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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 October 2022) | Viewed by 61028

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Prof. Dr. Marco Tulio Núñez

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Faculty of Sciences, Universidad de Chile, Santiago, Chile
Interests: iron homeostasis; neurodegenerative diseases; multi-target drugs; reactive oxygen species; iron/calcium interaction in the nervous system; intestinal iron absorption
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Dear Colleagues,

Growing evidence has indicated that oxidative stress, mitochondria dysfunction, inflammation, lysosomal dysfunction, protein aggregation, and iron deposition are key factors leading to neuronal death in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and a group of disorders known as neurodegeneration with brain iron accumulation. Most probably, several of these factors interact through positive feedback loops that conclude in neuronal dysfunction and death.

Recent developments link the function of mitochondria, which provides energy for the maintenance of neuronal homeostasis, and lysosomes, the major cellular organelle for iron recycling. Likewise, iron overload has been reported to associate with alterations of mitochondrial function as well as increased oxidative stress, autophagic defects, and diminished lysosomal function. Similarly, a link between iron, the endolysosomal system, and neuroinflammation has recently been proposed, and a positive feedback loop between oxidative stress, α-synuclein aggregation, and mitochondria dysfunction is firmly established.

The understanding of how these different players, mainly oxidative stress, protein aggregation, mitochondrial dysfunction, inflammation, and lysosomes, interact to generate neurodegeneration is an open field of huge importance. Equally relevant is the design of therapeutic strategies based on multifunctional drugs that target several or all these players in order to retard or stop the progress of these diseases.

Prof. Dr. Marco Tulio Núñez
Guest Editor

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Keywords

neurodegenerative diseases
oxidative stress and damage
ferroptosis
mitochondria dysfunction
protein aggregation
inflammation
multi-target drugs

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Published Papers (11 papers)

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Research

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13 pages, 1783 KiB

Open AccessArticle

α-Synuclein Toxicity in Drosophila melanogaster Is Enhanced by the Presence of Iron: Implications for Parkinson’s Disease

by Francesco Agostini, Luigi Bubacco, Sasanka Chakrabarti and Marco Bisaglia

Antioxidants 2023, 12(2), 261; https://doi.org/10.3390/antiox12020261 - 24 Jan 2023

Cited by 16 | Viewed by 3496

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by the preferential loss of dopaminergic neurons and by the accumulation of intracellular inclusions mainly composed of α-synuclein (α-Syn). While the etiopathogenesis of the disorder is still elusive, recent experimental evidence supports the involvement of ferroptosis, an iron-dependent cell death pathway, in the pathogenesis of PD. In the present work, using different ferroptosis inducers and inhibitors, we evaluated, in vivo, the involvement of iron in the α-Syn-mediated toxicity. Using a Drosophila melanogaster model of PD based on the selective over-expression of α-Syn within dopaminergic neurons, we demonstrated that the over-expression of α-Syn promotes the accumulation of protein aggregates, which is accompanied by dopaminergic neurodegeneration, locomotor impairment, and lifespan reduction. These pathological phenotypes were further exacerbated by reduced intracellular levels of glutathione or increased concentrations of iron. Coherently, both the use of an iron chelator and the presence of the antioxidant compound N-acetylcysteine exerted protective effects. Overall, our results support the involvement of ferroptosis in the α-Syn-mediated toxicity. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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21 pages, 5204 KiB

Open AccessArticle

Dynamic Metabolic and Transcriptional Responses of Proteasome-Inhibited Neurons

by Ilinca Suciu, Johannes Delp, Simon Gutbier, Anna-Katharina Ückert, Anna-Sophie Spreng, Philipp Eberhard, Christiaan Karreman, Falk Schreiber, Katrin Madjar, Jörg Rahnenführer, Ivana Celardo, Ivano Amelio and Marcel Leist

Antioxidants 2023, 12(1), 164; https://doi.org/10.3390/antiox12010164 - 10 Jan 2023

