[Show abstract][Hide abstract]ABSTRACT: The expression of neurogenesis marker - NeuroD2 transcription factor - in the hippocampal dentate gyrus was studied in rats exposed to severe destructive hypoxia, a single or three episodes of moderate hypobaric hypoxia, preconditioned severe hypoxia, and severe hypoxia followed by 3 sessions of postconditioning by moderate hypobaric hypoxia. All the studied hypoxic exposure modes led to an increase of NeuroD2 level. Three-fold moderate hypoxia per se and in the preconditioning mode (followed by exposure to severe hypoxia) produced most pronounced up-regulatory effect on NeuroD2 expression. The results indicated that stimulation of neurogenesis processes seemed to be one of the aspects of the neuroprotective effect of three-fold preconditioning moderate hypoxia, but not of hypoxic postconditioning.
Full-text Article · Feb 2016 · Bulletin of Experimental Biology and Medicine
[Show abstract][Hide abstract]ABSTRACT: Using the immunohistochemical method, we studied changes in the expression of the hypoxia-inducible factor (HIF-1 alpha) in the neocortex and hippocampus of rats after moderate preconditioning (MH), severe (SH) hypobaric hypoxia, and their combined action. We found that a three time but not a single MH had a pronounced effect on the activity of HIF-1; MH increases its expression in the regulatory oxygen-sensitive alpha subunit in neurons of the neocortex and hippocampus of rats. We also found that a three time (but not a single) hypoxic preconditioning enhances HIF-1 alpha expression in both the hippocampus and neocortex in response to the following SH, whereas in non-preconditioned animals MH substantially decreases the HIF-1 alpha level.
[Show abstract][Hide abstract]ABSTRACT: Quantitative immunohistochemical studies of changes in the expression of the neurotrophin BDNF (brain-derived neurotrophic factor) in the hippocampus and neocortex were performed in 24 male Wistar rats as they developed a poststress anxiety state in an experimental model of post-traumatic stress disorder and during correction of this condition by hypoxic postconditioning (PostC). The anxiety state was induced by combined psychoemotional stress (restraint stress, forced swimming, ether stress, and, after seven days, repeated restraint, i.e., restress). Correction of the anxiety state in the rats was with hypoxic postconditioning – three sessions of moderate hypobaric hypoxia (360 mmHg, 2 h). Formation of the anxiety state was accompanied by a significant reduction in the content of immunoreactive BDNF in the dorsal (CA1) and ventral (dentate gyrus) hippocampus and the neocortex, while hypoxic PostC led to partial (hippocampus) and complete (neocortex) restoration of BDNF expression. The results provided evidence that neurotrophic factors, particularly BDNF, appear to play an important role in the pathogenesis of anxious-depressive disorders and the realization of the proadaptive and neuroprotective actions of hypoxic PostC.
Article · Sep 2015 · Neuroscience and Behavioral Physiology
[Show abstract][Hide abstract]ABSTRACT: Experiments on 72 male Wistar rats using an immunocytochemical method addressed the level of expression of the antiapoptotic factor Bcl-2 in neocortical and hippocampal neurons on exposure to harmful severe (SH) and moderate hypobaric (MHH) hypoxia separately and in combination. SH (180 mmHg) suppressed or had no effect on Bcl-2 expression in neurons in these brain areas. Single episodes of preconditioning (360 mmHg) produced similar effects on Bcl-2 expression as SH. Conversely, repeated preconditioning significantly increased the level of Bcl-2 expression 3–24 h after SH, helping to prevent neuron injury due to SH. MHH itself increased the level of Bcl-2 expression only after multiple (3–6) sessions, while single sessions had no effect on Bcl-2 content. The increases in Bcl-2 expression seen in response to multiple exposures to MHH appear to be important for the formation of the mechanisms increasing the tolerance of cerebral neurons to harmful actions.
