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Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases

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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 (30 April 2023) | Viewed by 24305

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Dr. Ana-Maria Buga

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Biochemistry Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Interests: neurodegeneration; neuroprotection
Special Issues, Collections and Topics in MDPI journals

Dr. Carmen Nicoleta Oancea

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Guest Editor

Department of Biochemistry, University of Medicine and Pharmacy from Craiova, 200349 Craiova, Romania
Interests: neuroinflammation; oxidative stress; ageing; neurodegenerative disorders; autoimmune disorders; neurodevelopmental disorders; nanotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative disorders are characterised by an irreversible alteration of neural tissue structure and progressive loss of neuronal function. Oxidative stress is a key factor contributing to neurodegenerative disease progression. Neural tissue is extremely dependent on oxygen and also very sensitive to it. Neurons deeply depend on aerobic energy production involving the oxidative phosphorylation process. Additionally, these cells are highly sensitive to ROS production through oxidative phosphorylation. The enhanced capacity of neuronal cells to counteract ROS production is a protective measure against neuronal damage. The molecular basis of neuronal tissue damage involves lipids, proteins and DNA oxidation. Oxidative processes activate genetic and epigenetic mechanisms associated with neurodegeneration and cellular death. An imbalance between ROS production and antioxidative defence mechanisms promotes oxidative damage and oxidative-stress-mediated neurodegeneration.

This Special Issue aims to address several important questions. First, (i) is the neurodegeneration process a “one way ticket” to neuronal death, programmed early in life? and (ii) Can it be prevented by neuroprotective interventions? The growing body of literature on nutraceuticals, nutrigenomics and nutrigenetics demonstrates their promise as powerful neuroprotectors for future novel therapies that naturally enhance antioxidant capacity. Furthermore, different active compounds that target oxidative stress prove their efficiency. However, the delivery route of such compounds, which must pass through the BBB to infiltrate highly protective environments, remains obscure. In this light, it is our great pleasure to invite researchers to contribute relevant original research studies or review manuscripts to this Special Issue.

Dr. Ana-Maria Buga
Dr. Carmen Nicoleta Oancea
Guest Editors

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Keywords

neurodegeneration
antioxidants
nutrigenetics
nutraceuticals
mitochondrial dysfunction

Published Papers (11 papers)

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Editorial

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4 pages, 211 KiB

Open AccessEditorial

Oxidative Stress-Induced Neurodegeneration and Antioxidative Strategies: Current Stage and Future Perspectives

by Ana-Maria Buga and Carmen-Nicoleta Oancea

Antioxidants 2023, 12(9), 1762; https://doi.org/10.3390/antiox12091762 - 14 Sep 2023

Viewed by 880

Abstract

Neurodegenerative diseases (NDs) are the leading cause of neurological disorders, constituting a public health problem with an exponentially growing incidence rate [...] Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

Research

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17 pages, 3413 KiB

Open AccessArticle

Effects of Acetyl-L-Carnitine on Oxidative Stress in Amyotrophic Lateral Sclerosis Patients: Evaluation on Plasma Markers and Members of the Neurovascular Unit

by Elena Grossini, Fabiola De Marchi, Sakthipriyan Venkatesan, Angelica Mele, Daniela Ferrante and Letizia Mazzini

Antioxidants 2023, 12(10), 1887; https://doi.org/10.3390/antiox12101887 - 20 Oct 2023

Cited by 1 | Viewed by 1453

Abstract

Oxidative stress, the alteration of mitochondrial function, and the neurovascular unit (NVU), play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. We aimed to demonstrate the changes in the plasma redox system and nitric oxide (NO) in 32 new ALS-diagnosed patients in treatment with Acetyl-L-Carnitine (ALCAR) compared to healthy controls. We also evaluated the effects of plasma on human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. The analyses were performed at the baseline (T0), after three months (T1), and after six months (T2). In ALS patients at T0/T1, the plasma markers of lipid peroxidation, thiobarbituric acid reactive substances (TBARS) and 4-hydroxy nonenal (4-HNE) were higher, whereas the antioxidants, glutathione (GSH) and the glutathione peroxidase (GPx) activity were lower than in healthy controls. At T2, plasma TBARS and 4-HNE decreased, whereas plasma GSH and the GPx activity increased in ALS patients. As regards NO, the plasma levels were firmly lower at T0–T2 than those of healthy controls. Cell viability, and mitochondrial membrane potential in HUVEC/astrocytes treated with the plasma of ALS patients at T0–T2 were reduced, while the oxidant release increased. Those results, which confirmed the fundamental role of oxidative stress, mitochondrial function, and of the NVU in ALS pathogenesis, can have a double meaning, acting as disease markers at baseline and potential markers of drug effects in clinical practice and during clinical trials. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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20 pages, 4371 KiB

