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Hypoxia-Induced Oxidative Stress in the Brain

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A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 42687

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Dr. Elzbieta Salinska

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Department of Neurochemistry, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
Interests: birth asphyxia; brain ischemia; oxidative stress; glutamate receptors; calcium fluxes

Special Issue Information

Dear Colleagues,

Deprivation of the tissue of adequate oxygen supply, called hypoxia, usually involves damage of the tissue of organs it affects. The mammalian brain is a highly oxygen-consuming organ, which makes it especially sensitive to hypoxia. Brain hypoxia may occur in all age groups as a consequence of birth asphyxia, cardiac arrest, stroke, carbon monoxide poisoning or even sport activities like high mountain climbing or diving. Fathoming mechanisms of neuronal death triggered by free oxygen radicals formed in the brain under hypoxic conditions and reoxygenation as well as search for effective ways to suppress oxidative stress has occupied research for decades. Reports on such studies conducted on neuronal cell cultures and animal models of hypoxia and hypoxia–ischemia increase our knowledge on this subject every year. However, as we all know, there is still no good cure to stop oxidative stress-induced neuronal death.

This Special Issue “Hypoxia-Induced Oxidative Stress in the Brain” is dedicated to presenting current knowledge and future prospects on hypoxia-induced oxidative stress in the brain. We invite experts on various aspects of oxidative stress and its involvement in hypoxia induced brain damage. We welcome the submission of manuscripts either describing original research or reviewing the scientific literature in this field.

Dr. Elzbieta Salinska
Guest Editor

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Keywords

Brain hypoxia—in vivo and in vitro models
Reactive oxygen species
Neurodegeneration
Antioxidant defense
Therapeutic strategies

Published Papers (11 papers)

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Research

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13 pages, 4528 KiB

Open AccessArticle

Protective Effects of 6,7,4′-Trihydroxyflavanone on Hypoxia-Induced Neurotoxicity by Enhancement of HO-1 through Nrf2 Signaling Pathway

by Hyun-Su Lee and Gil-Saeng Jeong

Antioxidants 2021, 10(3), 341; https://doi.org/10.3390/antiox10030341 - 24 Feb 2021

Cited by 5 | Viewed by 2541

Abstract

Since hypoxia-induced neurotoxicity is one of the major causes of neurodegenerative disorders, including the Alzheimer’s disease, continuous efforts to find a novel antioxidant from natural products are required for public health. 6,7,4′-trihydroxyflavanone (THF), isolated from Dalbergia odorifera, has been shown to inhibit osteoclast formation and have an antibacterial activity. However, no evidence has reported whether THF has a protective role against hypoxia-induced neurotoxicity. In this study, we found that THF is not cytotoxic, but pre-treatment with THF has a cytoprotective effect on CoCl₂-induced hypoxia by restoring the expression of anti-apoptotic proteins in SH-SY5y cells. In addition, pre-treatment with THF suppressed CoCl₂-induced hypoxia-related genes including HIF1α, p53, VEGF, and GLUT1 at the mRNA and protein levels. Pre-treatment with THF also attenuated the oxidative stress occurred by CoCl₂-induced hypoxia by preserving antioxidant proteins, including SOD and CAT. We revealed that treatment with THF promotes HO-1 expression through Nrf2 nuclear translocation. An inhibitor assay using tin protoporphyrin IX (SnPP) confirmed that the enhancement of HO-1 by pre-treatment with THF protects SH-SY5y cells from CoCl₂-induced neurotoxicity under hypoxic conditions. Our results demonstrate the advantageous effects of THF against hypoxia-induced neurotoxicity through the HO-1/Nrf2 signaling pathway and provide a therapeutic insight for neurodegenerative disorders. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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20 pages, 3709 KiB

