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Oxidative Stress in Neurodegenerative Disease

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 30691

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Dr. Andrii Domanskyi

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Guest Editor

Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Interests: Parkinson’s disease; protein aggregation; animal models; fibril-induced alpha-synuclein aggregation; human iPCS-derived neurons; viral vectors for somatic transgenesis; neurotrophic factors; neuroinflammation; autophagy-lysosomal system; neurodegeneration
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Dr. Rosanna Parlato

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Co-Guest Editor

Department of Neurology/Division of Neurodegenerative Disorders, Medical Faculty Mannheim University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
Interests: Huntington’s disease; Parkinson’s disease; amyotropic lateral sclerosis; RNA metabolism; autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oxidative stress, along with mitochondrial dysfunction and pathological protein aggregation, is a hallmark of many neurodegenerative diseases. The brain is particularly susceptible to oxidative stress due to its high oxygen consumption and vulnerable endogenous antioxidant defense. Oxidative stress may lead to the death of neurons, either directly or indirectly, as a consequence of mitochondrial dysfunction, altered proteostasis, physiological neurotransmitter metabolism, inflammation, or deregulation of antioxidant pathways. Indeed, increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), together with impaired antioxidant defense mechanisms, are frequently observed in Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis (ALS). ROS and RNS cause oxidative damage to proteins, lipids, and nucleic acids, compromising cellular functions and activating cell death pathways. Critical importance of antioxidant defense pathways for neuronal survival is also supported by the genetic mutations observed in familial forms of several neurodegenerative diseases.

For this Special Issue, we aim to bring together the most recent information on the causes and consequences of oxidative stress in neurodegenerative diseases. We invite authors to submit their latest relevant research findings or review articles, including in vitro, in vivo, and clinical studies relating to any of the following topics: molecular and cellular responses to oxidative damage in the brain; age-related and/or disease-specific changes in neuronal antioxidant defense pathways; oxidative stress biomarkers for diagnostic and monitoring disease progression and treatment efficacy; methods to study oxidative stress in neurodegenerative disease models and patients; and antioxidant therapies for neurodegenerative diseases.

We look forward to your contribution.

Dr. Andrii Domanskyi
Dr. Rosanna Parlato
Guest Editors

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Keywords

reactive oxygen species
reactive nitrogen species
neurodegeneration
antioxidant defence
oxidative stress biomarkers
antioxidant therapy
oxidative stress sensors

Published Papers (10 papers)

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Editorial

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4 pages, 183 KiB

Open AccessEditorial

Oxidative Stress in Neurodegenerative Diseases

by Andrii Domanskyi and Rosanna Parlato

Antioxidants 2022, 11(3), 504; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11030504 - 05 Mar 2022

Cited by 15 | Viewed by 2099

Abstract

Oxidative stress is typically reported in neurodegenerative diseases [...] Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

Research

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11 pages, 782 KiB

Open AccessArticle

Oxidative Stress Biomarkers and Mitochondrial DNA Copy Number Associated with APOE4 Allele and Cholinesterase Inhibitor Therapy in Patients with Alzheimer’s Disease

by Chia-Wei Liou, Shih-Hsuan Chen, Tsu-Kung Lin, Meng-Han Tsai and Chiung-Chih Chang

Antioxidants 2021, 10(12), 1971; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10121971 - 10 Dec 2021

