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Oxidative Stress and Neurodegenerative Disorders II

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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 March 2022) | Viewed by 48154

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Special Issue Editors

Dr. Eugenio Barone

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Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Interests: insulin signaling; insulin resistance; aging; Alzheimer’s disease; Down syndrome; neurodegeneration; mitochondrial bioenergetics
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Dr. Andres Trostchansky

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Departamento de Bioquímica and Center for Free Radical and Biomedical Research (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo-Uruguay, Avda. Gral. Flores 2125, CP 11800 Montevideo, Uruguay
Interests: lipid oxidation; lipid signaling; lipidomics; α-synuclein; oxidative stress; Nrf2; Amyotrophic lateral sclerosis (ALS); Protein Disulfide Isomerase (PDI)

Special Issue Information

Dear Colleagues,

Increased oxidative stress levels have been found to greatly contribute to the onset and progression of neurodegenerative disorders, i.e., Alzheimer’s disease, Parkinson’s disease, Down syndrome, amyotrophic lateral sclerosis (ALS), and Huntington disease. The loss of physiological equilibrium between antioxidant and pro-oxidant stimuli, which normally contribute to the maintenance of low free radical levels, leads to increased generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that are toxic for brain cells in several ways. Indeed, augmented ROS and RNS production is responsible for damage to proteins, lipids, and nucleic acids, which accumulates within the cells and disrupts cellular homeostasis. Perturbation of mitochondrial activity further boosts ROS and RNS production, finally resulting in impaired metabolic pathways normally fueling brain cells’ energetic needs. In this frame, neurons display a distinctive bioenergetic metabolism, characterized by a particularly elevated mitochondrial oxygen consumption rate to sustain the high ATP (energy) expenditure. These features contribute to the exquisite sensitivity of the brain to the detrimental effects of oxidative stress. Recent findings suggest the crucial role of metabolic networks in the regulation of neuronal tolerance against oxidative stress. Furthermore, emerging evidence highlights the impact of metabolism and redox signaling on the genetic and epigenetic regulation of gene expression. Collectively, these elements indicate the extraordinary complexity of the multileveled molecular mechanisms deployed by brain cells to cope with oxidative stress.

This Special Issue will discuss preclinical and clinical evidence highlighting the central role of oxidative stress in the progression of neurodegenerative disorders and the strategies currently adopted to protect the brain.

Prof. Dr. Eugenio Barone
Dr. Andres Trostchansky
Guest Editors

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Keywords

Oxidative stress
Antioxidants
Brain metabolism
Autophagy
Proteosome
Mitochondria
Alzheimer disease
Parkinson disease
Down syndrome
Huntington disease
Amyotrophic lateral sclerosis (ALS)
Neurodevelopment

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Published Papers (10 papers)

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Research

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15 pages, 2790 KiB

Open AccessArticle

Combined Treatment with Bojungikgi-Tang and Riluzole Regulates Muscle Metabolism and Dysfunction in the hSOD1^G93A Mouse Model

by Mudan Cai and Eun Jin Yang

Antioxidants 2022, 11(3), 579; https://doi.org/10.3390/antiox11030579 - 18 Mar 2022

Cited by 6 | Viewed by 2624

Abstract

The progressive neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is characterized by muscle weakness and atrophy owing to selective motoneuron degeneration. The anti-glutamatergic drug, riluzole (RZ), is the standard-of-care treatment for ALS. Bojungikgi-tang (BJIGT), a traditional herbal formula, improves motor function and prolongs the survival of mice with ALS. As ALS is a multicomplex disease, effective therapies must target multiple mechanisms. Here, we evaluated the efficacy of a BJIGT/RZ combination (5-week treatment) in 2-month-old hSOD1^G93A mice with ALS. We performed quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and enzyme activity assays. BJIGT/RZ significantly attenuated inflammation, autophagy, and metabolic and mitochondrial dysfunctions in the gastrocnemius (GC) compared with the control. It reduced the mRNA and protein levels of muscle denervation-related proteins and creatine kinase levels. The total creatine level was significantly higher in the BJIGT/RZ-treated GC. Moreover, after BJIGT/RZ treatment, the number of Nissl-stained motoneurons and choline acetyl transferase-positive neurons in the spinal cord significantly increased via the regulation of proinflammatory cytokines. Collectively, the BJIGT/RZ treatment was superior to single-drug treatments in alleviating multiple ALS-related pathological mechanisms in the ALS mouse model. Overall, BJIGT can serve as a dietary supplement and be combined with RZ to achieve superior therapeutic effects against ALS. Full article

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

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14 pages, 1720 KiB

Open AccessArticle

Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone

by Daniela Valenti, Fiorenza Stagni, Marco Emili, Sandra Guidi, Renata Bartesaghi and Rosa Anna Vacca

Antioxidants 2022, 11(1), 62; https://doi.org/10.3390/antiox11010062 - 28 Dec 2021

Cited by 14 | Viewed by 3260

Abstract

Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3–P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3–P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1α. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS. Full article