Open AccessArticle

The Role of Mitochondria in Brain Cell Protection from Ischaemia by Differently Prepared Propolis Extracts

by Zbigniev Balion, Kristina Ramanauskienė, Aistė Jekabsone and Daiva Majienė

Antioxidants 2020, 9(12), 1262; https://doi.org/10.3390/antiox9121262 - 12 Dec 2020

Cited by 6 | Viewed by 2485

Abstract

Mitochondria are both the primary targets and mediators of ischaemic damage in brain cells. Insufficient oxygen causes reactive oxygen species that damage the mitochondria, leading to the loss of functionality and viability of highly energy-demanding neurons. We have recently found that aqueous (AqEP), polyethylene glycol-aqueous (Pg-AqEP) and ethanolic propolis extracts (EEP) can modulate mitochondria and ROS production in C6 cells of astrocytic origin. The aim of this study was to investigate the effect of the extracts on viability, mitochondrial efficiency and superoxide generation, and inflammatory cytokine release in primary rat cerebellar neuronal-glial cell cultures affected by ischaemia (mimicked by hypoxia +/− deoxyglucose). AqEP and Pg-AqEP (15–60 µg/mL of phenolic compounds, or PC) significantly increased neuronal viability in ischaemia-treated cultures, and this was accompanied by a reduction in mitochondrial superoxide levels. Less extended protection against ischaemia-induced superoxide production and death was exhibited by 2 to 4 µg/mL of PC EEP. Both Pg-AqEP and Ag-EP (but not EEP) significantly protected the cultures from hypoxia-induced elevation of TNF-α, IL-1β and IL-6. Only Pg-AqEP (but not AqEP or EEP) prevented hypoxia-induced loss of the mitochondrial basal and ATP-coupled respiration rate, and significantly increased the mitochondrial respiratory capacity. Summarising, the study revealed that hydrophilic propolis extracts might protect brain cells against ischaemic injury by decreasing the level of mitochondrial superoxide and preventing inflammatory cytokines, and, in the case of Pg-AqEP, by protecting mitochondrial function. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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17 pages, 2695 KiB

Open AccessArticle

N-Acetylaspartylglutamate (NAAG) Pretreatment Reduces Hypoxic-Ischemic Brain Damage and Oxidative Stress in Neonatal Rats

by Ewelina Bratek, Apolonia Ziembowicz and Elzbieta Salinska

Antioxidants 2020, 9(9), 877; https://doi.org/10.3390/antiox9090877 - 17 Sep 2020

Cited by 10 | Viewed by 2525

Abstract

N-acetylaspartylglutamate (NAAG), the most abundant peptide transmitter in the mammalian nervous system, activates mGluR3 at presynaptic sites, inhibiting the release of glutamate, and acts on mGluR3 on astrocytes, stimulating the release of neuroprotective growth factors (TGF-β). NAAG can also affect N-methyl-d-aspartate (NMDA) receptors in both synaptic and extrasynaptic regions. NAAG reduces neurodegeneration in a neonatal rat model of hypoxia-ischemia (HI), although the exact mechanism is not fully recognized. In the present study, the effect of NAAG application 24 or 1 h before experimental birth asphyxia on oxidative stress markers and the potential mechanisms of neuroprotection on 7-day old rats was investigated. The intraperitoneal application of NAAG at either time point before HI significantly reduced the weight deficit of the ischemic brain hemisphere, radical oxygen species (ROS) content and activity of antioxidant enzymes, and increased the concentration of reduced glutathione (GSH). No additional increase in the TGF-β concentration was observed after NAAG application. The fast metabolism of NAAG and the decrease in TGF-β concentration that resulted from NAAG pretreatment, performed up to 24 h before HI, excluded the involvement mGluR3 in neuroprotection. The observed effect may be explained by the activation of NMDA receptors induced by NAAG pretreatment 24 h before HI. Inhibition of the NAAG effect by memantine supports this conclusion. NAAG preconditioning 1 h before HI results in a mixture of mGluR3 and NMDA receptor activation. Preconditioning with NAAG induces the antioxidative defense system triggered by mild excitotoxicity in neurons. Moreover, this response to NAAG pretreatment is consistent with the commonly accepted mechanism of preconditioning. However, this theory requires further investigation. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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15 pages, 3925 KiB