Cited by 7 | Viewed by 3724

Abstract

Proteasome inhibition is associated with parkinsonian pathology in vivo and degeneration of dopaminergic neurons in vitro. We explored here the metabolome (386 metabolites) and transcriptome (3257 transcripts) regulations of human LUHMES neurons, following exposure to MG-132 [100 nM]. This proteasome inhibitor killed cells within 24 h but did not reduce viability for 12 h. Overall, 206 metabolites were changed in live neurons. The early (3 h) metabolome changes suggested a compromised energy metabolism. For instance, AMP, NADH and lactate were up-regulated, while glycolytic and citric acid cycle intermediates were down-regulated. At later time points, glutathione-related metabolites were up-regulated, most likely by an early oxidative stress response and activation of NRF2/ATF4 target genes. The transcriptome pattern confirmed proteostatic stress (fast up-regulation of proteasome subunits) and also suggested the progressive activation of additional stress response pathways. The early ones (e.g., HIF-1, NF-kB, HSF-1) can be considered a cytoprotective cellular counter-regulation, which maintained cell viability. For instance, a very strong up-regulation of AIFM2 (=FSP1) may have prevented fast ferroptotic death. For most of the initial period, a definite life–death decision was not taken, as neurons could be rescued for at least 10 h after the start of proteasome inhibition. Late responses involved p53 activation and catabolic processes such as a loss of pyrimidine synthesis intermediates. We interpret this as a phase of co-occurrence of protective and maladaptive cellular changes. Altogether, this combined metabolomics–transcriptomics analysis informs on responses triggered in neurons by proteasome dysfunction that may be targeted by novel therapeutic intervention in Parkinson’s disease. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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15 pages, 2889 KiB

Open AccessArticle

Vitamin B3 Provides Neuroprotection via Antioxidative Stress in a Rat Model of Anterior Ischemic Optic Neuropathy

by Tu-Wen Chen, Po-Ying Wu, Yao-Tseng Wen, Tushar Dnyaneshwar Desai, Chin-Te Huang, Pei-Kang Liu and Rong-Kung Tsai

Antioxidants 2022, 11(12), 2422; https://doi.org/10.3390/antiox11122422 - 8 Dec 2022

Cited by 13 | Viewed by 3445

Abstract

Supplementing with vitamin B3 has been reported to protect against retinal ganglion cell (RGC) damage events and exhibit multiple neuroprotective properties in a mouse model of optic nerve injury. In this study, a rat model of anterior ischemic optic neuropathy was used to assess the neuroprotective benefits of vitamin B3 (rAION). Vitamin B3 (500 mg/kg/day) or phosphate-buffered saline (PBS) was administered to the rAION-induced rats every day for 28 days. The vitamin B3-treated group had significantly higher first positive and second negative peak (P1-N2) amplitudes of flash visual-evoked potentials and RGC densities than the PBS-treated group (p < 0.05). A terminal deoxynucleotidyl transferase dUTP nick end labeling assay conducted on vitamin B3-treated rats revealed a significant reduction in apoptotic cells (p < 0.05). Superoxide dismutase and thiobarbituric acid reactive substance activity showed that vitamin B3 treatment decreased reactive oxygen species (p < 0.05). Therefore, vitamin B3 supplementation preserves vision in rAION-induced rats by reducing oxidative stress, neuroinflammation, and mitochondrial apoptosis. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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11 pages, 1467 KiB

Open AccessArticle

Evaluation of Selected Oxidant/Antioxidant Parameters in Patients with Relapsing-Remitting Multiple Sclerosis Undergoing Disease-Modifying Therapies

by Anna Bizoń, Justyna Chojdak-Łukasiewicz, Aleksandra Kołtuniuk, Sławomir Budrewicz, Anna Pokryszko-Dragan and Agnieszka Piwowar

Antioxidants 2022, 11(12), 2416; https://doi.org/10.3390/antiox11122416 - 7 Dec 2022