Article · Sep 2015 · Neuroscience and Behavioral Physiology
[Show abstract][Hide abstract]ABSTRACT: The study assessed involvement of Ca 2? sig-naling mediated by the metabotropic glutamate receptors mGluR1/5 in brain tolerance induced by hypoxic precon-ditioning. Acute slices of rat piriform cortex were tested 1 day after exposure of adult rats to mild hypobaric hypoxia for 2 h at a pressure of 480 hPa once a day for three consecutive days. We detected 44.1 ± 11.6 % suppression of in vitro anoxia-induced increases of intracel-lular Ca 2? levels and a fivefold increase in Ca 2? transients evoked by selective mGluR1/5 agonist, DHPG. Western blot analysis of cortical homogenates demonstrated a 11 ± 4 % decrease in mGluR1 immunoreactivity (IR), and in the nuclei-enriched fraction a 12 ± 3 % increase in IR of phospholipase Cb1 (PLCb1), which is a major mediator of mGluR1/5 signaling. Immunocytochemical analysis of the cortex revealed increase in the mGluR1/5 and PLCb1 IR in perikarya, and a decrease in IR of the neuronal inositol trisphosphate receptors (IP3Rs). We suggest that enhanced expression of mGluR5 and PLCb1 and potenti-ation of Ca 2? signaling may represent pro-survival upreg-ulation of Ca 2?-dependent genomic processes, while decrease in mGluR1 and IP3R IR may be attributed to a feedback mechanism preventing excessive intracellular Ca 2? release.
Full-text Article · Aug 2015 · Neurochemical Research
[Show abstract][Hide abstract]ABSTRACT: A quantitative immunohistochemical method was used to study the expression of antiapoptotic protein Bcl-2 and neurotrophin BDNF in hippocampal field CA1 in rats subjected to severe hypoxia (SH), the harmful consequences of which were compensated by three subsequent sessions of postconditioning (PostC) with moderate hypobaric hypoxia (360 mmHg, 2 h, three times with 24-h intervals). Decreases in the expression of these proteins were seen in the hippocampus of rats after SH. Hypoxic PostC, which improves structural-functional rehabilitation after severe hypoxia, increased Bcl-2 and BDNF expression in neurons in hippocampal field CA1 in rats subjected to SH. The results provided evidence of the involvement of Bcl-2 and BDNF in the processes of adaptation to SH and compensation of its damaging effects.
Full-text Article · May 2015 · Neuroscience and Behavioral Physiology
[Show abstract][Hide abstract]ABSTRACT: Using immunocytochemical method, the level of expression of Bcl-2 antiapoptotic factor was studied in neurons of the neocortex and hippocampus in 72 male Wistar rats exposed to damaging severe hypoxia (SH), moderate hypobaric hypoxia (MHH), as well as their combination. After SH (180 mmHg) Bcl-2 expression in the neurons of the brain regions examined was reduced or. unchanged. The effect of preconditioning with one trial of MHH (360 mmHg) on Bcl-2 expression was similar to that seen after SH. In contrast, preconditioning with repeated exposures to MHH significantly up-regulated Bcl-2 expression levels 3-24 h after SH that apparently protected neurons from SH-induced injury. MHH alone, not followed by SH, significantly increased Bcl-2 expression only after multiple (three or six) exposures whereas single MHH exposure had no effect on Bcl content. Hence, up-regulation of Bcl-2 seen in response to multiple MHH trials appears to be important for the formation of the mechanisms of brain neuronal tolerance to damaging factors.
Article · Mar 2015 · Morfologiia (Saint Petersburg, Russia)
[Show abstract][Hide abstract]ABSTRACT: Hippocampal gluco- and mineralocorticoid receptors (GR, MR) have important roles in the mechanisms regulating the activity of the hypothalamo-hypophyseal-adrenocortical system (HHAS), neuron survival/death, learning, and memory. Imbalance in MR and GR contents lead to impairments of HHAS activity and can promote neuron damage/death in extreme conditions. The present study used a quantitative immunocytochemistry method to provide the first comparative analysis of the effects of different regimes of hypobaric hypoxia on the nature of GR and MR expression in the dorsal (CA1) and ventral (dentate gyrus) parts of the hippocampus in rats. The data obtained here showed that severely harmful hypoxia induces marked impairments to the expression of both GR and MR in CA1 and dental gyrus cells, which correlated with damage/death of a significant proportion of neurons in CA1 and dysregulation of the activity of the HHAS. Series of three and six sessions (but not one session) of preconditioning with moderate hypoxia preceding severe hypoxia prevented these impairments.
