The article is focused on the role of the cell bioenergetic apparatus, mitochondria, involved in development of immediate and delayed molecular mechanisms for adaptation to hypoxic stress in brain cortex. Hypoxia induces reprogramming of respiratory chain function and switching from oxidation of NAD-related substrates (complex I) to succinate oxidation (complex II). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of immediate adaptation to hypoxia necessary for 1) succinate-related energy synthesis in the conditions of oxygen deficiency and formation of urgent resistance in the body; 2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation; 3) succinate-related activation of the succinate-specific receptor, GPR91.This mechanism participates in at least four critical regulatory functions: 1) sensor function related with changes in kinetic properties of complex I and complex II in response to a gradual decrease in ambient oxygen concentration; this function is designed for selection of the most efficient pathway for energy substrate oxidation in hypoxia; 2) compensatory function focused on formation of immediate adaptive responses to hypoxia and hypoxic resistance of the body; 3) transcriptional function focused on activated synthesis of HIF-1 and the genes providing long-term adaptation to low рО2; 4) receptor function, which reflects participation of mitochondria in the intercellular signaling system via the succinate-dependent receptor, GPR91. Inallcases, the desired result is achieved by activation of the succinate-dependent oxidation pathway, which allows considering succinate as a signaling molecule. Patterns of mitochondria-controlled activation of GPR-91- and HIF-1-dependent reaction were considered, and a possibility of their participation in cellular-intercellular-systemic interactions in hypoxia and adaptation was proved.

The pharmacological induction and activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a key regulator of ischemic brain tolerance, is a promising direction in neuroprotective therapy. Pharmacological agents with known abilities to modulate cerebral PGC-1α are scarce. This study focused on the potential PGC-1α-modulating activity of Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) and Semax (ACTH_(4–7) analog) in a rat model of photochemical-induced thrombosis (PT) in the prefrontal cortex. Mexidol (100 mg/kg) was administered intraperitoneally, and Semax (25 μg/kg) was administered intranasally, for 7 days each. The expression of PGC-1α and PGC-1α-dependent protein markers of mitochondriogenesis, angiogenesis, and synaptogenesis was measured in the penumbra via immunoblotting at Days 1, 3, 7, and 21 after PT. The nuclear content of PGC-1α was measured immunohistochemically. The suppression of PGC-1α expression was observed in the penumbra from 24 h to 21 days following PT and reflected decreases in both the number of neurons and PGC-1α expression in individual neurons. Administration of Mexidol or Semax was associated with preservation of the neuron number and neuronal expression of PGC-1α, stimulation of the nuclear translocation of PGC-1α, and increased contents of protein markers for PGC-1α activation. This study opens new prospects for the pharmacological modulation of PGC-1α in the ischemic brain.

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., daily, 10 days) and its combined administration with the succinate-containing drug Mexidol (100 mg/kg, i.p., daily, 10 days). Results. Dexamethasone caused a decrease in the content of all detectable parameters in the CC of 18-month-old rats, including anti-inflammatory IL-10, TGF-β1, PGC-1α, VEGF, BDNF, which progressed by 10 days, amounting to 40—60%, which is consistent with the literature data on transrepression by GR of key pro-inflammatory (NFkB, AP1, STAT1), anti-inflammatory (PPARγ, ERRα), pro-anabolic transcription factors (estrogen, androgen receptors). The administration of Mexidol daily an hour after the injection of dexamethasone did not affect the dexamethasone-induced suppression of pro-inflammatory cytokines, but increased the expression levels of anti-inflammatory cytokines, protein markers of mitochondrio-, angio- and synaptogenesis. Conclusion. The study demonstrates for the first time the prospect and pathogenetic foundation of the combined use of dexamethasone and Mexidol in an aging body in order to minimize the activity of GC aimed at suppressing pro-anabolic programs and mechanisms for resolving inflammation.

The SUCNR1 succinate receptor (GPR91) is constitutively expressed by the main populations of immunocytes. Succinate, as an immunometabolite (metabokine), performs SUCNR1-dependent modulation of the morphofunctional state of immune cells and is an important regulator of innate and adaptive immunity, as well as tissue homeostasis. Contradictory interpretations of the role of succinate signaling in the functioning of macrophages, the lack of studies of the effect of SUCNR1 on the morphofunctional transformation of microglia, the problem of low permeability of the blood-brain barrier (BBB) for any promising analogues of succinate have predetermined the conduct of this study. The aim of this study was to evaluate the effect of ethylmethylhydroxypyridine succinate on the polarization of microglia in chronic inflammation in the aging brain. The work was performed on white mongrel male rats aged 3 (young), 6 (middle-aged), and 18 months (old). The drug Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) was used as a succinate derivative that overcomes BBB. Mexidol was administered intraperitoneally at a dose of 100 mg/kg daily for 3, 7, and 14 days. Surface markers of the pro- (M1) and anti-inflammatory (M2) phenotype of microglia (CD86 and CD206, respectively), Iba1 cytoplasmic marker of microglia, as well as IL-1β and TNF-α pro-inflammatory cytokines (expressed by M1 microglia), TGF-β1 immunosuppressive cytokine and BDNF neurotrophin (expressed by M2 microglia) were detected in the samples of the cerebral cortex by immunoblotting. It was shown that the expression of cellular markers of pro- (CD86) and especially anti-inflammatory (CD206) microglia decreased in old rats; however, the level of the marker Iba1 that was expressed independently of the phenotype remained unchanged in all the studied groups, which indicated the maintenance of quantitatively equivalent populations of microglia in different age groups. At the same time, the levels of TNF-α and IL-1β increased, and the content of TGF-β1 and BDNF was significantly lower in old rats compared with young and middle-aged ones. In general, the data obtained indicated the dominance of the pro-inflammatory status of microglia in the aging brain. A 14-day course of Mexidol caused a slight decrease in the level of CD86 in old rats and a significant increase of 45% in the content of CD206 up to the level of CD206 in 6-month-old rats. The increase in the CD206 expression was associated with an increase in the levels of TGF-β1 and BDNF by 60% and 35%, respectively, which indicates the involvement of succinate/SUCNR1 signaling in the anti-inflammatory polarization of microglia in the aging brain. The obtained data develop ideas about the cerebral effects of succinate/SUCNR1 signaling and reveal a new component of the mechanism of the neuroprotective action of Mexidol.