Open AccessArticle

Oxidative Stress—Part of the Solution or Part of the Problem in the Hypoxic Environment of a Brain Tumor

by Kamil Krawczynski, Jakub Godlewski and Agnieszka Bronisz

Antioxidants 2020, 9(8), 747; https://doi.org/10.3390/antiox9080747 - 14 Aug 2020

Cited by 12 | Viewed by 3183

Abstract

Rapid growth of brain tumors such as glioblastoma often results in oxygen deprivation and the emergence of hypoxic zones. In consequence, the enrichment of reactive oxygen species occurs, harming nonmalignant cells and leading them toward apoptotic cell death. However, cancer cells survive such exposure and thrive in a hypoxic environment. As the mechanisms responsible for such starkly different outcomes are not sufficiently explained, we aimed to explore what transcriptome rearrangements are used by glioblastoma cells in hypoxic areas. Using metadata analysis of transcriptome in different subregions of the glioblastoma retrieved from the Ivy Glioblastoma Atlas Project, we created the reactive oxygen species-dependent map of the transcriptome. This map was then used for the analysis of differential gene expression in the histologically determined cellular tumors and hypoxic zones. The gene ontology analysis cross-referenced with the clinical data from The Cancer Genome Atlas revealed that the metabolic shift is one of the major prosurvival strategies applied by cancer cells to overcome hypoxia-related cytotoxicity. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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21 pages, 3763 KiB

Open AccessArticle

Characterization of a CholesteroNitrone (ISQ-201), a Novel Drug Candidate for the Treatment of Ischemic Stroke

by Emma Martínez-Alonso, Alejandro Escobar-Peso, Maria I. Ayuso, Rafael Gonzalo-Gobernado, Mourad Chioua, Juan J. Montoya, Joan Montaner, Israel Fernández, José Marco-Contelles and Alberto Alcázar

Antioxidants 2020, 9(4), 291; https://doi.org/10.3390/antiox9040291 - 31 Mar 2020

Cited by 9 | Viewed by 2838

Abstract

Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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14 pages, 3636 KiB

Open AccessArticle

Gelidium amansii Attenuates Hypoxia/Reoxygenation-Induced Oxidative Injury in Primary Hippocampal Neurons through Suppressing GluN2B Expression

by Md. Abdul Hannan, Md. Nazmul Haque, Md. Mohibbullah, Raju Dash, Yong-Ki Hong and Il Soo Moon

Antioxidants 2020, 9(3), 223; https://doi.org/10.3390/antiox9030223 - 09 Mar 2020

Cited by 20 | Viewed by 4017

Abstract

Oxidative stress is known to be critically implicated in the pathophysiology of several neurological disorders, including Alzheimer’s disease and ischemic stroke. The remarkable neurotrophic activity of Gelidium amansii, which has been reported consistently in a series of our previous studies, inspired us to investigate whether this popular agarophyte could protect against hypoxia/reoxygenation (H/R)-induced oxidative injury in hippocampal neurons. The primary culture of hippocampal neurons challenged with H/R suffered from a significant loss of cell survival, accompanied by apoptosis and necrosis, DNA damage, generation of reactive oxygen species (ROS), and dissipation of mitochondrial membrane potential (ΔΨ_m), which were successfully attenuated when the neuronal cultures were preconditioned with ethanolic extract of G. amansii (GAE). GAE also attenuated an H/R-mediated increase of BAX and caspase 3 expressions while promoting Bcl-2 expression. Moreover, the expression of N-methyl-d-acetate receptor subunit 2B (GluN2B), an extrasynaptic glutamate receptor, was significantly repressed, while synaptic GluN2A expression was preserved in GAE-treated neurons as compared to those without GAE intervention. Together, this study demonstrates that GAE attenuated H/R-induced oxidative injury in hippocampal neurons through, at least in part, a potential neuroprotective mechanism that involves inhibition of GluN2B-mediated excitotoxicity and suppression of ROS production, and suggests that this edible seaweed could be a potential source of bioactive metabolites with therapeutic significance against oxidative stress-related neurodegeneration, including ischemic stroke and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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Review