Article · Jul 2014 · Neuroscience and Behavioral Physiology
[Show abstract][Hide abstract]ABSTRACT: Using immunohistochemistry, we studied the expression of the alpha regulatory subunit of the hypoxia-inducible factor (HIF-1α) and the product of its target gene, which encodes the protective cytokine erythropoietin in the hippocampal CA1 field of rats in response to damaging severe hypoxia and severe hypoxia followed by three sessions of postconditioning with mild hypobaric hypoxia. We found that the immunoreactivity to the proteins studied in the hippocampus of rats was reduced in response to severe hypoxia. Hypoxic postconditioning sessions of mild hypobaric hypoxia (360 mmHg, 2 h, three times at intervals of 24 h) up regulated the expression of HIF-1α and erythropoietin in hippocampal CA1 neurons of rats that survived after severe hypoxia. Our results indicate that postconditioning led to compensation of hypoxia-induced neuron damage in the brain, which actively involved HIF-1α and erythropoietin.
[Show abstract][Hide abstract]ABSTRACT: Transcription factor NF-kappaB plays a pivotal role in mechanisms of brain neuron survival and degeneration under injurious stimuli, first of all different types of hypoxia. In the present work, using quantitative immunohystochemistry, we provide analysis of expression of different subunits of NF-kappaB (p65 and c-Rel) in the rat neocortex in response to severe injurious hypobaric hypoxia (HH) or after a single or multiple sessions of mild protective HH. Severe hypoxia (SH), resulting in loss of brain neurons, has no effect on the level of expression of p65 but suppresses expression of c-Rel. Multiple (but not single one) trials of preconditioning using mild HH which reduce neuronal damage promote p65 expression and prevent suppression of c-Rel level after SH. Triple session of mild HH itself when applied as a preconditioning stimulus upregulate expression of both subunits, while single administration or sixfold trials has no effect on the level of immunoreactivity of both subunits. The revealed peculiarities of the expression of p65 and c-Rcl implies that these subunits of NF-kappaB appear to contribute to the mechanisms of brain tolerance to SH.
[Show abstract][Hide abstract]ABSTRACT: Using quantitative immunohistochemistry, neuronal expression of alpha-subunit of the transcriptional factor HIF-1 in hippocampus and neocortex of rats in response to pathogenic psychoemotional (model of posttraumatic stress disorder, PTSD) and hypoxic (severe hypobaric hypoxia, 180 Torr, 3 h), as well as to neuroprotective exposures to hypoxic pre- and postconditioning has been studied. Elongated overexpression of HIF-1alpha in hippocampus and neocortex of rats in response to the psychoemotional stress in PTSD paradigm, but not hypoxic stress, has been observed. Hypoxic pre- and postconditioning with mild hypobaric hypoxia (360 Torr, 2 h, 3 trials spaced at 24 h), those induced adaptation to the psychoemotional stress, abolished the elongated HIF-1alpha overexpression. Hypoxic postconditioning which improved structure and functional rehabilitation following severe hypoxic stress up-regulated HIF-1alpha expression in the brain neurons of rats survived severe hypoxia. The findings indicate that transcription factor HIF-1 is particularly involved in the processes of adaptation/ maladaptation to the action of injurious stresses, but its role depends upon the nature of stressor.
