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Antioxidants
Special Issues
Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies
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Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies

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: 20 January 2025 | Viewed by 7147

Special Issue Editors

Prof. Dr. Ana M. Munoz

E-Mail Website
Guest Editor
1. Laboratory of Cell and Molecular Neurobiology of Parkinson's Disease, Department of Morphological Sciences, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
2. Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain
Interests: Parkinson's disease; dyskinesia; neurodegeneration; oxidative stress; neuroinflammation; neuroprotection
Dr. Jannette Rodríguez-Pallares

E-Mail Website
Guest Editor
1. Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
2. Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain
Interests: neuroscience; neurodegeneration; neuroprotection; cell therapy; Parkinson's disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are the leading causes of disability and dependency, and the second leading cause of mortality worldwide. With the increase in life expectancy, the incidence of neurodegenerative diseases and their global socioeconomic impact has increased considerably in recent years and is expected to increase further in the coming decades. Aging is one of the main risk factors for these diseases, accelerating the cellular death process. It has been described that different neurodegenerative diseases have common mechanisms underlying neuronal death, even when the symptoms and the areas of the nervous system affected are different. Oxidative stress and chronic neuroinflammation are common pathological mechanisms in diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis. Microglia activation could induce the release of cytokines and an upregulated production of reactive oxygen species leading to mitochondrial dysfunction and neuronal death.  Nevertheless, the mechanisms involved in the different diseases are not fully understood. Consistent with this, strategies modulating oxidative stress and neuroinflammatory pathways are proposed as effective therapies to counteract the progression of neurodegeneration, and numerous assays in experimental models and clinical trials are carried out. However, there is still no effective therapy for these diseases, and many issues should be addressed.   

This Special Issue aims to publish original research studies or reviews to broaden the knowledge of the mechanisms related to oxidative stress and neuroinflammation in neurodegenerative diseases to develop new therapeutical approaches targeting these pathways.

We invite you to submit your contribution to this Special Issue, and we are highly grateful to receive your manuscripts.

Prof. Dr. Ana M. Munoz
Dr. Jannette Rodríguez-Pallares
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegeneration
  • aging
  • neuroprotection
  • mitochondrial dysfunction
  • cytokines
  • apoptosis
  • autophagy
  • microglia
  • astroglia
  • antioxidants
  • free radicals

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Published Papers (7 papers)

