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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.

Abstract: Effects of mild (preconditioning) and severe injurious hypobaric hypoxia (SH), as well as of their combination on hippocampal expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors and HPA axis activity have been examined in rats. As revealed by quantitative immunocytochemistry, three-trial exposure to mild hypoxia produced robust GR and MR overexpression located mainly in the neuronal nuclei in the dentate gyrus (DG) but only MR overexpression was observed in the CA1. SH induced sharp reduction of MR levels and enhanced GR expression in the CA1, suggesting that the unbalance of GR and MR observed might be at the bottom of the extensive neuronal loss seen in this area in response to SH. Contrastingly, SH in tolerant (preconditioned) rats failed to imbalance GR and MR expression in CA1 and up-regulated GR levels in DG. Radioimmunoassay of serum corticosterone showed that both preconditioning hypoxia itself and SH in tolerant rats produced moderate activation of HPA axis followed by its proper inactivation. In the non-preconditioned rats, HPA axis response to SH was impaired. Taken together, these novel results suggest that modifications of the hippocampal expression of GR and MR produced by preconditioning may contribute to the molecular and neuroendocrine mechanisms of tolerance to severe hypoxic stress. [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]

S100 calcium-binding protein A8 (S100A8), a danger-associated molecular pattern, has emerged as an important mediator of the pro-inflammatory response. Some S100 proteins play a prominent role in neuroinflammatory disorders and increase the secretion of pro-inflammatory cytokines in microglial cells. The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action. In this study, we reported that the S100A8 protein expression was increased in mouse neuronal and microglial cells when exposed to hypoxia, and induced neuroinflammation and neuronal apoptosis. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia. Also, phosphorylation of ERK via the TLR4 receptor induced the priming of the NLRP3 inflammasome. The changes in Cyclooxygenase-2 (COX-2) expression, a well-known inflammatory activator, were regulated by the S100A8 expression in microglial cells. Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia. These results suggested that S100A8 may be an important molecule for bidirectional microglia-neuron communication and a new therapeutic target for neurological disorders caused by microglial inflammation during hypoxia. [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]

Abstract: Severe hypoxia results in functional and structural injury of the brain. A preconditioning with repetitive episodes of mild hypoxia considerably ameliorates neuronal resistance to subsequent severe hypoxia. Activation of endogenous antioxidants including Cu, Zn-depending superoxide dismutase (Cu, Zn-SOD) (EC.1.15.1.1) is one of the main cell defense mechanisms against oxidative stress induced by hypoxia. Alterations of expression and enzyme activity of Cu, Zn-SOD 3 and 24h after severe hypobaric hypoxia in forebrain structures of preconditioned and non-preconditioned rats were investigated. We found that hypoxia without preconditioning suppressed the Cu, Zn-SOD enzyme activity at 3h time-point but preconditioning essentially modified the reaction to severe hypoxia by increasing the expression and activity of Cu, Zn-SOD during early stages of reoxygenation crucial for apoptosis initiation. [Copyright &y& Elsevier]