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Oxidative Stress in Neurodegeneration

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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 (10 October 2022) | Viewed by 22587

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Prof. Dr. Barbara Tavazzi

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Departmental Faculty of Medicine and Surgery, UniCamillus-Saint Camillus International University of Health and Medical Sciences, via di Sant’Alessandro 8, 00131 Rome, Italy
Interests: neurodegenerative acute (traumatic brain injury) and chronic (multiple sclerosis) disorders; oxidative and nitrosative stresses; oxidation mechanisms; antioxidants; metabolomics; biochemical analytical techniques; lipid peroxidation products; dietary antioxidants; carotenoids; polyphenols; vitamin E; vitamin C; antioxidant activity/capacity
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Prof. Dr. Giacomo Lazzarino

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UniCamillus—Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy
Interests: mitochondrial dysfunction; oxidative/nitrosative stress; neurodegenerations; multiple sclerosis; traumatic brain injury; metabolic cell reprogramming
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Special Issue Information

Dear Colleagues,

Carrying out a search on PubMed for “Oxidative Stress + neurodegeneration” on 16 February 2022, we found that 7953 full-length papers have been published to that date. This highlights the central role displayed by oxidative stress in the pathobiological mechanisms of development and progression of acute (stroke, traumatic brain injury) and chronic (amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, etc.) neurodegenerations. A better understanding of biochemical/metabolic/molecular processes involving the raising of oxidative stress in acute and chronic neurodegenerations may represent the main road to increasing our knowledge regarding the molecular mechanisms responsible for cellular malfunctioning and also for the development of new effective pharmacological approaches.

The goal of this Special Issue is to provide new advances connecting alterations of the pattern of antioxidants and scavenger compounds, mitochondrial dysfunction, imbalance of energy metabolism, and oxidative stress with onset and/or progression of acute and chronic neurodegenerations, either obtained in experimental cellular/animal models or in clinical studies. Papers reporting data on new drug treatments aiming to reduce or avoid oxidative stress are highly welcome. Reviews highlighting the most recent information in specific acute or chronic neurodegenerative disease will also be taken into consideration.

Prof. Dr. Barbara Tavazzi
Prof. Dr. Giacomo Lazzarino
Guest Editors

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Published Papers (9 papers)

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Research

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27 pages, 3517 KiB

Open AccessArticle

N-Acetylcysteine Treatment May Compensate Motor Impairments through Dopaminergic Transmission Modulation in a Striatal 6-Hydroxydopamine Parkinson’s Disease Rat Model

by Rita Caridade-Silva, Bruna Araújo, Joana Martins-Macedo and Fábio G. Teixeira

Antioxidants 2023, 12(6), 1257; https://doi.org/10.3390/antiox12061257 - 11 Jun 2023

Cited by 1 | Viewed by 2767

Abstract

Preventing degeneration and the loss of dopaminergic neurons (DAn) in the brain while mitigating motor symptoms remains a challenge in Parkinson’s Disease (PD) treatment development. In light of this, developing or repositioning potential disease-modifying approaches is imperative to achieve meaningful translational gains in PD research. Under this concept, N-acetylcysteine (NAC) has revealed promising perspectives in preserving the dopaminergic system capability and modulating PD mechanisms. Although NAC has been shown to act as an antioxidant and (neuro)protector of the brain, it has yet to be acknowledged how this repurposed drug can improve motor symptomatology and provide disease-modifying properties in PD. Therefore, in the present work, we assessed the impact of NAC on motor and histological deficits in a striatal 6-hydroxydopamine (6-OHDA) rat model of PD. The results revealed that NAC enhanced DAn viability, as we found that it could restore dopamine transporter (DAT) levels compared to the untreated 6-OHDA group. Such findings were positively correlated with a significant amelioration in the motor outcomes of the 6-OHDA-treated animals, demonstrating that NAC may, somehow, be a modulator of PD degenerative mechanisms. Overall, we postulated a proof-of-concept milestone concerning the therapeutic application of NAC. Nevertheless, it is extremely important to understand the complexity of this drug and how its therapeutical properties interact with the cellular and molecular PD mechanisms. Full article

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

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22 pages, 3964 KiB

Open AccessArticle

Voltage-Gated Proton Channel Hv1 Regulates Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson’s Disease Models

by Matthew L. Neal, Eric E. Beier, Muhammad M. Hossain, Alexa Boyle, Jiaying Zheng, Chunki Kim, Isha Mhatre-Winters, Long-Jun Wu and Jason R. Richardson

Antioxidants 2023, 12(3), 582; https://doi.org/10.3390/antiox12030582 - 25 Feb 2023

