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Antioxidants
Special Issues
Reactive Oxygen Species in Central Nervous System Disorders
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Reactive Oxygen Species in Central Nervous System Disorders

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 (15 June 2022) | Viewed by 15953

Special Issue Editors

Dr. Tawfeeq Shekh-Ahmad

E-Mail Website
Guest Editor
The Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Interests: neurodegenerative diseases; epilepsy; epileptogenesis; oxidative stress; Keap1-Nrf2 pathway; NADPH oxidase enzyme; gene therapy for CNS disorders
Prof. Dr. Ron Kohen

E-Mail Website
Guest Editor
Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Interests: antioxidants; skin oxidative stress; skin microbiome; skin defense mechanisms; Nrf2-keap1 pathway; skin aging; non-invasive techniques; biological redox

Special Issue Information

Dear Colleagues,

A large body of evidence has been accumulated that reactive oxygen species (ROS) play key roles in normal central nervous system (CNS) function, as well as in the pathophysiological context of many neurological diseases.

ROS regulate crucial physiological processes, however, when available in excess, these molecules react with lipids, proteins, and nucleic acids, and are thus responsible for structural and functional alterations of target molecules, leading to extensive tissue dysfunction and injury. ROS have been implicated in the development of several CNS diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, Huntington's disease and others.

Despite the extensive pre-clinical data available on the involvement of ROS in CNS diseases, there is still no conclusive evidence on the potential sources of ROS in these CNS diseases or on the molecular mechanism of which ROS is responsible for cell damage or cell death. Moreover, little is known on the role of ROS in the pathophysiology of these diseases in humans. However, to date antioxidant therapies for CNS diseases have largely failed, and none have demonstrated any substantial benefit in patients.

Altogether, the belief remains that ROS do contribute to many CNS diseases, however, a better understanding of the specific ROS type and the major source that contributes to their burden is required, as well as a better understanding of how these ROS are involved in each disease for better targeting, and developing more promising antioxidant therapies.

In this Special Issue entitled “Reactive Oxygen Species in Central Nervous System Disorders”, we invite researchers to provide original research articles as well as review articles on the role of ROS in different CNS disorders, the potential mechanism by which ROS may contribute to the pathology of these diseases, and on potential treatment strategies for targeting ROS in the CNS.

Dr. Tawfeeq Shekh-Ahmad
Prof. Dr. Ron Kohen
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

  • Reactive oxygen species
  • Free radicals
  • Oxidative stress
  • Superoxide
  • Hydroxyl radical
  • Hydrogen peroxide
  • Antioxidant enzymes
  • Neurodegenerative disorders
  • Alzheimer's disease
  • Parkinson's disease
  • Epilepsy
  • Multiple sclerosis
  • Huntington's disease

Published Papers (6 papers)