Cited by 9 | Viewed by 2333

Abstract

Studies of the oxidative/anti-oxidative status in patients with Alzheimer’s disease (AD) carrying different alleles of the apolipoprotein E (APOE) gene are currently inconclusive; meanwhile, data regarding mitochondrial DNA copy number (mtCN) remain limited. We herein determined the thiobarbituric acid reactive substances (TBARS), thiols, and mtCN in blood samples of 600 AD patients and 601 controls. A significantly higher oxidative TBARS (1.64 μmol/L), lower antioxidative thiols (1.60 μmol/L), and lower mtCN (2.34 log Delta Ct) were found in the AD cohort as compared to the non-AD cohort (1.54 μmol/L, 1.71 μmol/L, 2.46 log Delta Ct). We further identified the ε4 alleles (APOE4) and separated subjects into three groups according to the number of APOE4. A significant trend was noted in the TBARS levels of both AD and non-AD cohorts, highest in the homozygous two alleles (1.86 and 1.80 μmol/L), followed by heterozygous one allele (1.70 and 1.74 μmol/L), and lowest in the no APOE4 allele (1.56 and 1.48 μmol/L). Similar trends of lower thiols and mtCN were also found in the AD cohort. In our study of the influence of cholinesterase inhibitor therapy, we found significantly reduced TBARS levels, and elevated mtCN in AD patients receiving rivastigmine and galantamine therapy. Our study demonstrates associations between the APOE4 allele and oxidative stress biomarkers and mtCN. Using cholinesterase inhibitor therapy may benefit AD patients through attenuation of oxidative stress and manipulation of the mtCN. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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20 pages, 3958 KiB

Open AccessArticle

Neuroprotective Activity of Melittin—The Main Component of Bee Venom—Against Oxidative Stress Induced by Aβ_25–35 in In Vitro and In Vivo Models

by Cong Duc Nguyen and Gihyun Lee

Antioxidants 2021, 10(11), 1654; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10111654 - 21 Oct 2021

Cited by 16 | Viewed by 3056

Abstract

Melittin, a 26-amino acid peptide, is the main component of the venom of four honeybee species and exhibits neuroprotective actions. However, it is unclear how melittin ameliorates neuronal cells in oxidative stress and how it affects memory impairment in an in vivo model. We evaluated the neuroprotective effect of melittin on Aβ_25–35-induced neuro-oxidative stress in both in vitro HT22 cells and in vivo animal model. Melittin effectively protected against HT22 cell viability and significantly deregulated the Aβ_25–35-induced overproduction of intracellular reactive oxygen species. Western blot analysis showed that melittin suppressed cell apoptosis and regulated Bax/Bcl-2 ratio, as well as the expression of proapoptotic related factors: Apoptosis-inducing factor (AIF), Calpain, Cytochrome c (CytoC), Cleaved caspase-3 (Cleacas3). Additionally, melittin enhanced the antioxidant defense pathway by regulating the nuclear translocation of nuclear factor erythroid 2-like 2 (Nrf2) thus upregulated the production of the heme oxygenase-1 (HO-1), a major cellular antioxidant enzyme combating neuronal oxidative stress. Furthermore, melittin treatment activated the Tropomyosin-related kinase receptor B (TrkB)/cAMP Response Element-Binding (CREB)/Brain-derived neurotrophic factor (BDNF), contributing to neuronal neurogenesis, and regulating the normal function of synapses in the brain. In our in vivo experiment, melittin was shown to enhance the depleted learning and memory ability, a novel finding. A mouse model with cognitive deficits induced by Aβ_25–35 intracerebroventricular injection was used. Melittin had dose-dependently enhanced neural-disrupted animal behavior and enhanced neurogenesis in the dentate gyrus hippocampal region. Further analysis of mouse brain tissue and serum confirmed that melittin enhanced oxidant–antioxidant balance, cholinergic system activity, and intercellular neurotrophic factors regulation, which were all negatively altered by Aβ_25–35. Our study shows that melittin exerts antioxidant and neuroprotective actions against neural oxidative stress. Melittin can be a potential therapeutic agent for neurodegenerative disorders. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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14 pages, 1911 KiB

Open AccessArticle

An Unrecognized Fundamental Relationship between Neurotransmitters: Glutamate Protects against Catecholamine Oxidation

by Wenping Wang, Ximing Wu, Chung S. Yang and Jinsong Zhang

Antioxidants 2021, 10(10), 1564; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10101564 - 30 Sep 2021