Cited by 2 | Viewed by 2214

Abstract

Although the precise mechanisms for neurodegeneration in Parkinson’s disease (PD) are unknown, evidence suggests that neuroinflammation is a critical factor in the pathogenic process. Here, we sought to determine whether the voltage-gated proton channel, Hv1 (HVCN1), which is expressed in microglia and regulates NADPH oxidase, is associated with dopaminergic neurodegeneration. We utilized data mining to evaluate the mRNA expression of HVCN1 in the brains of PD patients and controls and uncovered increased expression of the gene encoding Hv1, HVCN1, in the brains of PD patients compared to controls, specifically in male PD patients. In an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 × 16 mg/kg) mouse model of PD, Hvcn1 gene expression was increased 2-fold in the striatum. MPTP administration to wild-type (WT) mice resulted in a ~65% loss of tyrosine hydroxylase positive neurons (TH⁺) in the substantia nigra (SN), while a ~39% loss was observed in Hv1 knockout (KO) mice. Comparable neuroprotective effects of Hv1 deficiency were found in a repeated-dose LPS model. Neuroprotection was associated with decreased pro-inflammatory cytokine levels and pro-oxidant factors in both neurotoxicant animal models. These in vivo results were confirmed in primary microglial cultures, with LPS treatment increasing Hvcn1 mRNA levels and Hv1 KO microglia failing to exhibit the LPS-mediated inflammatory response. Conditioned media from Hv1 KO microglia treated with LPS resulted in an attenuated loss of cultured dopamine neuron cell viability compared to WT microglia. Taken together, these data suggest that Hv1 is upregulated and mediates microglial pro-inflammatory cytokine production in parkinsonian models and therefore represents a novel target for neuroprotection. Full article

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

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20 pages, 11769 KiB

Open AccessArticle

Oxidative Damages on the Alzheimer’s Related-Aβ Peptide Alters Its Ability to Assemble

by Clémence Cheignon, Fabrice Collin, Laurent Sabater and Christelle Hureau

Antioxidants 2023, 12(2), 472; https://doi.org/10.3390/antiox12020472 - 13 Feb 2023

Viewed by 1461

Abstract

Oxidative stress that can lead to oxidation of the amyloid-β (Aβ) peptide is considered a key feature in Alzheimer’s disease (AD), influencing the ability of Aβ to assemble into β-sheet rich fibrils that are commonly found in senile plaques of AD patients. The present study aims at investigating the fallouts of Aβ oxidation on the assembly properties of the Aβ peptide. To accomplish this, we performed kinetics and analysis on an oxidized Aβ (^oxAβ) peptide, resulting from the attack of reactive oxygen species (ROS) that are formed by the biologically relevant Cu/Aβ/dioxygen/ascorbate system. ^oxAβ was still able to assemble but displayed ill-defined and small oligomeric assemblies compared to the long and thick β-sheet rich fibrils from the non-oxidized counterpart. In addition, ^oxAβ does affect the assembly of the parent Aβ peptide. In a mixture of the two peptides, ^oxAβ has a mainly kinetic effect on the assembly of the Aβ peptide and was able to slow down the formation of Aβ fibril in a wide pH range [6.0–7.4]. However, ^oxAβ does not change the quantity and morphology of the Aβ fibrils formed to a significant extent. In the presence of copper or zinc di-cations, ^oxAβ assembled into weakly-structured aggregates rather than short, untangled Cu-Aβ fibrils and long untangled Zn-Aβ fibrils. The delaying effect of ^oxAβ on metal altered Aβ assembly was also observed. Hence, our results obtained here bring new insights regarding the tight interconnection between (i) ROS production leading to Aβ oxidation and (ii) Aβ assembly, in particular via the modulation of the Aβ assembly by ^oxAβ. It is the first time that co-assembly of ^oxAβ and Aβ under various environmental conditions (pH, metal ions …) are reported. Full article

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

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22 pages, 1166 KiB

Open AccessArticle

Genetic Polymorphisms in Oxidative Stress and Inflammatory Pathways as Potential Biomarkers in Alzheimer’s Disease and Dementia

by David Vogrinc, Milica Gregorič Kramberger, Andreja Emeršič, Saša Čučnik, Katja Goričar and Vita Dolžan

Antioxidants 2023, 12(2), 316; https://doi.org/10.3390/antiox12020316 - 29 Jan 2023