[Show abstract][Hide abstract]ABSTRACT: A comparative analysis of the effects of severe hypobaric hypoxia in different prenatal periods on expression profiles of glucocorticoid receptors (GR) in dorsal (CA1) and ventral (dental gyrus) hippocampus and neocortex of rats, their stress reactivity and working memory has been performed in the present study for the first time. According to the data obtained, severe hypoxia in the prenatal period induces remarkable disturbances of GR expression in the neurons of neocortex of adult males but not females, that correlates to the disruption of working memory in adult males exposed to hypoxia on the prenatal 14-16th days. Elevation of stress plasma corticosterone levels have been observed only in the females subjected to hypoxia on the prenatal 17-19th days. Hypoxia in the females and males results in the differential changes in functions of hippocampus, as well as of other brain areas involved in learning.
[Show abstract][Hide abstract]ABSTRACT: The effects of repetitive mild hypobaric hypoxic preconditioning upon pro- and antioxidant systems in rat hippocampus were studied. It was found that three-trial preconditioning by mild hypobaric hypoxia (360 mm Hg, 2 h) induced moderate oxidative stress immediately after the last preconditioning trial. In addition, it down-regualted the levels of peptide antioxidants (Trx-1, Trx-2, Cu,Zn-SOD) and several lipid peroxidation products 24 h later.
[Show abstract][Hide abstract]ABSTRACT: Gluco- and mineralocorticoid receptors are believed to play important roles in mechanisms of the hypothalamic-pituitary-adrenal axis (HPA) regulation, neuronal death/survival, as well as learning and memory processes. Imbalanced levels of MR and GR result in impairment of HPA activity and can promote neuronal injury and loss following exposures to extreme factors. In the present study, using quantitative immunohistochemistry, the comparative analysis of the effects of hypobaric hypoxia in several modes on expression profiles of GR and MR in dorsal (CA1) and ventral (dentate gyrus) hippocampus was performed. According to the data obtained, severe injurious hypoxia induced prominent disturbances of GR and MR expression in the cells of CA1 and dentate gyrus that correlated to the remarkable neuronal injury/loss in CA1 and dysregulated HPA activity. Sets of three- or six-trial (but not one-trial) preconditioning using mild hypoxia prior to severe hypoxia prevented these abnormalities.
Article · Feb 2013 · Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk
[Show abstract][Hide abstract]ABSTRACT: Group I of metabotropic glutamate receptors (ImGluRs) are a family of G-protein-coupled receptors which activate a multitude of signaling pathways important for modulating neuronal excitability and synaptic plasticity as well as anti- and prosurvival pathways initiated by hypoxia. However these functions are still not complete and sometimes controversial. The present work is a review of data concerning involvement of ImGluRs in mechanisms of cell response to hypoxia. We also present original data demonstrating their participation in forming pathogenic and adaptogenic intracellular events, appearing in rat neocortex during a day after severe or moderate hypobaric hypoxia, respectively. Ca2+ responses to ImGluRs stimulation in survival cortical slices and expression of ImGluRs, IP3Rs and PLCbeta1 in immunolabelled cortical preparations were estimated for these two different hypoxic models.
Full-text Article · Oct 2012 · Patologicheskaia fiziologiia i eksperimental'naia terapiia
[Show abstract][Hide abstract]ABSTRACT: Hypobaric hypoxia may have either detrimental or adaptive effect on structural and functional characteristics of brain neurons. In this study, the effect of different regimes of hypobaric hypoxia on the structural and functional characteristics of hippocampal and neocortical neurons was examined in rats (n = 30). It was shown that severe hypoxia (induced by pressure in the pressure chamber equal to 180 Torr) caused structural neuronal damage both in the fronto-parietal neocortex and dorsal and ventral hippocampus 3 days after the exposure. The preconditioning using mild hypobaric hypoxia (pressure equal to 360 Torr) had varied effect on the morphological characteristics of brain neurons of rats, subjected to severe hypoxia. Multiple (three-trial or six-trial) preconditioning prevents structural damage of neurons induced by subsequent severe hypoxia. On the contrary, single preconditioning trial of mild hypoxia was ineffective in terms of neuroprotection.
Article · Jun 2012 · Morfologiia (Saint Petersburg, Russia)
[Show abstract][Hide abstract]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.