Cited by 4 | Viewed by 2266

Abstract

The aim of this study was to evaluate oxidative stress parameters, specifically the concentration of advanced oxidation protein products (AOPP) and ferric-reducing antioxidant power (FRAP), in the serum of patients with relapsing-remitting multiple sclerosis (RRMS). We also analyzed the relationships between each parameter and selected clinical/laboratory multiple-sclerosis-related parameters. The study group comprised 204 patients with RRMS and 29 healthy, age-matched controls. The concentration of AOPP was significantly higher in the RRMS patients than in controls. ROC analysis showed the ability of AOPP to distinguish between the patients with RRMS and controls (the value of AUC was 94.8%, with a sensitivity of 89.69% and specificity of 89.3%). AOPP and FRAP were significantly higher in male than in female RRMS patients. Correlations were found between AOPP and the laboratory markers of inflammation. AOPP differed in the subgroups of patients treated with particular medications. Our findings indicate an increase in the markers of oxidative stress in the serum of RRMS patients, possibly linked with chronic inflammation. Gender and type of treatment affected the markers of oxidative stress. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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25 pages, 4418 KiB

Open AccessArticle

Lutein Decreases Inflammation and Oxidative Stress and Prevents Iron Accumulation and Lipid Peroxidation at Glutamate-Induced Neurotoxicity

by Ramóna Pap, Edina Pandur, Gergely Jánosa, Katalin Sipos, Tamás Nagy, Attila Agócs and József Deli

Antioxidants 2022, 11(11), 2269; https://doi.org/10.3390/antiox11112269 - 17 Nov 2022

Cited by 23 | Viewed by 3771

Abstract

The xanthophyll carotenoid lutein has been widely used as supplementation due to its protective effects in light-induced oxidative stress. Its antioxidant and anti-inflammatory features suggest that it has a neuroprotective role as well. Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), which plays a key role in regulating brain function. Excess accumulation of intracellular glutamate accelerates an increase in the concentration of reactive oxygen species (ROS) in neurons leading to glutamate neurotoxicity. In this study, we focused on the effects of glutamate on SH-SY5Y neuroblastoma cells to identify the possible alterations in oxidative stress, inflammation, and iron metabolism that affect the neurological function itself and in the presence of antioxidant lutein. First, ROS measurements were performed, and then catalase (CAT) and Superoxide Dismutase (SOD) enzyme activity were determined by enzyme activity assay kits. The ELISA technique was used to detect proinflammatory TNFα, IL-6, and IL-8 cytokine secretions. Alterations in iron uptake, storage, and release were followed by gene expression measurements and Western blotting. Total iron level detections were performed by a ferrozine-based iron detection method, and a heme assay kit was used for heme measurements. The gene expression toward lipid-peroxidation was determined by RT-PCR. Our results show glutamate changes ROS, inflammation, and antioxidant enzyme activity, modulate iron accumulation, and may initiate lipid peroxidation in SH-SY5Y cells. Meanwhile, lutein attenuates the glutamate-induced effects on ROS, inflammation, iron metabolism, and lipid peroxidation. According to our findings, lutein could be a beneficial, supportive treatment in neurodegenerative disorders. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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12 pages, 1558 KiB

Open AccessArticle

Antioxidant Response in Human X-Linked Adrenoleukodystrophy Fibroblasts

by Sara Petrillo, Jessica D’Amico, Francesco Nicita, Caterina Torda, Gessica Vasco, Enrico S. Bertini, Marco Cappa and Fiorella Piemonte

Antioxidants 2022, 11(11), 2125; https://doi.org/10.3390/antiox11112125 - 28 Oct 2022

Cited by 6 | Viewed by 2513

Abstract

Redox imbalance, mitochondrial dysfunction, and inflammation play a major role in the pathophysiology of X-linked adrenoleukodystrophy (X-ALD), an inherited neurodegenerative disease caused by mutations in the ABCD1 gene, encoding the protein responsible for peroxisomal import and degradation of very long chain fatty acids (VLCFAs). Therefore, VLCFAs accumulate in tissues and plasma, constituting a pathognomonic biomarker for diagnosis. However, the precise role of VLCFA accumulation on the diverse clinical phenotypes of X-ALD and the pathogenic link between VLCFAs and oxidative stress remain currently unclear. This study proposes ferroptosis as a crucial contributor to the disease development and progression. The expression profiles of “GPX4-glutathione” and “NQO1-CoQ₁₀” ferroptosis pathways have been analyzed in fibroblasts of one patient with AMN, the late onset and slowly progressive form of X-ALD, and in two patients with cALD, the cerebral inflammatory demyelinating form of early childhood. Furthermore, as no effective treatments are currently available, especially for the rapidly progressing form of X-ALD (cALD), the efficacy of NAC treatment has also been evaluated to open the way toward novel combined therapies. Our findings demonstrate that lipid peroxides accumulate in X-ALD fibroblasts and ferroptosis-counteracting enzymes are dysregulated, highlighting a different antioxidant response in patients with AMN and cALD. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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14 pages, 2585 KiB