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Research

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14 pages, 2202 KiB  
Article
LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma
by Alessia Filippone, Deborah Mannino, Laura Cucinotta, Irene Paterniti, Emanuela Esposito and Michela Campolo
Antioxidants 2022, 11(9), 1634; https://doi.org/10.3390/antiox11091634 - 23 Aug 2022
Cited by 3 | Viewed by 1837
Abstract
Spinal cord injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade, and immune system. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with Parkinson’s disease (PD), moreover, its kinase activity was found to be upregulated after instigated [...] Read more.
Spinal cord injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade, and immune system. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with Parkinson’s disease (PD), moreover, its kinase activity was found to be upregulated after instigated inflammation of the central nervous system (CNS). Here, we aimed to investigate the PF06447475 (abbreviated as PF-475) role as a pharmacological LRRK2 antagonist by counteracting pathological consequences of spinal cord trauma. The in vivo model of SCI was induced by extradural compression of the spinal cord, then mice were treated with PF0-475 (2.5–5 and 10 mg/kg i.p) 1 and 6 h after SCI. We found that PF-475 treatments at the higher doses (5 and 10 mg/kg) showed a great ability to significantly reduce the degree of spinal cord tissue injury, glycogen accumulation, and demyelination of neurons associated with trauma. Furthermore, oxidative stress and cytokines expression levels, including interleukins (IL-1, IL-6, IL-10, and 12), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), secreted and released after trauma were decreased by LRRK2 antagonist treatments. Our results suggest that the correlations between LRRK2 and inflammation of the CNS exist and that LRRK2 activity targeting could have direct effects on the intervention of neuroinflammatory disorders. Full article
(This article belongs to the Special Issue Reactive Oxygen Species in Central Nervous System Disorders)
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19 pages, 1303 KiB  
Article
A Novel Pathway Phenotype of Temporal Lobe Epilepsy and Comorbid Psychiatric Disorders: Results of Precision Nomothetic Medicine
by Michael Maes, Décio Sabbatini Barbosa, Abbas F. Almulla and Buranee Kanchanatawan
Antioxidants 2022, 11(5), 803; https://doi.org/10.3390/antiox11050803 - 20 Apr 2022
Cited by 4 | Viewed by 2071
Abstract
No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities have been developed to date. This observational study aimed to develop a precision nomothetic, data-driven comorbid TLE model with endophenotype classes and pathway phenotypes that may have prognostic and therapeutical [...] Read more.
No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities have been developed to date. This observational study aimed to develop a precision nomothetic, data-driven comorbid TLE model with endophenotype classes and pathway phenotypes that may have prognostic and therapeutical implications. We recruited forty healthy controls and 108 TLE patients for this research and assessed TLE and psychopathology (PP) features as well as oxidative stress (OSTOX, e.g., malondialdehyde or MDA, lipid hydroperoxides, and advanced oxidation protein products) and antioxidant (paraoxonase 1 or PON1 status, -SH groups, and total radical trapping potential or TRAP) biomarkers. A large part (57.2%) of the variance in a latent vector (LV) extracted from the above TLE and PP features was explained by these OSTOX and antioxidant biomarkers. The PON1 Q192R genetic variant showed indirect effects on this LV, which were completely mediated by PON1 activity and MDA. Factor analysis showed that a common core could be extracted from TLE, PP, OSTOX and antioxidant scores, indicating that these features are manifestations of a common underlying construct, i.e., a novel pathway phenotype of TLE. Based on the latter, we constructed a new phenotype class that is characterized by increased severity of TLE, PP and OSTOX features and lowered antioxidant defenses. A large part of the variance in episode frequency was explained by increased MDA, lowered antioxidant, and nitric oxide metabolite levels. In conclusion, (a) PP symptoms belong to the TLE phenome, and the signal increased severity; and (b) cumulative effects of aldehyde formation and lowered antioxidants determine epileptogenic kindling. Full article
(This article belongs to the Special Issue Reactive Oxygen Species in Central Nervous System Disorders)
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16 pages, 18572 KiB  
Article
Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model
by Sereen Sandouka and Tawfeeq Shekh-Ahmad
Antioxidants 2021, 10(11), 1702; https://doi.org/10.3390/antiox10111702 - 27 Oct 2021
Cited by 17 | Viewed by 2712
Abstract
Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by [...] Read more.
Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development. Full article
(This article belongs to the Special Issue Reactive Oxygen Species in Central Nervous System Disorders)
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10 pages, 1807 KiB  
Article
RT001 in Progressive Supranuclear Palsy—Clinical and In-Vitro Observations
by Plamena R. Angelova, Kristin M. Andruska, Mark G. Midei, Mario Barilani, Paldeep Atwal, Oliver Tucher, Peter Milner, Frederic Heerinckx and Mikhail S. Shchepinov
Antioxidants 2021, 10(7), 1021; https://doi.org/10.3390/antiox10071021 - 25 Jun 2021
Cited by 8 | Viewed by 2645
Abstract
Progressive supranuclear palsy (PSP) is a progressive movement disorder associated with lipid peroxidation and intracerebral accumulation of tau. RT001 is a deuterium reinforced isotopologue of linoleic acid that prevents lipid peroxidation (LPO) through the kinetic isotope effect. The effects of RT001 pre-treatment on [...] Read more.
Progressive supranuclear palsy (PSP) is a progressive movement disorder associated with lipid peroxidation and intracerebral accumulation of tau. RT001 is a deuterium reinforced isotopologue of linoleic acid that prevents lipid peroxidation (LPO) through the kinetic isotope effect. The effects of RT001 pre-treatment on various oxidative and bioenergetic parameters were evaluated in mesenchymal stem cells (MSC) derived from patients with PSP compared to controls. In parallel, 3 patients with PSP were treated with RT001 and followed clinically. MSCs derived from PSP patients had a significantly higher rate of LPO (161.8 ± 8.2% of control; p < 0.001). A 72-h incubation with RT001 restored the PSP MSCs to normal levels. Mitochondrial reactive oxygen species (ROS) overproduction in PSP-MSCs significantly decreased the level of GSH compared to control MSCs (to 56% and 47% of control; p < 0.05). Incubation with RT001 significantly increased level of GSH in PSP MSCs. The level of mitochondrial DNA in the cells was significantly lower in PSP-MSCs (67.5%), compared to control MSCs. Changes in mitochondrial membrane potential, size, and shape were also observed. Three subjects with possible or probable PSP were treated with RT001 for a mean duration of 26 months. The slope of the PSPRS changed from the historical decline of 0.91 points/month to a mean decline of 0.16 points/month (+/−0.23 SEM). The UPDRS slope changed from an expected increase of 0.95 points/month to an average increase in score of 0.28 points/month (+/−0.41 SEM). MSCs derived from patients with PSP have elevated basal levels of LPO, ROS, and mitochondrial dysfunction. These findings are reversed after incubation with RT001. In PSP patients, the progression of disease may be reduced by treatment with RT001. Full article
(This article belongs to the Special Issue Reactive Oxygen Species in Central Nervous System Disorders)
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Review