Cited by 5 | Viewed by 1910

Abstract

Oxidative stress and neuroinflammation are important processes involved in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Numerous risk factors, including genetic background, can affect the complex interplay between those mechanisms in the aging brain and can also affect typical AD hallmarks: amyloid plaques and neurofibrillary tangles. Our aim was to evaluate the association of polymorphisms in oxidative stress- and inflammation-related genes with cerebrospinal fluid (CSF) biomarker levels and cognitive test results. The study included 54 AD patients, 14 MCI patients with pathological CSF biomarker levels, 20 MCI patients with normal CSF biomarker levels and 62 controls. Carriers of two polymorphic IL1B rs16944 alleles had higher CSF Aβ_1–42 levels (p = 0.025), while carriers of at least one polymorphic NFE2L2 rs35652124 allele had lower CSF Aβ_1–42 levels (p = 0.040). Association with IL1B rs16944 remained significant in the AD group (p = 0.029). Additionally, MIR146A rs2910164 was associated with Aβ_42/40 ratio (p = 0.043) in AD. Significant associations with cognitive test scores were observed for CAT rs1001179 (p = 0.022), GSTP1 rs1138272 (p = 0.005), KEAP1 rs1048290 and rs9676881 (both p = 0.019), as well as NFE2L2 rs35652124 (p = 0.030). In the AD group, IL1B rs1071676 (p = 0.004), KEAP1 rs1048290 and rs9676881 (both p = 0.035) remained associated with cognitive scores. Polymorphisms in antioxidative and inflammation genes might be associated with CSF biomarkers and cognitive test scores and could serve as additional biomarkers contributing to early diagnosis of dementia. Full article

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

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25 pages, 6227 KiB

Open AccessArticle

Intranasal Administration of KYCCSRK Peptide Rescues Brain Insulin Signaling Activation and Reduces Alzheimer’s Disease-like Neuropathology in a Mouse Model for Down Syndrome

by Antonella Tramutola, Simona Lanzillotta, Giuseppe Aceto, Sara Pagnotta, Gabriele Ruffolo, Pierangelo Cifelli, Federico Marini, Cristian Ripoli, Eleonora Palma, Claudio Grassi, Fabio Di Domenico, Marzia Perluigi and Eugenio Barone

Antioxidants 2023, 12(1), 111; https://doi.org/10.3390/antiox12010111 - 02 Jan 2023

Cited by 9 | Viewed by 2019

Abstract

Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer’s disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in childhood, and even before AD onset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the KYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating the insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent a promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued insulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced oxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of the KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1 protein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide elicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS due to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step forward in searching for new molecules useful to reduce intellectual disability and counteract AD development in DS. Full article

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

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14 pages, 2579 KiB

Open AccessArticle

DJ-1 and SOD1 Act Independently in the Protection against Anoxia in Drosophila melanogaster

by Federica De Lazzari, Francesco Agostini, Davide Doni, Sandro Malacrida, Mauro A. Zordan, Paola Costantini, Luigi Bubacco, Federica Sandrelli and Marco Bisaglia

Antioxidants 2022, 11(8), 1527; https://doi.org/10.3390/antiox11081527 - 05 Aug 2022

Cited by 1 | Viewed by 1817

Abstract

Redox homeostasis is a vital process the maintenance of which is assured by the presence of numerous antioxidant small molecules and enzymes and the alteration of which is involved in many pathologies, including several neurodegenerative disorders. Among the different enzymes involved in the antioxidant response, SOD1 and DJ-1 have both been associated with the pathogenesis of amyotrophic lateral sclerosis and Parkinson’s disease, suggesting a possible interplay in their mechanism of action. Copper deficiency in the SOD1-active site has been proposed as a central determinant in SOD1-related neurodegeneration. SOD1 maturation mainly relies on the presence of the protein copper chaperone for SOD1 (CCS), but a CCS-independent alternative pathway also exists and functions under anaerobic conditions. To explore the possible involvement of DJ-1 in such a pathway in vivo, we exposed Drosophila melanogaster to anoxia and evaluated the effect of DJ-1 on fly survival and SOD1 levels, in the presence or absence of CCS. Loss of DJ-1 negatively affects the fly response to the anoxic treatment, but our data indicate that the protective activity of DJ-1 is independent of SOD1 in Drosophila, indicating that the two proteins may act in different pathways. Full article

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

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20 pages, 5402 KiB

Open AccessArticle

Biochemical Discrimination of the Down Syndrome-Related Metabolic and Oxidative/Nitrosative Stress Alterations from the Physiologic Age-Related Changes through the Targeted Metabolomic Analysis of Serum

by Giacomo Lazzarino, Angela M. Amorini, Renata Mangione, Miriam Wissam Saab, Enrico Di Stasio, Michelino Di Rosa, Barbara Tavazzi, Giuseppe Lazzarino, Graziano Onder and Angelo Carfì

Antioxidants 2022, 11(6), 1208; https://doi.org/10.3390/antiox11061208 - 20 Jun 2022