Cited by 9 | Viewed by 2431

Abstract

Neurotransmitter catecholamines (dopamine, epinephrine, and norepinephrine) are liable to undergo oxidation, which copper is deeply involved in. Catecholamine oxidation-derived neurotoxicity is recognized as a pivotal pathological mechanism in neurodegenerative diseases. Glutamate, as an excitatory neurotransmitter, is enriched in the brain at extremely high concentrations. However, the chemical biology relationship of these two classes of neurotransmitters remains largely unknown. In the present study, we assessed the influences of glutamate on the autoxidation of catecholamines, the copper- and copper-containing ceruloplasmin-mediated oxidation of catecholamines, the catecholamine-induced formation of quinoprotein, catecholamine/copper-induced hydroxyl radicals, and DNA damage in vitro. The results demonstrate that glutamate, at a physiologically achievable molar ratio of glutamate/catecholamines, has a pronounced inhibitory effect on catecholamine oxidation, catecholamine oxidation-evoked hydroxyl radicals, quinoprotein, and DNA damage. The protective mechanism of glutamate against catecholamine oxidation could be attributed to its restriction of the redox activity of copper via chelation. This previously unrecognized link between glutamate, catecholamines, and copper suggests that neurodegenerative disorders may occur and develop once the built-in equilibrium is disrupted and brings new insight into developing more effective prevention and treatment strategies for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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20 pages, 19082 KiB

Open AccessArticle

Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

by Rasem Mustafa, Chahinaz Rawas, Nadja Mannal, Grzegorz Kreiner, Björn Spittau, Katarzyna Kamińska, Rüstem Yilmaz, Christina Pötschke, Joachim Kirsch, Birgit Liss, Kerry L. Tucker and Rosanna Parlato

Antioxidants 2021, 10(8), 1284; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081284 - 13 Aug 2021

Cited by 5 | Viewed by 2886

Abstract

Primary cilia (PC) are microtubule-based protrusions of the cell membrane transducing molecular signals during brain development. Here, we report that PC are required for maintenance of Substantia nigra (SN) dopaminergic (DA) neurons highly vulnerable in Parkinson’s disease (PD). Targeted blockage of ciliogenesis in differentiated DA neurons impaired striato-nigral integrity in adult mice. The relative number of SN DA neurons displaying a typical auto-inhibition of spontaneous activity in response to dopamine was elevated under control metabolic conditions, but not under metabolic stress. Strikingly, in the absence of PC, the remaining SN DA neurons were less vulnerable to the PD neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP). Our data indicate conserved PC-dependent neuroadaptive responses to DA lesions in the striatum. Moreover, PC control the integrity and dopamine response of a subtype of SN DA neurons. These results reinforce the critical role of PC as sensors of metabolic stress in PD and other disorders of the dopamine system. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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16 pages, 1941 KiB

Open AccessArticle

A Grape Juice Supplemented with Natural Grape Extracts Is Well Accepted by Consumers and Reduces Brain Oxidative Stress

by Miriam Bobadilla, Carlos Hernández, María Ayala, Ixone Alonso, Ana Iglesias, Josune García-Sanmartín, Eduardo Mirpuri, José Ignacio Barriobero and Alfredo Martínez

Antioxidants 2021, 10(5), 677; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10050677 - 26 Apr 2021