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Research

18 pages, 3471 KiB  
Article
Hydrogen Sulfide Modulates Astrocytic Toxicity in Mouse Spinal Cord Cultures: Implications for Amyotrophic Lateral Sclerosis
by Susanna De Stefano, Marta Tiberi, Illari Salvatori, Marco De Bardi, Juliette Gimenez, Mahsa Pirshayan, Viviana Greco, Giovanna Borsellino, Alberto Ferri, Cristiana Valle, Nicola B. Mercuri, Valerio Chiurchiù, Alida Spalloni and Patrizia Longone
Antioxidants 2024, 13(10), 1241; https://doi.org/10.3390/antiox13101241 - 15 Oct 2024
Viewed by 336
Abstract
Hydrogen sulfide (H2S), a known inhibitor of the electron transport chain, is endogenously produced in the periphery as well as in the central nervous system, where is mainly generated by glial cells. It affects, as a cellular signaling molecule, many different [...] Read more.
Hydrogen sulfide (H2S), a known inhibitor of the electron transport chain, is endogenously produced in the periphery as well as in the central nervous system, where is mainly generated by glial cells. It affects, as a cellular signaling molecule, many different biochemical processes. In the central nervous system, depending on its concentration, it can be protective or damaging to neurons. In the study, we have demonstrated, in a primary mouse spinal cord cultures, that it is particularly harmful to motor neurons, is produced by glial cells, and is stimulated by inflammation. However, its role on glial cells, especially astrocytes, is still under-investigated. The present study was designed to evaluate the impact of H2S on astrocytes and their phenotypic heterogeneity, together with the functionality and homeostasis of mitochondria in primary spinal cord cultures. We found that H2S modulates astrocytes’ morphological changes and their phenotypic transformation, exerts toxic properties by decreasing ATP production and the mitochondrial respiration rate, disturbs mitochondrial depolarization, and alters the energetic metabolism. These results further support the hypothesis that H2S is a toxic mediator, mainly released by astrocytes, possibly acting as an autocrine factor toward astrocytes, and probably involved in the non-cell autonomous mechanisms leading to motor neuron death. Full article
(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies)
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19 pages, 7151 KiB  
Article
PET Imaging with [18F]ROStrace Detects Oxidative Stress and Predicts Parkinson’s Disease Progression in Mice
by Yi Zhu, Neha Kohli, Anthony Young, Malkah Sheldon, Jani Coni, Meera Rajasekaran, Lozen Robinson, Rea Chroneos, Shaipreeah Riley, Joseph W. Guarnieri, Joshua Jose, Nisha Patel, Douglas C. Wallace, Shihong Li, Hsiaoju Lee, Robert H. Mach and Meagan J. McManus
Antioxidants 2024, 13(10), 1226; https://doi.org/10.3390/antiox13101226 - 12 Oct 2024
Viewed by 653
Abstract
Although the precise molecular mechanisms responsible for neuronal death and motor dysfunction in late-onset Parkinson’s disease (PD) are unknown, evidence suggests that mitochondrial dysfunction and neuroinflammation occur early, leading to a collective increase in reactive oxygen species (ROS) production and oxidative stress. However, [...] Read more.
Although the precise molecular mechanisms responsible for neuronal death and motor dysfunction in late-onset Parkinson’s disease (PD) are unknown, evidence suggests that mitochondrial dysfunction and neuroinflammation occur early, leading to a collective increase in reactive oxygen species (ROS) production and oxidative stress. However, the lack of methods for tracking oxidative stress in the living brain has precluded its use as a potential biomarker. The goal of the current study is to address this need through the evaluation of the first superoxide (O2•−)-sensitive radioactive tracer, [18F]ROStrace, in a model of late-onset PD. To achieve this goal, MitoPark mice with a dopaminergic (DA) neuron-specific deletion of transcription factor A mitochondrial (Tfam) were imaged with [18F]ROStrace from the prodromal phase to the end-stage of PD-like disease. Our data demonstrate [18F]ROStrace was sensitive to increased oxidative stress during the early stages of PD-like pathology in MitoPark mice, which persisted throughout the disease course. Similarly to PD patients, MitoPark males had the most severe parkinsonian symptoms and metabolic impairment. [18F]ROStrace retention was also highest in MitoPark males, suggesting oxidative stress as a potential mechanism underlying the male sex bias of PD. Furthermore, [18F]ROStrace may provide a method to identify patients at risk of Parkinson’s before irreparable neurodegeneration occurs and enhance clinical trial design by identifying patients most likely to benefit from antioxidant therapies. Full article
(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies)
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31 pages, 7695 KiB  
Article
Unraveling the Protective Role of Oleocanthal and Its Oxidation Product, Oleocanthalic Acid, against Neuroinflammation
by Maria Cristina Barbalace, Michela Freschi, Irene Rinaldi, Lorenzo Zallocco, Marco Malaguti, Clementina Manera, Gabriella Ortore, Mariachiara Zuccarini, Maurizio Ronci, Doretta Cuffaro, Marco Macchia, Silvana Hrelia, Laura Giusti, Maria Digiacomo and Cristina Angeloni
Antioxidants 2024, 13(9), 1074; https://doi.org/10.3390/antiox13091074 - 3 Sep 2024
Viewed by 674
Abstract
Neuroinflammation is a critical aspect of various neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. This study investigates the anti-neuroinflammatory properties of oleocanthal and its oxidation product, oleocanthalic acid, using the BV-2 cell line activated with lipopolysaccharide. Our findings revealed that oleocanthal significantly [...] Read more.