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16 pages, 458 KiB

Open AccessReview

The Antioxidant Role of One-Carbon Metabolism on Stroke

by Kassidy Burgess, Calli Bennett, Hannah Mosnier, Neha Kwatra, Forrest Bethel and Nafisa M. Jadavji

Antioxidants 2020, 9(11), 1141; https://doi.org/10.3390/antiox9111141 - 17 Nov 2020

Cited by 11 | Viewed by 2934

Abstract

One-carbon (1C) metabolism is a metabolic network that is centered on folate, a B vitamin; it integrates nutritional signals with biosynthesis, redox homeostasis, and epigenetics. This metabolic pathway also reduces levels of homocysteine, a non-protein amino acid. High levels of homocysteine are linked to increased risk of hypoxic events, such as stroke. Several preclinical studies have suggested that 1C metabolism can impact stroke outcome, but the clinical data are unclear. The objective of this paper was to review preclinical and clinical research to determine whether 1C metabolism has an antioxidant role on stroke. To accomplish the objective, we searched for publications using the following medical subject headings (MeSH) keywords: antioxidants, hypoxia, stroke, homocysteine, one-carbon metabolism, folate, methionine, and dietary supplementation of one-carbon metabolism. Both pre-clinical and clinical studies were retrieved and reviewed. Our review of the literature suggests that deficiencies in 1C play an important role in the onset and outcome of stroke. Dietary supplementation of 1C provides beneficial effects on stroke outcome. For stroke-affected patients or individuals at high risk for stroke, the data suggest that nutritional modifications in addition to other therapies could be incorporated into a treatment plan. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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23 pages, 1083 KiB

Open AccessReview

How to Improve the Antioxidant Defense in Asphyxiated Newborns—Lessons from Animal Models

by Hanna Kletkiewicz, Maciej Klimiuk, Alina Woźniak, Celestyna Mila-Kierzenkowska, Karol Dokladny and Justyna Rogalska

Antioxidants 2020, 9(9), 898; https://doi.org/10.3390/antiox9090898 - 21 Sep 2020

Cited by 6 | Viewed by 3247

Abstract

Oxygen free radicals have been implicated in brain damage after neonatal asphyxia. In the early phase of asphyxia/reoxygenation, changes in antioxidant enzyme activity play a pivotal role in switching on and off the cascade of events that can kill the neurons. Hypoxia/ischemia (H/I) forces the brain to activate endogenous mechanisms (e.g., antioxidant enzymes) to compensate for the lost or broken neural circuits. It is important to evaluate therapies to enhance the self-protective capacity of the brain. In animal models, decreased body temperature during neonatal asphyxia has been shown to increase cerebral antioxidant capacity. However, in preterm or severely asphyxiated newborns this therapy, rather than beneficial seems to be harmful. Thus, seeking new therapeutic approaches to prevent anoxia-induced complications is crucial. Pharmacotherapy with deferoxamine (DFO) is commonly recognized as a beneficial regimen for H/I insult. DFO, via iron chelation, reduces oxidative stress. It also assures an optimal antioxidant protection minimizing depletion of the antioxidant enzymes as well as low molecular antioxidants. In the present review, some aspects of recently acquired insight into the therapeutic effects of hypothermia and DFO in promoting neuronal survival after H/I are discussed. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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59 pages, 4437 KiB