Open AccessArticle

Black Pepper (Piper nigrum) Alleviates Oxidative Stress, Exerts Potential Anti-Glycation and Anti-AChE Activity: A Multitargeting Neuroprotective Agent against Neurodegenerative Diseases

by Himadri Sharma, Niti Sharma and Seong Soo A. An

Antioxidants 2023, 12(5), 1089; https://doi.org/10.3390/antiox12051089 - 12 May 2023

Cited by 3 | Viewed by 2677

Abstract

Neurodegenerative diseases (NDs) are a family of disorders that cause progressive structural and functional degeneration of neurons. Among all the organs in the body, the brain is the one that is the most affected by the production and accumulation of ROS. Various studies have shown that an increase in oxidative stress is a common pathophysiology for almost all NDs, which further affects various other pathways. The available drugs lack the wide spectrum necessary to confront these complexities altogether. Hence, a safe therapeutic approach to target multiple pathways is highly desirable. In the present study, the hexane and ethyl acetate extracts of Piper nigrum (black pepper), an important spice, were evaluated for their neuroprotective potential in hydrogen peroxide-induced oxidative stress in human neuroblastoma cells (SH-SY5Y). The extracts were also subjected to GC/MS to identify the important bioactives present. The extracts exhibited neuroprotection by significantly decreasing the oxidative stress and restoring the mitochondrial membrane potential in the cells. Additionally, the extracts displayed potent anti-glycation and significant anti-Aβ fibrilization activities. The extracts were competitive inhibitors of AChE. The multitarget neuroprotective mechanism displayed by Piper nigrum indicates it as a potential candidate in the treatment of NDs. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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23 pages, 2926 KiB

Open AccessArticle

Defects in Glutathione System in an Animal Model of Amyotrophic Lateral Sclerosis

by Franziska T. Wunsch, Nils Metzler-Nolte, Carsten Theiss and Veronika Matschke

Antioxidants 2023, 12(5), 1014; https://doi.org/10.3390/antiox12051014 - 27 Apr 2023

Cited by 1 | Viewed by 1784

Abstract

Amyotrophic lateral sclerosis (ALS) is a progredient neurodegenerative disease characterized by a degeneration of the first and second motor neurons. Elevated levels of reactive oxygen species (ROS) and decreased levels of glutathione, which are important defense mechanisms against ROS, have been reported in the central nervous system (CNS) of ALS patients and animal models. The aim of this study was to determine the cause of decreased glutathione levels in the CNS of the ALS model wobbler mouse. We analyzed changes in glutathione metabolism in the spinal cord, hippocampus, cerebellum, liver, and blood samples of the ALS model, wobbler mouse, using qPCR, Western Blot, HPLC, and fluorometric assays. Here, we show for the first time a decreased expression of enzymes involved in glutathione synthesis in the cervical spinal cord of wobbler mice. We provide evidence for a deficient glutathione metabolism, which is not restricted to the nervous system, but can be seen in various tissues of the wobbler mouse. This deficient system is most likely the reason for an inefficient antioxidative system and, thus, for elevated ROS levels. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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22 pages, 10842 KiB

Open AccessArticle

Protective Effects of Dipterocarpus tuberculatus in Blue Light-Induced Macular Degeneration in A2E-Laden ARPE19 Cells and Retina of Balb/c Mice

by Su Jin Lee, Yu Jeong Roh, Ji Eun Kim, You Jeong Jin, Hee Jin Song, Ayun Seol, So Hae Park, Bounleuane Douangdeuane, Onevilay Souliya, Sun Il Choi and Dae Youn Hwang