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

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29 pages, 13514 KiB

Open AccessArticle

Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress

by Mohamed H. Elsherbeny, Jushin Kim, Noha A. Gouda, Lizaveta Gotina, Jungsook Cho, Ae Nim Pae, Kyeong Lee, Ki Duk Park, Ahmed Elkamhawy and Eun Joo Roh

Antioxidants 2021, 10(10), 1641; https://doi.org/10.3390/antiox10101641 - 19 Oct 2021

Cited by 17 | Viewed by 3073

Abstract

Monoamine oxidase B (MAO-B) is responsible for dopamine metabolism and plays a key role in oxidative stress by changing the redox state of neuronal and glial cells. To date, no disease-modifying therapy for Parkinson’s disease (PD) has been identified. However, MAO-B inhibitors have emerged as a viable therapeutic strategy for PD patients. Herein, a novel series of indole-based small molecules was synthesized as new MAO-B inhibitors with the potential to counteract the induced oxidative stress in PC12 cells. At a single dose concentration of 10 µM, 10 compounds out of 30 were able to inhibit MAO-B with more than 50%. Among them, compounds 7b, 8a, 8b, and 8e showed 84.1, 99.3, 99.4, and 89.6% inhibition over MAO-B and IC₅₀ values of 0.33, 0.02, 0.03, and 0.45 µM, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), compounds 7b, 8a, 8b and 8e showed remarkable selectivity indices (SI > 305, 3649, 3278, and 220, respectively). A further kinetic study displayed a competitive mode of action for 8a and 8b over MAO-B with Ki values of 10.34 and 6.63 nM. Molecular docking studies of the enzyme-inhibitor binding complexes in MAO-B revealed that free NH and substituted indole derivatives share a common favorable binding mode: H-bonding with a crucial water “anchor” and Tyr326. Whereas in MAO-A the compounds failed to form favorable interactions, which explained their high selectivity. In addition, compounds 7b, 8a, 8b, and 8e exhibited safe neurotoxicity profiles in PC12 cells and partially reversed 6-hydroxydopamine- and rotenone-induced cell death. Accordingly, we report compounds 7b, 8a, 8b, and 8e as novel promising leads that could be further exploited for their multi-targeted role in the development of a new oxidative stress-related PD therapy. Full article

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

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18 pages, 652 KiB

Open AccessReview

Physical-Exercise-Induced Antioxidant Effects on the Brain and Skeletal Muscle

by Jennyffer Souza, Rodrigo Augusto da Silva, Débora da Luz Scheffer, Rafael Penteado, Alexandre Solano, Leonardo Barros, Henning Budde, Andrés Trostchansky and Alexandra Latini

Antioxidants 2022, 11(5), 826; https://doi.org/10.3390/antiox11050826 - 23 Apr 2022

Cited by 15 | Viewed by 3700

Abstract

Erythroid-related nuclear factor 2 (NRF2) and the antioxidant-responsive-elements (ARE) signaling pathway are the master regulators of cell antioxidant defenses, playing a key role in maintaining cellular homeostasis, a scenario in which proper mitochondrial function is essential. Increasing evidence indicates that the regular practice of physical exercise increases cellular antioxidant defenses by activating NRF2 signaling. This manuscript reviewed classic and ongoing research on the beneficial effects of exercise on the antioxidant system in both the brain and skeletal muscle. Full article

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

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22 pages, 544 KiB

Open AccessReview

Neonatal Anesthesia and Oxidative Stress

by David A. Gascoigne, Mohammed M. Minhaj and Daniil P. Aksenov

Antioxidants 2022, 11(4), 787; https://doi.org/10.3390/antiox11040787 - 16 Apr 2022

Cited by 9 | Viewed by 3664

Abstract

Neonatal anesthesia, while often essential for surgeries or imaging procedures, is accompanied by significant risks to redox balance in the brain due to the relatively weak antioxidant system in children. Oxidative stress is characterized by concentrations of reactive oxygen species (ROS) that are elevated beyond what can be accommodated by the antioxidant defense system. In neonatal anesthesia, this has been proposed to be a contributing factor to some of the negative consequences (e.g., learning deficits and behavioral abnormalities) that are associated with early anesthetic exposure. In order to assess the relationship between neonatal anesthesia and oxidative stress, we first review the mechanisms of action of common anesthetic agents, the key pathways that produce the majority of ROS, and the main antioxidants. We then explore the possible immediate, short-term, and long-term pathways of neonatal-anesthesia-induced oxidative stress. We review a large body of literature describing oxidative stress to be evident during and immediately following neonatal anesthesia. Moreover, our review suggests that the short-term pathway has a temporally limited effect on oxidative stress, while the long-term pathway can manifest years later due to the altered development of neurons and neurovascular interactions. Full article

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

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13 pages, 640 KiB

Open AccessReview

Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection

by Sun Joo Cha and Kiyoung Kim

Antioxidants 2022, 11(2), 195; https://doi.org/10.3390/antiox11020195 - 20 Jan 2022