Neuroinflammation is a critical aspect of various neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. This study investigates the anti-neuroinflammatory properties of oleocanthal and its oxidation product, oleocanthalic acid, using the BV-2 cell line activated with lipopolysaccharide. Our findings revealed that oleocanthal significantly inhibited the production of pro-inflammatory cytokines and reduced the expression of inflammatory genes, counteracted oxidative stress induced by lipopolysaccharide, and increased cell phagocytic activity. Conversely, oleocanthalic acid was not able to counteract lipopolysaccharide-induced activation. The docking analysis revealed a plausible interaction of oleocanthal, with both CD14 and MD-2 leading to a potential interference with TLR4 signaling. Since our data show that oleocanthal only partially reduces the lipopolysaccharide-induced activation of NF-kB, its action as a TLR4 antagonist alone cannot explain its remarkable effect against neuroinflammation. Proteomic analysis revealed that oleocanthal counteracts the LPS modulation of 31 proteins, including significant targets such as gelsolin, clathrin, ACOD1, and four different isoforms of 14-3-3 protein, indicating new potential molecular targets of the compound. In conclusion, oleocanthal, but not oleocanthalic acid, mitigates neuroinflammation through multiple mechanisms, highlighting a pleiotropic action that is particularly important in the context of neurodegeneration. Full article
(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies)
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28 pages, 8918 KiB  
Article
Targeting Circadian Protein Rev-erbα to Alleviate Inflammation, Oxidative Stress, and Enhance Functional Recovery Following Brain Trauma
by Arief Gunawan Darmanto, Jing-Shiun Jan, Ting-Lin Yen, Shin-Wei Huang, Ruei-Dun Teng, Jia-Yi Wang, Rajeev Taliyan, Joen-Rong Sheu and Chih-Hao Yang
Antioxidants 2024, 13(8), 901; https://doi.org/10.3390/antiox13080901 - 25 Jul 2024
Viewed by 695
Abstract
Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide, and its pathophysiology is characterized by oxidative stress and inflammation. Despite extensive research, effective treatments for TBI remain elusive. Recent studies highlighted the critical interplay between TBI and circadian rhythms, [...] Read more.
Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide, and its pathophysiology is characterized by oxidative stress and inflammation. Despite extensive research, effective treatments for TBI remain elusive. Recent studies highlighted the critical interplay between TBI and circadian rhythms, but the detailed regulation remains largely unknown. Motivated by the observed sustained decrease in Rev-erbα after TBI, we aimed to understand the critical role of Rev-erbα in the pathophysiology of TBI and determine its feasibility as a therapeutic target. Using a mouse model of TBI, we observed that TBI significantly downregulates Rev-erbα levels, exacerbating inflammatory and oxidative stress pathways. The regulation of Rev-erbα with either the pharmacological activator or inhibitor bidirectionally modulated inflammatory and oxidative events, which in turn influenced neurobehavioral outcomes, highlighting the protein’s protective role. Mechanistically, Rev-erbα influences the expression of key oxidative stress and inflammatory regulatory genes. A reduction in Rev-erbα following TBI likely contributes to increased oxidative damage and inflammation, creating a detrimental environment for neuronal survival and recovery which could be reversed via the pharmacological activation of Rev-erbα. Our findings highlight the therapeutic potential of targeting Rev-erbα to mitigate TBI-induced damage and improve outcomes, especially in TBI-susceptible populations with disrupted circadian regulation. Full article
(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies)
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12 pages, 3952 KiB  
Article
2-(4-Methylthiazol-5-yl) Ethyl Nitrate Hydrochloride Ameliorates Cognitive Impairment via Modulation of Oxidative Stress and Nuclear Factor Kappa B (NF-κB) Signaling Pathway in Chronic Cerebral Hypoperfusion-Associated Spontaneously Hypertensive Rats
by Jiang Li, Shaofeng Xu, Ling Wang and Xiaoliang Wang
Antioxidants 2024, 13(5), 585; https://doi.org/10.3390/antiox13050585 - 10 May 2024
Cited by 1 | Viewed by 976
Abstract
Hypertension reduces the bioavailability of vascular nitric oxide (NO) and contributes to the onset of vascular dementia (VaD). A loss of NO bioavailability increases inflammation and oxidative stress. 2-(4-Methylthiazol-5-yl) ethyl nitrate hydrochloride (W1302) is a novel nitric oxide donor (NOD) which is undergoing [...] Read more.
Hypertension reduces the bioavailability of vascular nitric oxide (NO) and contributes to the onset of vascular dementia (VaD). A loss of NO bioavailability increases inflammation and oxidative stress. 2-(4-Methylthiazol-5-yl) ethyl nitrate hydrochloride (W1302) is a novel nitric oxide donor (NOD) which is undergoing phase I clinical trials in China for the treatment of VaD. In this study, we investigated the protective effects of W1302 in VaD rats induced by the permanent occlusion of a bilateral common carotid arteries model related to spontaneous hypertension (SHR-2VO), and we further explored the underlying mechanisms. Nimodipine was used as a positive control. Our results showed that W1302 treatment for 4 weeks (10 mg/Kg/day) exhibited stronger improvement in the spatial learning and memory deficits in SHR-2VO rats compared with nimodipine with slightly lower systolic blood pressure (SBP). Meanwhile, W1302 treatment significantly increased NO and cGMP production, restored mitochondrial membrane potential and attenuated oxidative stress as evidenced by increasing ATP production and reducing malondialdehyde (MDA) levels in the brain. Furthermore, W1302 treatment markedly inhibited the iNOS activity and decreased TNF-α expression via inhibiting the nuclear factor kappa B (NF-κB) signaling pathway. Nimodipine treatment also restored these aberrant changes, but its ATP production was weaker than that of W1302, and there was no significant effect on NO release. Taken together, W1302 exhibited beneficial effects on complications in VaD with hypertension, which is involved in suppressing oxidative damage, and the inflammatory reaction might be mediated by an increase in NO release. Therefore, W1302 has therapeutic potential for the treatment of VaD caused by chronic cerebral hypoperfusion-associated spontaneous hypertension. Full article