Open AccessArticle

New Players in Neuronal Iron Homeostasis: Insights from CRISPRi Studies

by Daniel A. Bórquez, Francisco Castro, Marco T. Núñez and Pamela J. Urrutia

Antioxidants 2022, 11(9), 1807; https://doi.org/10.3390/antiox11091807 - 14 Sep 2022

Cited by 3 | Viewed by 3225

Abstract

Selective regional iron accumulation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The underlying mechanisms of neuronal iron dyshomeostasis have been studied, mainly in a gene-by-gene approach. However, recent high-content phenotypic screens using CRISPR/Cas9-based gene perturbations allow for the identification of new pathways that contribute to iron accumulation in neuronal cells. Herein, we perform a bioinformatic analysis of a CRISPR-based screening of lysosomal iron accumulation and the functional genomics of human neurons derived from induced pluripotent stem cells (iPSCs). Consistent with previous studies, we identified mitochondrial electron transport chain dysfunction as one of the main mechanisms triggering iron accumulation, although we substantially expanded the gene set causing this phenomenon, encompassing mitochondrial complexes I to IV, several associated assembly factors, and coenzyme Q biosynthetic enzymes. Similarly, the loss of numerous genes participating through the complete macroautophagic process elicit iron accumulation. As a novelty, we found that the impaired synthesis of glycophosphatidylinositol (GPI) and GPI-anchored protein trafficking also trigger iron accumulation in a cell-autonomous manner. Finally, the loss of critical components of the iron transporters trafficking machinery, including MON2 and PD-associated gene VPS35, also contribute to increased neuronal levels. Our analysis suggests that neuronal iron accumulation can arise from the dysfunction of an expanded, previously uncharacterized array of molecular pathways. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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27 pages, 2652 KiB

Open AccessArticle

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer’s Disease

by Alessia Carocci, Alexia Barbarossa, Rosalba Leuci, Antonio Carrieri, Leonardo Brunetti, Antonio Laghezza, Marco Catto, Francesco Limongelli, Sílvia Chaves, Paolo Tortorella, Cosimo Damiano Altomare, Maria Amélia Santos, Fulvio Loiodice and Luca Piemontese

Antioxidants 2022, 11(9), 1631; https://doi.org/10.3390/antiox11091631 - 23 Aug 2022

Cited by 14 | Viewed by 3410

Abstract

Alzheimer’s disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Aβ_1-40 aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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21 pages, 1588 KiB

Open AccessFeature PaperReview

Multifunctional Metallothioneins as a Target for Neuroprotection in Parkinson’s Disease

by Ikuko Miyazaki and Masato Asanuma

Antioxidants 2023, 12(4), 894; https://doi.org/10.3390/antiox12040894 - 6 Apr 2023

Cited by 13 | Viewed by 5811

Abstract

Parkinson’s disease (PD) is characterized by motor symptoms based on a loss of nigrostriatal dopaminergic neurons and by non-motor symptoms which precede motor symptoms. Neurodegeneration accompanied by an accumulation of α-synuclein is thought to propagate from the enteric nervous system to the central nervous system. The pathogenesis in sporadic PD remains unknown. However, many reports indicate various etiological factors, such as oxidative stress, inflammation, α-synuclein toxicity and mitochondrial impairment, drive neurodegeneration. Exposure to heavy metals contributes to these etiopathogenesis and increases the risk of developing PD. Metallothioneins (MTs) are cysteine-rich metal-binding proteins; MTs chelate metals and inhibit metal-induced oxidative stress, inflammation and mitochondrial dysfunction. In addition, MTs possess antioxidative properties by scavenging free radicals and exert anti-inflammatory effects by suppression of microglial activation. Furthermore, MTs recently received attention as a potential target for attenuating metal-induced α-synuclein aggregation. In this article, we summarize MTs expression in the central and enteric nervous system, and review protective functions of MTs against etiopathogenesis in PD. We also discuss neuroprotective strategies for the prevention of central dopaminergic and enteric neurodegeneration by targeting MTs. This review highlights multifunctional MTs as a target for the development of disease-modifying drugs for PD. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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30 pages, 1601 KiB

