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Brain Hypoxia: Mechanisms of Resilience and Tolerance

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 21839

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Special Issue Editor

Dr. Elena Rybnikova

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Guest Editor

Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg (ex Leningrad), Russia
Interests: hypoxia/ischemia; hypoxic tolerance of the brain; hypoxic signalling; neuroendocrine factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A significant number of common diseases, including neurological and neuropsychiatric ones, occur as a result of the damaging effect on the brain of various adverse factors, among which the leading role is assigned to hypoxia—a condition of insufficient oxygen. Resistance to hypoxia can be increased through the application of various techniques and medications leading to hypoxic tolerance of the brain. Uncovering the molecular mechanisms of underlying processes will allow us to accumulate the information necessary for the development of new successful preventive and therapeutic approaches.

The Special Issue “Brain Hypoxia: Mechanisms of Resilience and Tolerance" aims in comprehensive integration of the most topical trends in this area of research to stimulate further progress. This Special Issue will accept articles on the molecular basis of neuronal reactions to hypoxia or ischemia, the contribution of neuron–glial interactions, neuroprotective or pro-degenerative roles of hypoxia-inducible factors, in particular HIF-1, and the mechanisms of pre- and postconditioning impacts. A puzzle of the complex interaction between multiple molecular pathways will be the focus of this Special issue to identify perspective targets for protective pharmacological interventions.

Dr. Elena Rybnikova
Guest Editor

Manuscript Submission Information

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Keywords

Cerebral hypoxia
Neurological diseases
Stroke
Posthypoxic pathology
Neuronal reactions to hypoxia
Neuron–glial interactions
Hypoxic/ischemic injury
Hypoxic tolerance
HIF-1
HIF-1 target genes
Epigenetic regulation
Mitochondria signaling
Oxidative stress
Antioxidants
Neuroinflammation

Published Papers (7 papers)

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Research

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24 pages, 6365 KiB

Open AccessArticle

Signaling Role of Mitochondrial Enzymes and Ultrastructure in the Formation of Molecular Mechanisms of Adaptation to Hypoxia

by Ludmila Lukyanova, Elita Germanova, Natalya Khmil, Lybov Pavlik, Irina Mikheeva, Maria Shigaeva and Galina Mironova

Int. J. Mol. Sci. 2021, 22(16), 8636; https://doi.org/10.3390/ijms22168636 - 11 Aug 2021

Cited by 11 | Viewed by 2277

Abstract

This study was the first comprehensive investigation of the dependence of mitochondrial enzyme response (catalytic subunits of mitochondrial complexes (MC) I-V, including NDUFV2, SDHA, Cyt b, COX1 and ATP5A) and mitochondrial ultrastructure in the rat cerebral cortex (CC) on the severity and duration of in vivo hypoxic exposures. The role of individual animal’s resistance to hypoxia was also studied. The respiratory chain (RC) was shown to respond to changes in environmental [O₂] as follows: (a) differential reaction of mitochondrial enzymes, which depends on the severity of the hypoxic exposure and which indicates changes in the content and catalytic properties of mitochondrial enzymes, both during acute and multiple exposures; and (b) ultrastructural changes in mitochondria, which reflect various degrees of mitochondrial energization. Within a specific range of reduced O₂ concentrations, activation of the MC II is a compensatory response supporting the RC electron transport function. In this process, MC I develops new kinetic properties, and its function recovers in hypoxia by reprograming the RC substrate site. Therefore, the mitochondrial RC performs as an in vivo molecular oxygen sensor. Substantial differences between responses of rats with high and low resistance to hypoxia were determined. Full article

(This article belongs to the Special Issue Brain Hypoxia: Mechanisms of Resilience and Tolerance)

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23 pages, 4279 KiB

Open AccessArticle

Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression

by Shami Kanekar, Robert Ettaro, Michael D. Hoffman, Hendrik J. Ombach, Jadeda Brown, Cayla Lynch, Chandni S. Sheth and Perry F. Renshaw

Int. J. Mol. Sci. 2021, 22(15), 8195; https://doi.org/10.3390/ijms22158195 - 30 Jul 2021

Cited by 6 | Viewed by 4267

Abstract

Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin. Full article

(This article belongs to the Special Issue Brain Hypoxia: Mechanisms of Resilience and Tolerance)

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17 pages, 1858 KiB

Open AccessArticle

Double-Edged Sword of Vitamin D3 Effects on Primary Neuronal Cultures in Hypoxic States

by Maria Loginova, Tatiana Mishchenko, Maria Savyuk, Svetlana Guseva, Maria Gavrish, Mikhail Krivonosov, Mikhail Ivanchenko, Julia Fedotova and Maria Vedunova

Int. J. Mol. Sci. 2021, 22(11), 5417; https://doi.org/10.3390/ijms22115417 - 21 May 2021