Cited by 5 | Viewed by 3335

Abstract

Neurodegenerative diseases pose a major health problem for developed countries. Stress, which induces oxidation in the brain, has been identified as the main risk factor for these disorders. We have developed an antioxidant-enriched drink and have examined its protective properties against acute oxidative stress. We found that addition of red grape polyphenols and MecobalActive^® to grape juice did not provoke changes in juice organoleptic characteristics, and that the pasteurization process did not greatly affect the levels of flavonoids and vitamin B12. Out of all combinations, grape juice with red grape polyphenols was selected by expert judges (28.6% selected it as their first choice). In vivo, oral administration of grape juice supplemented with red grape polyphenols exerted an antioxidant effect in the brain of stressed mice reducing two-fold the expression of genes involved in inflammation and oxidation mechanisms and increasing three-fold the expression of genes related to protection against oxidative stress. In addition, we found that this drink augmented antioxidant enzyme activity (17.8 vs. 8.2 nmol/mg), and prevented lipid peroxidation in the brain (49.7 vs. 96.5 nmol/mg). Therefore, we propose supporting the use of this drink by the general population as a new and global strategy for the prevention of neurodegeneration. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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14 pages, 3777 KiB

Open AccessArticle

Melatonin Protects against the Side-Effects of 5-Fluorouracil on Hippocampal Neurogenesis and Ameliorates Antioxidant Activity in an Adult Rat Hippocampus and Prefrontal Cortex

by Kornrawee Suwannakot, Nataya Sritawan, Ram Prajit, Anusara Aranarochana, Apiwat Sirichoat, Wanassanun Pannangrong, Peter Wigmore and Jariya Umka Welbat

Antioxidants 2021, 10(4), 615; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10040615 - 16 Apr 2021

Cited by 24 | Viewed by 2865

Abstract

Melatonin is an endogenous hormone that exhibits antioxidant functions and neuroprotective effects. The hippocampus and the prefrontal cortex (PFC) play an important role linked to working memory. 5-fluorouracil (5-FU) can induce oxidative stress and reduce neurogenesis in the subgranular zone (SGZ) of the dentate gyrus in a rat hippocampus and these alterations are related to working memory deficits. This study aimed to determine the effect of melatonin on 5-FU-induced oxidative stress that interferes with the antioxidant enzymes and protein expression levels in a rat hippocampus and PFC. A total of 68 male Sprague Dawley rats were divided into four groups: vehicle, 5-FU, melatonin and melatonin+5-FU groups. Rats were administered 5-FU (25 mg/kg, i.v.) on days 9, 12, 15, 18 and 21 and received melatonin (8 mg/kg, i.p.) at 19:00 from day 1 to day 21 of the experiment. Lipid peroxidation was assessed by measuring malondialdehyde (MDA) levels. Antioxidant enzyme levels including glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) were determined. p21 immunofluorescence staining and Western blotting were used to detect the cell cycle arrest and protein expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), doublecortin (DCX) and brain derived neurotrophic factor (BDNF), respectively. The results showed that melatonin reduced the number of p21-positive cells in the SGZ of the dentate gyrus and increased Nrf2, DCX and BDNF protein expression in rats treated with 5-FU. Moreover, melatonin restored antioxidant enzyme levels and reduced oxidative stress in the hippocampus and PFC caused by 5-FU. These findings reveal a mechanism of the neuroprotective properties of melatonin against 5-FU in a rat hippocampus and PFC. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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21 pages, 9472 KiB

Open AccessArticle

Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson’s Disease

by Federica Rey, Sara Ottolenghi, Toniella Giallongo, Alice Balsari, Carla Martinelli, Robert Rey, Raffaele Allevi, Anna Maria Di Giulio, Gian Vincenzo Zuccotti, Serena Mazzucchelli, Roberta Foresti, Michele Samaja and Stephana Carelli

Antioxidants 2021, 10(1), 121; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10010121 - 15 Jan 2021

