Neuroadaptive Biochemical Mechanisms of Remote Ischemic Conditioning.

This review summarizes the currently known biochemical neuroadaptive mechanisms of remote ischemic conditioning. In particular, it focuses on the significance of the pro-adaptive effects of remote ischemic conditioning which allow for the prevention of the neurological and cognitive impairments associated with hippocampal dysregulation after brain damage. The neuroimmunohumoral pathway transmitting a conditioning stimulus, as well as the molecular basis of the early and delayed phases of neuroprotection, including anti-apoptotic, anti-oxidant, and anti-inflammatory components, are also outlined. Based on the close interplay between the effects of ischemia, especially those mediated by interaction of hypoxia-inducible factors (HIFs) and steroid hormones, the involvement of the hypothalamic-pituitary-adrenocortical system in remote ischemic conditioning is also discussed.

Differences in the Autophagy Response to Hypoxia in the Hippocampus and Neocortex of Rats.

Autophagy is a regulated mechanism of degradation of misfolded proteins and organelles in the cell. Neurons are highly differentiated cells with extended projections, and therefore, their functioning largely depends on the mechanisms of autophagy. For the first time in an animal model using immunohistochemistry, dot analysis, and qRT-PCR, the autophagy (macroautophagy) activity in neurons of two brain regions (hippocampus and neocortex) under normoxia and after exposure to hypoxia was studied. It was found that under normoxia, the autophagic activity was higher in the hippocampal neurons than in the neocortex of rats. In the hippocampus, the exposure of rats to hypoxia resulted in a decrease in the content of autophagy markers LC3 and p62, which was followed by activation of the autophagy-related gene expression. In the neocortex, no changes in these marker proteins were observed after the exposure to hypoxia. These data indicate that the neurons in the hippocampus and neocortex differ in the autophagy response to hypoxia, which may reflect the physiological and functional differences of the pyramidal cells of these brain regions and may to some extent account for the extreme vulnerability of the CA1 hippocampal neurons and relatively high resistance of the neocortical neurons to hypoxia.

Intermittent Hypoxic Training as an Effective Tool for Increasing the Adaptive Potential, Endurance and Working Capacity of the Brain.

This review is devoted to the phenomenon of intermittent hypoxic training and is aimed at drawing the attention of researchers to the necessity of studying the mechanisms mediating the positive, particularly neuroprotective, effects of hypoxic training at the molecular level. The review briefly describes the historical aspects of studying the beneficial effects of mild hypoxia, as well as the use of hypoxic training in medicine and sports. The physiological mechanisms of hypoxic adaptation, models of hypoxic training and their effectiveness are summarized, giving examples of their beneficial effects in various organs including the brain. The review emphasizes a high, far from being realized at present, potential of hypoxic training in preventive and clinical medicine especially in the area of neurodegeneration and age-related cognitive decline.

Mild hypobaric hypoxia preconditioning up-regulates expression of transcription factors c-Fos and NGFI-A in rat neocortex and hippocampus.

Transcription factors c-Fos and NGFI-A encoded by immediate early genes largely participate in the biochemical cascade leading to genomically driven lasting adaptation by neurons to injurious exposures including hypoxia/ischemia. Present study was designed to examine the involvement of c-Fos and NGFI-A in the development of brain hypoxic tolerance induced by mild hypoxic preconditioning. Earlier we have reported that preconditioning by repetitive mild hypobaric hypoxia (MHH) considerably increases neuronal resistance to subsequent severe injurious exposures. Herein, changes of c-Fos and NGFI-A expression in vulnerable rat brain areas (hippocampus, neocortex) in response to preconditioning MHH itself were studied using quantitative immunocytochemistry. Exposure to MHH differentially enhanced c-Fos and NGFI-A expression in neocortex and hippocampal fields 3-24h following the last MHH trial. The c-Fos up-regulation was the most pronounced in neocortex, CA1, and dentate gyrus, but it was twice lower in CA3/CA4. The up-regulation of NGFI-A in CA1, dentate gyrus and neocortex was 1.5-2-fold lower than that of c-Fos; but in CA3 and CA4 the rates of the c-Fos and NGFI-A induction were comparable. The present findings indicate that cooperative but differential activation of c-Fos and NGFI-A expression in vulnerable brain areas contribute to the development of tolerance achieved by MHH preconditioning.

Preconditioning induces prolonged expression of transcription factors pCREB and NF-kappa B in the neocortex of rats before and following severe hypobaric hypoxia.

Preconditioning using mild repetitive hypobaric hypoxia is known to increase a tolerance of brain neurons to severe hypoxia and other injurious exposures. In the present study, the effects of mild hypoxic preconditioning on the expression of transcription factors NF-kappaB and phosphorylated CREB (pCREB) has been studied in the neocortex of rats exposed to severe hypobaric hypoxia. As revealed by quantitative immunocytochemistry, the injurious severe hypobaric hypoxia (180 Torr, 3 h) remarkably reduced the neocortical levels of pCREB and NF-kappaB. The three-trial hypoxic preconditioning (360 Torr, 2 h, 3 days) induced persistent up-regulation of pCREB and NF-kappaB expression in the neocortex of rats 3-24 h following the severe hypoxia. In addition, the preconditioning alone which was not followed by the severe hypoxia, considerably increased neocortical pCREB and NF-kappaB levels. The findings suggest a role for transcription factors cAMP response element-binding protein and NF-kappaB in the neuroprotective mechanisms activated by the hypoxic preconditioning.