Cited by 8 | Viewed by 2059

Abstract

The use of vitamin D3 along with traditional therapy opens up new prospects for increasing the adaptive capacity of nerve cells to the effects of a wide range of stress factors, including hypoxia-ischemic processes. However, questions about prophylactic and therapeutic doses of vitamin D3 remain controversial. The purpose of our study was to analyze the effects of vitamin D3 at different concentrations on morpho-functional characteristics of neuron–glial networks in hypoxia modeling in vitro. We showed that a single administration of vitamin D3 at a high concentration (1 µM) in a normal state has no significant effect on the cell viability of primary neuronal cultures; however, it has a pronounced modulatory effect on the functional calcium activity of neuron–glial networks and causes destruction of the network response. Under hypoxia, the use of vitamin D3 (1 µM) leads to total cell death of primary neuronal cultures and complete negation of functional neural network activity. In contrast, application of lower concentrations of vitamin D3 (0.01 µM and 0.1 µM) caused a pronounced dose-dependent neuroprotective effect during the studied post-hypoxic period. While the use of vitamin D3 at a concentration of 0.1 µM maintained cell viability, preventive administration of 0.01 µM not only partially preserved the morphological integrity of primary neuronal cells but also maintained the functional structure and activity of neuron–glial networks in cultures. Possible molecular mechanisms of neuroprotective action of vitamin D3 can be associated with the increased expression level of transcription factor HIF-1α and maintaining the relationship between the levels of BDNF and TrkB expression in cells of primary neuronal cultures. Full article

(This article belongs to the Special Issue Brain Hypoxia: Mechanisms of Resilience and Tolerance)

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16 pages, 3728 KiB

Open AccessArticle

Intermittent Hypobaric Hypoxic Preconditioning Provides Neuroprotection by Increasing Antioxidant Activity, Erythropoietin Expression and Preventing Apoptosis and Astrogliosis in the Brain of Adult Rats Exposed to Acute Severe Hypoxia

by Débora Coimbra-Costa, Fernando Garzón, Norma Alva, Tiago C. C. Pinto, Fernando Aguado, Joan Ramon Torrella, Teresa Carbonell and Ramón Rama

Int. J. Mol. Sci. 2021, 22(10), 5272; https://doi.org/10.3390/ijms22105272 - 17 May 2021

Cited by 15 | Viewed by 2341

Abstract

Background: Exposure to intermittent hypoxia has been demonstrated to be an efficient tool for hypoxic preconditioning, preventing damage to cells and demonstrating therapeutic benefits. We aimed to evaluate the effects of respiratory intermittent hypobaric hypoxia (IHH) to avoid brain injury caused by exposure to acute severe hypoxia (ASH). Methods: biomarkers of oxidative damage, mitochondrial apoptosis, and transcriptional factors in response to hypoxia were assessed by Western blot and immunohistochemistry in brain tissue. Four groups of rats were used: (1) normoxic (NOR), (2) exposed to ASH (FiO₂ 7% for 6 h), (3) exposed to IHH for 3 h per day over 8 days at 460 mmHg, and (4) ASH preconditioned after IHH. Results: ASH animals underwent increased oxidative-stress-related parameters, an upregulation in apoptotic proteins and had astrocytes with phenotype forms compatible with severe diffuse reactive astrogliosis. These effects were attenuated and even prevented when the animals were preconditioned with IHH. These changes paralleled the inhibition of NF-κB expression and the increase of erythropoietin (EPO) levels in the brain. Conclusions: IHH exerted neuroprotection against ASH-induced oxidative injury by preventing oxidative stress and inhibiting the apoptotic cascade, which was associated with NF-κB downregulation and EPO upregulation. Full article

(This article belongs to the Special Issue Brain Hypoxia: Mechanisms of Resilience and Tolerance)

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31 pages, 6580 KiB

Open AccessArticle

Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats

by Andrea Tapia-Bustos, Carolyne Lespay-Rebolledo, Valentina Vío, Ronald Pérez-Lobos, Emmanuel Casanova-Ortiz, Fernando Ezquer, Mario Herrera-Marschitz and Paola Morales

Int. J. Mol. Sci. 2021, 22(6), 3275; https://doi.org/10.3390/ijms22063275 - 23 Mar 2021

Cited by 6 | Viewed by 3160

Abstract

The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 μL of vehicle (10% plasma) or 5 × 10⁴ MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter. Full article

(This article belongs to the Special Issue Brain Hypoxia: Mechanisms of Resilience and Tolerance)

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15 pages, 3234 KiB

Open AccessArticle

Hypoxia-Induced S100A8 Expression Activates Microglial Inflammation and Promotes Neuronal Apoptosis

by Ji Sun Ha, Hye-Rim Choi, In Sik Kim, Eun-A Kim, Sung-Woo Cho and Seung-Ju Yang

Int. J. Mol. Sci. 2021, 22(3), 1205; https://doi.org/10.3390/ijms22031205 - 26 Jan 2021

Cited by 18 | Viewed by 3275

Abstract

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. Full article

(This article belongs to the Special Issue Brain Hypoxia: Mechanisms of Resilience and Tolerance)

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Review

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15 pages, 887 KiB

Open AccessReview

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia

by Elena Rybnikova and Natalia Nalivaeva

Int. J. Mol. Sci. 2021, 22(15), 7982; https://doi.org/10.3390/ijms22157982 - 26 Jul 2021

Cited by 14 | Viewed by 3347

Abstract

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. Full article

(This article belongs to the Special Issue Brain Hypoxia: Mechanisms of Resilience and Tolerance)

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