Cited by 2 | Viewed by 2112

Abstract

Down Syndrome (DS) is a neurodevelopmental disorder that is characterized by an accelerated aging process, frequently associated with the development of Alzheimer’s disease (AD). Previous studies evidenced that DS patients have various metabolic anomalies, easily measurable in their serum samples, although values that were found in DS patients were compared with those of age-matched non-DS patients, thus hampering to discriminate the physiologic age-related changes of serum metabolites from those that are truly caused by the pathologic processes associated with DS. In the present study we performed a targeted metabolomic evaluation of serum samples from DS patients without dementia of two age classes (Younger DS Patients, YDSP, aging 20–40 years; Aged DS Patients, ADSP, aging 41–60 years), comparing the results with those that were obtained in two age classes of non-DS patients (Younger non-DS Patients, YnonDSP, aging 30–60 years; Aged-nonDS Patients, AnonDSP, aging 75–90 years). Of the 36 compounds assayed, 30 had significantly different concentrations in Pooled non-DS Patients (PnonDSP), compared to Pooled DS Patients (PDSP). Age categorization revealed that 11/30 compounds were significantly different in AnonDSP, compared to YnonDSP, indicating physiologic, age-related changes of their circulating concentrations. A comparison between YDSP and ADSP showed that 19/30 metabolites had significantly different values from those found in the corresponding classes of non-DS patients, strongly suggesting pathologic, DS-associated alterations of their serum levels. Twelve compounds selectively and specifically discriminated PnonDSP from PDSP, whilst only three discriminated YDSP from ADSP. The results allowed to determine, for the first time and to the best of our knowledge, the true, age-independent alterations of metabolism that are measurable in serum and attributable only to DS. These findings may be of high relevance for better strategies (pharmacological, nutritional) aiming to specifically target the dysmetabolism and decreased antioxidant defenses that are associated with DS. Full article

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

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Review

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29 pages, 984 KiB

Open AccessReview

Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy

by Krzysztof Łukawski and Stanisław J. Czuczwar

Antioxidants 2023, 12(5), 1049; https://doi.org/10.3390/antiox12051049 - 05 May 2023

Cited by 12 | Viewed by 2406

Abstract

Free radicals are generated in the brain, as well as in other organs, and their production is proportional to the brain activity. Due to its low antioxidant capacity, the brain is particularly sensitive to free radical damage, which may affect lipids, nucleic acids, and proteins. The available evidence clearly points to a role for oxidative stress in neuronal death and pathophysiology of epileptogenesis and epilepsy. The present review is devoted to the generation of free radicals in some animal models of seizures and epilepsy and the consequences of oxidative stress, such as DNA or mitochondrial damage leading to neurodegeneration. Additionally, antioxidant properties of antiepileptic (antiseizure) drugs and a possible use of antioxidant drugs or compounds in patients with epilepsy are reviewed. In numerous seizure models, the brain concentration of free radicals was significantly elevated. Some antiepileptic drugs may inhibit these effects; for example, valproate reduced the increase in brain malondialdehyde (a marker of lipid peroxidation) concentration induced by electroconvulsions. In the pentylenetetrazol model, valproate prevented the reduced glutathione concentration and an increase in brain lipid peroxidation products. The scarce clinical data indicate that some antioxidants (melatonin, selenium, vitamin E) may be recommended as adjuvants for patients with drug-resistant epilepsy. Full article

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

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23 pages, 1157 KiB

Open AccessReview

Oxidative Stress in Tauopathies: From Cause to Therapy

by Fernando Bartolome, Eva Carro and Carolina Alquezar

Antioxidants 2022, 11(8), 1421; https://doi.org/10.3390/antiox11081421 - 22 Jul 2022

Cited by 11 | Viewed by 4856

Abstract

Oxidative stress (OS) is the result of an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of cells. Due to its high oxygen demand, the human brain is highly susceptible to OS and, thus, it is not a surprise that OS has emerged as an essential component of the pathophysiology of several neurodegenerative diseases, including tauopathies. Tauopathies are a heterogeneous group of age-related neurodegenerative disorders characterized by the deposition of abnormal tau protein in the affected neurons. With the worldwide population aging, the prevalence of tauopathies is increasing, but effective therapies have not yet been developed. Since OS seems to play a key role in tauopathies, it has been proposed that the use of antioxidants might be beneficial for tau-related neurodegenerative diseases. Although antioxidant therapies looked promising in preclinical studies performed in cellular and animal models, the antioxidant clinical trials performed in tauopathy patients have been disappointing. To develop effective antioxidant therapies, the molecular mechanisms underlying OS in tauopathies should be completely understood. Here, we review the link between OS and tauopathies, emphasizing the causes of OS in these diseases and the role of OS in tau pathogenesis. We also summarize the antioxidant therapies proposed as a potential treatment for tauopathies and discuss why they have not been completely translated to clinical trials. This review aims to provide an integrated perspective of the role of OS and antioxidant therapies in tauopathies. In doing so, we hope to enable a more comprehensive understanding of OS in tauopathies that will positively impact future studies. Full article

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

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