Open AccessReview

Oxidative Stress and Antioxidants in Neurodegenerative Disorders

by Edward O. Olufunmilayo, Michelle B. Gerke-Duncan and R. M. Damian Holsinger

Antioxidants 2023, 12(2), 517; https://doi.org/10.3390/antiox12020517 - 18 Feb 2023

Cited by 267 | Viewed by 23997

Abstract

Neurodegenerative disorders constitute a substantial proportion of neurological diseases with significant public health importance. The pathophysiology of neurodegenerative diseases is characterized by a complex interplay of various general and disease-specific factors that lead to the end point of neuronal degeneration and loss, and the eventual clinical manifestations. Oxidative stress is the result of an imbalance between pro-oxidant species and antioxidant systems, characterized by an elevation in the levels of reactive oxygen and reactive nitrogen species, and a reduction in the levels of endogenous antioxidants. Recent studies have increasingly highlighted oxidative stress and associated mitochondrial dysfunction to be important players in the pathophysiologic processes involved in neurodegenerative conditions. In this article, we review the current knowledge of the general effects of oxidative stress on the central nervous system, the different specific routes by which oxidative stress influences the pathophysiologic processes involved in Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease, and how oxidative stress may be therapeutically reversed/mitigated in order to stall the pathological progression of these neurodegenerative disorders to bring about clinical benefits. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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31 pages, 2995 KiB

Open AccessReview

On the Chemical and Biological Characteristics of Multifunctional Compounds for the Treatment of Parkinson’s Disease

by Olimpo García-Beltrán, Pamela J. Urrutia and Marco T. Núñez

Antioxidants 2023, 12(2), 214; https://doi.org/10.3390/antiox12020214 - 17 Jan 2023

Cited by 13 | Viewed by 3953

Abstract

Protein aggregation, mitochondrial dysfunction, iron dyshomeostasis, increased oxidative damage and inflammation are pathognomonic features of Parkinson’s disease (PD) and other neurodegenerative disorders characterized by abnormal iron accumulation. Moreover, the existence of positive feed-back loops between these pathological components, which accelerate, and sometimes make irreversible, the neurodegenerative process, is apparent. At present, the available treatments for PD aim to relieve the symptoms, thus improving quality of life, but no treatments to stop the progression of the disease are available. Recently, the use of multifunctional compounds with the capacity to attack several of the key components of neurodegenerative processes has been proposed as a strategy to slow down the progression of neurodegenerative processes. For the treatment of PD specifically, the necessary properties of new-generation drugs should include mitochondrial destination, the center of iron-reactive oxygen species interaction, iron chelation capacity to decrease iron-mediated oxidative damage, the capacity to quench free radicals to decrease the risk of ferroptotic neuronal death, the capacity to disrupt α-synuclein aggregates and the capacity to decrease inflammatory conditions. Desirable additional characteristics are dopaminergic neurons to lessen unwanted secondary effects during long-term treatment, and the inhibition of the MAO-B and COMPT activities to increase intraneuronal dopamine content. On the basis of the published evidence, in this work, we review the molecular basis underlying the pathological events associated with PD and the clinical trials that have used single-target drugs to stop the progress of the disease. We also review the current information on multifunctional compounds that may be used for the treatment of PD and discuss the chemical characteristics that underlie their functionality. As a projection, some of these compounds or modifications could be used to treat diseases that share common pathology features with PD, such as Friedreich’s ataxia, Multiple sclerosis, Huntington disease and Alzheimer’s disease. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Neurodegenerative Disorders)

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