Open AccessReview

Genetically Encoded Tools for Research of Cell Signaling and Metabolism under Brain Hypoxia

by Alexander I. Kostyuk, Aleksandra D. Kokova, Oleg V. Podgorny, Ilya V. Kelmanson, Elena S. Fetisova, Vsevolod V. Belousov and Dmitry S. Bilan

Antioxidants 2020, 9(6), 516; https://doi.org/10.3390/antiox9060516 - 11 Jun 2020

Cited by 9 | Viewed by 7779

Abstract

Hypoxia is characterized by low oxygen content in the tissues. The central nervous system (CNS) is highly vulnerable to a lack of oxygen. Prolonged hypoxia leads to the death of brain cells, which underlies the development of many pathological conditions. Despite the relevance of the topic, different approaches used to study the molecular mechanisms of hypoxia have many limitations. One promising lead is the use of various genetically encoded tools that allow for the observation of intracellular parameters in living systems. In the first part of this review, we provide the classification of oxygen/hypoxia reporters as well as describe other genetically encoded reporters for various metabolic and redox parameters that could be implemented in hypoxia studies. In the second part, we discuss the advantages and disadvantages of the primary hypoxia model systems and highlight inspiring examples of research in which these experimental settings were combined with genetically encoded reporters. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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22 pages, 522 KiB

Open AccessReview

Prenatal Hypoxia and Placental Oxidative Stress: Insights from Animal Models to Clinical Evidences

by Serena Silvestro, Valeria Calcaterra, Gloria Pelizzo, Placido Bramanti and Emanuela Mazzon

Antioxidants 2020, 9(5), 414; https://doi.org/10.3390/antiox9050414 - 12 May 2020

Cited by 21 | Viewed by 5871

Abstract

Hypoxia is a common form of intrauterine stress characterized by exposure to low oxygen concentrations. Gestational hypoxia is associated with the generation of reactive oxygen species. Increase in oxidative stress is responsible for damage to proteins, lipids and DNA with consequent impairment of normal cellular functions. The purpose of this review is to propose a summary of preclinical and clinical evidences designed to outline the correlation between fetal hypoxia and oxidative stress. The results of the studies described show that increases of oxidative stress in the placenta is responsible for changes in fetal development. Specifically, oxidative stress plays a key role in vascular, cardiac and neurological disease and reproductive function dysfunctions. Moreover, the different finding suggests that the prenatal hypoxia-induced oxidative stress is associated with pregnancy complications, responsible for changes in fetal programming. In this way, fetal hypoxia predisposes the offspring to congenital anomalies and chronic diseases in future life. Several antioxidant agents, such as melatonin, erythropoietin, vitamin C, resveratrol and hydrogen, shown potential protective effects in prenatal hypoxia. However, future investigations will be needed to allow the implementation of these antioxidants in clinical practice for the promotion of health in early intrauterine life, in fetuses and children. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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15 pages, 549 KiB

Open AccessReview

Effect of Acupuncture on Oxidative Stress Induced by Cerebral Ischemia-Reperfusion Injury

by Chao-Hsien Chen and Ching-Liang Hsieh

Antioxidants 2020, 9(3), 248; https://doi.org/10.3390/antiox9030248 - 19 Mar 2020

Cited by 28 | Viewed by 3872

Abstract

In this article, we review how acupuncture regulates oxidative stress to prevent ischemia–reperfusion injury. We electronically searched databases, including PubMed, Clinical Key and the Cochrane Library, from their inception to November 2019 by using the following medical subject headings and keywords: acupuncture, ischemia-reperfusion injury, oxidative stress, reactive oxygen species, and antioxidants. We concluded that acupuncture is effective in treating oxidation after ischemia-reperfusion injury. In addition to increasing the activity of antioxidant enzymes and downregulating the generation of reactive oxygen species (ROS), acupuncture also repairs the DNA, lipids, and proteins attacked by ROS and mediates downstream of the ROS pathway to apoptosis. Full article

(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)

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