Cited by 31 | Viewed by 5177

Abstract

Edaravone, the first known free radical scavenger, has demonstrated cellular protective properties in animals and humans. Owing to its antioxidant activity, edaravone modulates oxidative damage in various diseases, especially neurodegenerative diseases. In 2015, edaravone was approved in Japan to treat amyotrophic lateral sclerosis. The distinguishing pathogenic features of neurodegenerative diseases include high reactive oxygen species levels and mitochondrial dysfunction. However, the correlation between mitochondria and edaravone has not been elucidated. This review highlights recent studies on novel therapeutic perspectives of edaravone in terms of its effect on oxidative stress and mitochondrial function. Full article

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

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25 pages, 2783 KiB

Open AccessReview

Hydrogen Peroxide and Amyotrophic Lateral Sclerosis: From Biochemistry to Pathophysiology

by Nitesh Sanghai and Geoffrey K. Tranmer

Antioxidants 2022, 11(1), 52; https://doi.org/10.3390/antiox11010052 - 27 Dec 2021

Cited by 20 | Viewed by 6192

Abstract

Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H₂O₂) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H₂O₂ in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H₂O₂ in ALS, we believe will encourage scientists to target pathological concentrations of H₂O₂ thereby halting the misfolding of SOD1. Full article

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

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22 pages, 2324 KiB

Open AccessReview

Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?

by Erica Staurenghi, Serena Giannelli, Gabriella Testa, Barbara Sottero, Gabriella Leonarduzzi and Paola Gamba

Antioxidants 2021, 10(12), 1890; https://doi.org/10.3390/antiox10121890 - 26 Nov 2021

Cited by 24 | Viewed by 5108

Abstract

In recent decades, the impairment of cholesterol metabolism in the pathogenesis of Alzheimer’s disease (AD) has been intensively investigated, and it has been recognized to affect amyloid β (Aβ) production and clearance, tau phosphorylation, neuroinflammation and degeneration. In particular, the key role of cholesterol oxidation products, named oxysterols, has emerged. Brain cholesterol metabolism is independent from that of peripheral tissues and it must be preserved in order to guarantee cerebral functions. Among the cells that help maintain brain cholesterol homeostasis, astrocytes play a starring role since they deliver de novo synthesized cholesterol to neurons. In addition, other physiological roles of astrocytes are to modulate synaptic transmission and plasticity and support neurons providing energy. In the AD brain, astrocytes undergo significant morphological and functional changes that contribute to AD onset and development. However, the extent of this contribution and the role played by oxysterols are still unclear. Here we review the current understanding of the physiological role exerted by astrocytes in the brain and their contribution to AD pathogenesis. In particular, we focus on the impact of cholesterol dysmetabolism on astrocyte functions suggesting new potential approaches to develop therapeutic strategies aimed at counteracting AD development. Full article

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

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14 pages, 848 KiB

Open AccessReview

The Blood–Brain Barrier, Oxidative Stress, and Insulin Resistance

by William A. Banks and Elizabeth M. Rhea

Antioxidants 2021, 10(11), 1695; https://doi.org/10.3390/antiox10111695 - 27 Oct 2021

Cited by 37 | Viewed by 6296

Abstract

The blood–brain barrier (BBB) is a network of specialized endothelial cells that regulates substrate entry into the central nervous system (CNS). Acting as the interface between the periphery and the CNS, the BBB must be equipped to defend against oxidative stress and other free radicals generated in the periphery to protect the CNS. There are unique features of brain endothelial cells that increase the susceptibility of these cells to oxidative stress. Insulin signaling can be impacted by varying levels of oxidative stress, with low levels of oxidative stress being necessary for signaling and higher levels being detrimental. Insulin must cross the BBB in order to access the CNS, levels of which are important in peripheral metabolism as well as cognition. Any alterations in BBB transport due to oxidative stress at the BBB could have downstream disease implications. In this review, we cover the interactions of oxidative stress at the BBB, how insulin signaling is related to oxidative stress, and the impact of the BBB in two diseases greatly affected by oxidative stress and insulin resistance: diabetes mellitus and Alzheimer’s disease. Full article

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

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21 pages, 886 KiB

Open AccessReview

Linking Oxidative Stress and Proteinopathy in Alzheimer’s Disease

by Chanchal Sharma and Sang Ryong Kim

Antioxidants 2021, 10(8), 1231; https://doi.org/10.3390/antiox10081231 - 30 Jul 2021

Cited by 79 | Viewed by 7837

Abstract

Proteinopathy and excessive production of reactive oxygen species (ROS), which are the principal features observed in the Alzheimer’s disease (AD) brain, contribute to neuronal toxicity. β-amyloid and tau are the primary proteins responsible for the proteinopathy (amyloidopathy and tauopathy, respectively) in AD, which depends on ROS production; these aggregates can also generate ROS. These mechanisms work in concert and reinforce each other to drive the pathology observed in the aging brain, which primarily involves oxidative stress (OS). This, in turn, triggers neurodegeneration due to the subsequent loss of synapses and neurons. Understanding these interactions may thus aid in the identification of potential neuroprotective therapies that could be clinically useful. Here, we review the role of β-amyloid and tau in the activation of ROS production. We then further discuss how free radicals can influence structural changes in key toxic intermediates and describe the putative mechanisms by which OS and oligomers cause neuronal death. Full article

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

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