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26 pages, 3407 KiB  
Review
The Potential Role of m6A in the Regulation of TBI-Induced BGA Dysfunction
by Peizan Huang, Min Liu, Jing Zhang, Xiang Zhong and Chunlong Zhong
Antioxidants 2022, 11(8), 1521; https://doi.org/10.3390/antiox11081521 - 04 Aug 2022
Cited by 4 | Viewed by 2926
Abstract
The brain–gut axis (BGA) is an important bidirectional communication pathway for the development, progress and interaction of many diseases between the brain and gut, but the mechanisms remain unclear, especially the post-transcriptional regulation of BGA after traumatic brain injury (TBI). RNA methylation is [...] Read more.
The brain–gut axis (BGA) is an important bidirectional communication pathway for the development, progress and interaction of many diseases between the brain and gut, but the mechanisms remain unclear, especially the post-transcriptional regulation of BGA after traumatic brain injury (TBI). RNA methylation is one of the most important modifications in post-transcriptional regulation. N6-methyladenosine (m6A), as the most abundant post-transcriptional modification of mRNA in eukaryotes, has recently been identified and characterized in both the brain and gut. The purpose of this review is to describe the pathophysiological changes in BGA after TBI, and then investigate the post-transcriptional bidirectional regulation mechanisms of TBI-induced BGA dysfunction. Here, we mainly focus on the characteristics of m6A RNA methylation in the post-TBI BGA, highlight the possible regulatory mechanisms of m6A modification in TBI-induced BGA dysfunction, and finally discuss the outcome of considering m6A as a therapeutic target to improve the recovery of the brain and gut dysfunction caused by TBI. Full article
(This article belongs to the Special Issue Reactive Oxygen Species in Central Nervous System Disorders)
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20 pages, 2181 KiB  
Review
Oxidative Stress as a Potential Mechanism Underlying Membrane Hyperexcitability in Neurodegenerative Diseases
by Ricardo Pardillo-Díaz, Patricia Pérez-García, Carmen Castro, Pedro Nunez-Abades and Livia Carrascal
Antioxidants 2022, 11(8), 1511; https://doi.org/10.3390/antiox11081511 - 02 Aug 2022
Cited by 11 | Viewed by 2683
Abstract
Neurodegenerative diseases are characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems that produce brain damage from which there is no recovery. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear to be similar, suggesting [...] Read more.
Neurodegenerative diseases are characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems that produce brain damage from which there is no recovery. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear to be similar, suggesting common neurodegenerative pathways. It is well known that oxidative stress and the production of reactive oxygen radicals plays a key role in neuronal cell damage. It has been proposed that this stress, among other mechanisms, could contribute to neuronal degeneration and might be one of the factors triggering the development of these pathologies. Another common feature in most neurodegenerative diseases is neuron hyperexcitability, an aberrant electrical activity. This review, focusing mainly on primary motor cortex pyramidal neurons, critically evaluates the idea that oxidative stress and inflammation may be involved in neurodegeneration via their capacity to increase membrane excitability. Full article
(This article belongs to the Special Issue Reactive Oxygen Species in Central Nervous System Disorders)
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