Cited by 28 | Viewed by 3706

Abstract

Existing therapies for Parkinson’s disease (PD) are only symptomatic. As erythropoietin (EPO) is emerging for its benefits in neurodegenerative diseases, here, we test the protective effect driven by EPO in in vitro (SH-SY5Y cells challenged by MPP⁺) and in vivo (C57BL/6J mice administered with MPTP) PD models. EPO restores cell viability in both protective and restorative layouts, enhancing the dopaminergic recovery. Specifically, EPO rescues the PD-induced damage to mitochondria, as shown by transmission electron microscopy, Mitotracker assay and PINK1 expression. Moreover, EPO promotes a rescue of mitochondrial respiration while markedly enhancing the glycolytic rate, as shown by the augmented extracellular acidification rate, contributing to elevated ATP levels in MPP⁺-challenged cells. In PD mice, EPO intrastriatal infusion markedly improves the outcome of behavioral tests. This is associated with the rescue of dopaminergic markers and decreased neuroinflammation. This study demonstrates cellular and functional recovery following EPO treatment, likely mediated by the 37 Kda isoform of the EPO-receptor. We report for the first time, that EPO-neuroprotection is exerted through restoring ATP levels by accelerating the glycolytic rate. In conclusion, the redox imbalance and neuroinflammation associated with PD may be successfully treated by EPO. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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Review

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27 pages, 958 KiB

Open AccessReview

Oxidative Stress in Optic Neuropathies

by Berta Sanz-Morello, Hamid Ahmadi, Rupali Vohra, Sarkis Saruhanian, Kristine Karla Freude, Steffen Hamann and Miriam Kolko

Antioxidants 2021, 10(10), 1538; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10101538 - 28 Sep 2021

Cited by 28 | Viewed by 3598

Abstract

Increasing evidence indicates that changes in the redox system may contribute to the pathogenesis of multiple optic neuropathies. Optic neuropathies are characterized by the neurodegeneration of the inner-most retinal neurons, the retinal ganglion cells (RGCs), and their axons, which form the optic nerve. Often, optic neuropathies are asymptomatic until advanced stages, when visual impairment or blindness is unavoidable despite existing treatments. In this review, we describe systemic and, whenever possible, ocular redox dysregulations observed in patients with glaucoma, ischemic optic neuropathy, optic neuritis, hereditary optic neuropathies (i.e., Leber’s hereditary optic neuropathy and autosomal dominant optic atrophy), nutritional and toxic optic neuropathies, and optic disc drusen. We discuss aspects related to anti/oxidative stress biomarkers that need further investigation and features related to study design that should be optimized to generate more valuable and comparable results. Understanding the role of oxidative stress in optic neuropathies can serve to develop therapeutic strategies directed at the redox system to arrest the neurodegenerative processes in the retina and RGCs and ultimately prevent vision loss. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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24 pages, 922 KiB

Open AccessReview

Preclinical Evidence for the Interplay between Oxidative Stress and RIP1-Dependent Cell Death in Neurodegeneration: State of the Art and Possible Therapeutic Implications

by Danuta Jantas and Władysław Lasoń

Antioxidants 2021, 10(10), 1518; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10101518 - 24 Sep 2021

Cited by 13 | Viewed by 3042

Abstract

Neurodegenerative diseases are the most frequent chronic, age-associated neurological pathologies having a major impact on the patient’s quality of life. Despite a heavy medical, social and economic burden they pose, no causative treatment is available for these diseases. Among the important pathogenic factors contributing to neuronal loss during neurodegeneration is elevated oxidative stress resulting from a disturbed balance between endogenous prooxidant and antioxidant systems. For many years, it was thought that increased oxidative stress was a cause of neuronal cell death executed via an apoptotic mechanism. However, in recent years it has been postulated that rather programmed necrosis (necroptosis) is the key form of neuronal death in the course of neurodegenerative diseases. Such assumption was supported by biochemical and morphological features of the dying cells as well as by the fact that various necroptosis inhibitors were neuroprotective in cellular and animal models of neurodegenerative diseases. In this review, we discuss the relationship between oxidative stress and RIP1-dependent necroptosis and apoptosis in the context of the pathomechanism of neurodegenerative disorders. Based on the published data mainly from cellular models of neurodegeneration linking oxidative stress and necroptosis, we postulate that administration of multipotential neuroprotectants with antioxidant and antinecroptotic properties may constitute an efficient pharmacotherapeutic strategy for the treatment of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Disease)

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