(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies)
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16 pages, 2648 KiB  
Article
Selenium-Enriched E. coli Bacteria Mitigate the Age-Associated Degeneration of Cholinergic Neurons in C. elegans
by Palina Zytner, Anne Kutschbach, Weiye Gong, Verena Alexia Ohse, Laura Taudte, Anna Patricia Kipp, Lars-Oliver Klotz, Josephine Priebs and Holger Steinbrenner
Antioxidants 2024, 13(4), 492; https://doi.org/10.3390/antiox13040492 - 20 Apr 2024
Viewed by 1324
Abstract
Selenium (Se) is an essential trace element for humans and animals, but high-dose supplementation with Se compounds, most notably selenite, may exert cytotoxic and other adverse effects. On the other hand, bacteria, including Escherichia coli (E. coli), are capable of reducing [...] Read more.
Selenium (Se) is an essential trace element for humans and animals, but high-dose supplementation with Se compounds, most notably selenite, may exert cytotoxic and other adverse effects. On the other hand, bacteria, including Escherichia coli (E. coli), are capable of reducing selenite to red elemental Se that may serve as a safer Se source. Here, we examined how a diet of Se-enriched E. coli bacteria affected vital parameters and age-associated neurodegeneration in the model organism Caenorhabditis elegans (C. elegans). The growth of E. coli OP50 for 48 h in medium supplemented with 1 mM sodium selenite resulted in reddening of the bacterial culture, accompanied by Se accumulation in the bacteria. Compared to nematodes supplied with the standard E. coli OP50 diet, the worms fed on Se-enriched bacteria were smaller and slimmer, even though their food intake was not diminished. Nevertheless, given the choice, the nematodes preferred the standard diet. The fecundity of the worms was not affected by the Se-enriched bacteria, even though the production of progeny was somewhat delayed. The levels of the Se-binding protein SEMO-1, which serves as a Se buffer in C. elegans, were elevated in the group fed on Se-enriched bacteria. The occurrence of knots and ruptures within the axons of cholinergic neurons was lowered in aged nematodes provided with Se-enriched bacteria. In conclusion, C. elegans fed on Se-enriched E. coli showed less age-associated neurodegeneration, as compared to nematodes supplied with the standard diet. Full article
(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies)
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20 pages, 2192 KiB  
Article
Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer’s Disease
by Erica Staurenghi, Gabriella Testa, Valerio Leoni, Rebecca Cecci, Lucrezia Floro, Serena Giannelli, Eugenio Barone, Marzia Perluigi, Gabriella Leonarduzzi, Barbara Sottero and Paola Gamba
Antioxidants 2024, 13(4), 435; https://doi.org/10.3390/antiox13040435 - 3 Apr 2024
Viewed by 1561
Abstract
Down syndrome (DS) is a complex chromosomal disorder considered as a genetically determined form of Alzheimer’s disease (AD). Maintenance of brain cholesterol homeostasis is essential for brain functioning and development, and its dysregulation is associated with AD neuroinflammation and oxidative damage. Brain cholesterol [...] Read more.
Down syndrome (DS) is a complex chromosomal disorder considered as a genetically determined form of Alzheimer’s disease (AD). Maintenance of brain cholesterol homeostasis is essential for brain functioning and development, and its dysregulation is associated with AD neuroinflammation and oxidative damage. Brain cholesterol imbalances also likely occur in DS, concurring with the precocious AD-like neurodegeneration. In this pilot study, we analyzed, in the brain of the Ts2Cje (Ts2) mouse model of DS, the expression of genes encoding key enzymes involved in cholesterol metabolism and of the levels of cholesterol and its main precursors and products of its metabolism (i.e., oxysterols). The results showed, in Ts2 mice compared to euploid mice, the downregulation of the transcription of the genes encoding the enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and 24-dehydrocholesterol reductase, the latter originally recognized as an indicator of AD, and the consequent reduction in total cholesterol levels. Moreover, the expression of genes encoding enzymes responsible for brain cholesterol oxidation and the amounts of the resulting oxysterols were modified in Ts2 mouse brains, and the levels of cholesterol autoxidation products were increased, suggesting an exacerbation of cerebral oxidative stress. We also observed an enhanced inflammatory response in Ts2 mice, underlined by the upregulation of the transcription of the genes encoding for α-interferon and interleukin-6, two cytokines whose synthesis is increased in the brains of AD patients. Overall, these results suggest that DS and AD brains share cholesterol cycle derangements and altered oxysterol levels, which may contribute to the oxidative and inflammatory events involved in both diseases. Full article
(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Therapies)
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