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Highlights from the article: Impaired oxygen supply (hypoxia) or reduced blood flow (ischemia) to the brain causes significant metabolic changes in neuronal and non-neural cells. The Research Topic "Brain hypoxia and ischemia: new insights into neurodegeneration and neuroprotection" evaluates recent progress in our understanding of the effects of hypoxia and ischemia on the brain at the molecular, morphological, and physiological levels. The authors suggest that alternate breathing or yogic intervention techniques can be considered as important non-invasive measures to protect the brain against hypoxia-associated pathology and discuss its efficacy for treatment of such neurodegenerative disease as AD.

Exposure of organisms to repetitive mild hypoxia results in development of brain hypoxic/ischemic tolerance and cross-tolerance to injurious factors of a psycho-emotional nature. Such preconditioning by mild hypobaric hypoxia functions as a "warning" signal which prepares an organism, and in particular the brain, to subsequent more harmful conditions. The endogenous defense processes which are mobilized by hypoxic preconditioning and result in development of brain tolerance are based on evolutionarily acquired gene-determined mechanisms of adaptation and neuroprotection. They involve an activation of intracellular cascades including kinases, transcription factors and changes in expression of multiple regulatory proteins in susceptible areas of the brain. On the other hand they lead to multilevel modifications of the hypothalamic-pituitary-adrenal endocrine axis regulating various functions in the organism. All these components are engaged sequentially in the initiation, induction and expression of hypoxia-induced tolerance. A special role belongs to the epigenetic regulation of gene expression, in particular of histone acetylation leading to changes in chromatin structure which ensure access of pro-adaptive transcription factors activated by preconditioning to the promoters of target genes. Mechanisms of another, relatively novel, neuroprotective phenomenon termed hypoxic postconditioning (an application of mild hypoxic episodes after severe insults) are still largely unknown but according to recent data they involve apoptosis-related proteins, hypoxia-inducible factor and neurotrophins. The fundamental data accumulated to date and discussed in this review open new avenues for elaboration of the effective therapeutic applications of hypoxic pre- and postconditioning. [ABSTRACT FROM AUTHOR]

Summary: The preconditioning (PC) by using mild intermittent hypobaric hypoxia (PC) increases a resistance of the brain to severe hypoxia/ischemia and various stresses. Recently, potent antidepressant-like effects of PC have been described in animal models of depression. In the present study, the impact of PC on the activity and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA) impaired in depression has been studied in the model of shock-induced depression in rats. PC completely prevented depressive-like behavior (54% reduction in ambulance, 59% reduction in rearing in the open field, 654% increase of the anxiety level in the elevated plus maze), the HPA hyperactivity and the impairment of HPA feedback regulation that appeared in response to the inescapable footshock. Not affecting basal HPA activity, PC remarkably enhanced the HPA reactivity to stresses and substantially up-regulated the expression of glucocorticoid receptors in the ventral hippocampus following footshock that apparently contributes to the mechanisms responsible for the antidepressant-like action of PC. [Copyright &y& Elsevier]

Abstract: The effects of preconditioning using mild repetitive hypobaric hypoxia (360Torr for 2h each of 3 days) have been studied in the learned helplessness model of depression in rats. Male Wistar rats displayed persistent depressive symptoms (depressive-like behaviour in open field, increased anxiety levels in elevated plus maze, ahedonia, elevated plasma glucocorticoids and impaired dexamethasone test) following the exposure to unpredictable and inescapable footshock in the learned helplessness paradigm. Antidepressant treatment (ludiomil, 5mg/kg i.p.) augmented the development of the depressive state. The hypoxic preconditioning had a clear antidepressive action returning the behavioural and hormonal parameters to the control values and was equally effective in terms of our study as the antidepressant. The findings suggest hypoxic preconditioning as an effective tool for the prophylaxis of post-stress affective pathologies in humans. [Copyright &y& Elsevier]

Abstract: The patterns of expression of the Bcl-2, Bax, and Bcl-xL proteins were examined immunocytochemically in rat hippocampus and neocortex after severe hypobaric hypoxia (180 Torr for 3 h) and severe hypoxia preconditioned by intermittent mild hypoxia (360 Torr for 2 h daily, for 3 consecutive days, 24 h prior to severe hypoxia). As revealed by TUNEL assay, severe hypobaric hypoxia produced extensive apoptotic damage to the neurons of hippocampal CA1–CA4 and the neocortex but not the dentate gyrus granule cells. Remarkable posthypoxic up-regulation of Bax expression maximal at 24 h was detected in the CA1–CA4 areas of hippocampus and neocortex 3–72 h after severe hypoxia. The preconditioning to severe hypoxia protected neurons from the posthypoxic apoptotic transformations, the up-regulation of Bax expression, and resulted in persistent overexpression of Bcl-2 and Bcl-xL. We conclude that the protective action of hypoxic preconditioning is at least in part mediated by shifting of neuronal Bax/Bcl-2–Bcl-xL ratio to a favor of antiapoptotic proteins Bcl-2 and Bcl-xL. [Copyright &y& Elsevier]

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies. [ABSTRACT FROM AUTHOR]

Acetylation of nucleosome histones results in relaxation of DNA and its availability for the transcriptional regulators, and is generally associated with the enhancement of gene expression. Although it is well known that activation of a variety of pro-adaptive genes represents a key event in the development of brain hypoxic/ischemic tolerance, the role of epigenetic mechanisms, in particular histone acetylation, in this process is still unexplored. The aim of the present study was to investigate changes in acetylation of histones in vulnerable brain neurons using original well-standardized model of hypobaric hypoxia and preconditioning-induced tolerance of the brain. Using quantitative immunohistochemistry and Western blot, effects of severe injurious hypobaric hypoxia (SH, 180 mm Hg, 3 h) and neuroprotective preconditioning mode (three episodes of 360 mm Hg for 2 h spaced at 24 h) on the levels of the acetylated proteins and acetylated H3 Lys24 (H3K24ac) in the neocortex and hippocampus of rats were studied. SH caused global repression of the acetylation processes in the neocortex (layers II–III, V) and hippocampus (CA1, CA3) by 3–24 h, and this effect was prevented by the preconditioning. Moreover, hypoxic preconditioning remarkably increased the acetylation of H3K24 in response to SH in the brain areas examined. The preconditioning hypoxia without subsequent SH also stimulated acetylation processes in the neocortex and hippocampus. The moderately enhanced expression of the acetylated proteins in the preconditioned rats was maintained for 24 h, whereas acetylation of H3K24 was intense but transient, peaked at 3 h. The novel data obtained in the present study indicate that large activation of the acetylation processes, in particular acetylation of histones might be essential for the development of brain hypoxic tolerance. [ABSTRACT FROM AUTHOR]