expression of hypoxia-inducible factor-1α (HIF-1α) in the neocortex of rats with different tolerance to acute hypoxia underwent focal ischemic stroke prefrontal cortex].

Using immunohistochemical method, it was demonstrated that neurons of the cerebral cortex have the capacity to express hypoxia-inducible factor-1 alpha (HIF-1α) in normoxia. Intensity of this process is different for rats having unequal tolerance to hypoxia. Basal HIF-1α expression in neurons of rats with low-resistance (LR) to hypoxia is higher compared to rats with high-resistance (HR).

Phenotypic features of the dynamics of HIF-1α levels in rat neocortex in different hypoxia regimens.

There are tissue-specific and phenotypic differences in the basal levels of HIF-1α under normoxic conditions. Induction of short-term adaptation to hypoxia and formation of long-term adaptation are genetically determined. These phenomena are observed only in animals with low resistance to hypoxia and are associated with biphasic expression of HIF-1α in the neocortex only during hypoxic preconditioning.

Role of proinflammatory factors, nitric oxide, and some parameters of lipid metabolism in the development of immediate adaptation to hypoxia and HIF-1α accumulation.

The development of immediate and delayed long-term resistance to hypoxia during a course of intermittent normobaric hypoxia (15 daily sessions of alternating exposure to 10% O2 and atmospheric air for 1 h) correlated with biphasic expression of HIF-1α in neocortex of hypoxia-intolerant rats, which suggests involvement of this protein factor not only in the formation of long-term adaptation, but also in triggering immediate adaptation to hypoxia. Both processes develop under conditions promoting down-regulation of oxidative modification of LDL and increasing tolerance of biological membranes to hypoxia in the absence of activation of the free radical processes, which therefore do not trigger HIF-1α expression under these conditions. Neither cytokines nor NO are the inducers of immediate adaptation, and they are not related to HIF-1α expression during the early post-hypoxic period.

Effect of hypoxic preconditioning on free radical processes in tissues of rats with different resistance to hypoxia.

We studied the effect of single hypoxic preconditioning exposure (hypobaric hypoxia, 5000 m, 60 min) on free radical processes, glutathione system, and antioxidant defense enzymes in tissues of rats with different resistance to acute hypoxia. The intensity of free radical processes was shown to increase or decrease on day 1 after hypoxic preconditioning. These changes were tissue-specific and opposite in animals with genetically determined differences in the resistance to hypoxia.

Urgent reaction of the complement system to hypoxic exposure in rats sensitive to hypoxia.

Different modes of hypoxic exposure led to phasic changes in activities of the complement system components in rats sensitive to hypoxia starting from the first minutes of the posthypoxic period and persisting for 24 h and longer. The direction of shifts in the complement system depended on the duration and intensity of oxygen deficiency. Single one-hour interval hypoxia led to a moderate elevation of activities of virtually all the studied components.