Antioxidants 2023, 12(2), 329; https://doi.org/10.3390/antiox12020329 - 31 Jan 2023

Cited by 3 | Viewed by 2112

Abstract

Natural products with significant antioxidant activity have been receiving attention as one of the treatment strategies to prevent age-related macular degeneration (AMD). Reactive oxygen intermediates (ROI) including oxo-N-retinylidene-N-retinylethanolamine (oxo-A2E) and singlet oxygen-induced damage, are believed to be one of the major causes of the development of AMD. To investigate the therapeutic effects of methanol extracts of Dipterocarpus tuberculatus Roxb. (MED) against blue light (BL)-caused macular degeneration, alterations in the antioxidant activity, apoptosis pathway, neovascularization, inflammatory response, and retinal degeneration were analyzed in A2E-laden ARPE19 cells and Balb/c mice after exposure of BL. Seven bioactive components, including 2α-hydroxyursolic acid, ε-viniferin, asiatic acid, bergenin, ellagic acid, gallic acid and oleanolic acid, were detected in MED. MED exhibited high DPPH and ABTS free radical scavenging activity. BL-induced increases in intracellular reactive oxygen species (ROS) production and nitric oxide (NO) concentration were suppressed by MED treatment. A significant recovery of antioxidant capacity by an increase in superoxide dismutase enzyme (SOD) activity, SOD expression levels, and nuclear factor erythroid 2–related factor 2 (NRF2) expression were detected as results of MED treatment effects. The activation of the apoptosis pathway, the expression of neovascular proteins, cyclooxygenase-2 (COX-2)-induced inducible nitric oxide synthase (iNOS) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was remarkably inhibited in the MED treated group compared to the Vehicle-treated group in the AMD cell model. Furthermore, MED displayed protective effects in BL-induced retinal degeneration through improvement in the thickness of the whole retina, outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) in Balb/c mice. Taken together, these results indicate that MED exhibits protective effects in BL-induced retinal degeneration and has the potential in the future to be developed as a treatment option for dry AMD with atrophy of retinal pigment epithelial (RPE) cells. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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17 pages, 6335 KiB

Open AccessArticle

Vitamin C Deficiency Reduces Neurogenesis and Proliferation in the SVZ and Lateral Ventricle Extensions of the Young Guinea Pig Brain

by Nery Jara, Manuel Cifuentes, Fernando Martínez, Iván González-Chavarría, Katterine Salazar, Lucas Ferrada and Francisco Nualart

Antioxidants 2022, 11(10), 2030; https://doi.org/10.3390/antiox11102030 - 14 Oct 2022

Cited by 5 | Viewed by 1967

Abstract

Although scurvy, the severe form of vitamin C deficiency, has been almost eradicated, the prevalence of subclinical vitamin C deficiency is much higher than previously estimated and its impact on human health might not be fully understood. Vitamin C is an essential molecule, especially in the central nervous system where it performs numerous, varied and critical functions, including modulation of neurogenesis and neuronal differentiation. Although it was originally considered to occur only in the embryonic brain, it is now widely accepted that neurogenesis also takes place in the adult brain. The subventricular zone (SVZ) is the neurogenic niche where the largest number of new neurons are born; however, the effect of vitamin C deficiency on neurogenesis in this key region of the adult brain is unknown. Therefore, through BrdU labeling, immunohistochemistry, confocal microscopy and transmission electron microscopy, we analyzed the proliferation and cellular composition of the SVZ and the lateral ventricle (LVE) of adult guinea pigs exposed to a vitamin-C-deficient diet for 14 and 21 days. We found that neuroblasts in the SVZ and LVE were progressively and significantly decreased as the days under vitamin C deficiency elapsed. The neuroblasts in the SVZ and LVE decreased by about 50% in animals with 21 days of deficiency; this was correlated with a reduction in BrdU positive cells in the SVZ and LVE. In addition, the reduction in neuroblasts was not restricted to a particular rostro–caudal area, but was observed throughout the LVE. We also found that vitamin C deficiency altered cellular morphology at the ultrastructural level, especially the cellular and nuclear morphology of ependymal cells of the LVE. Therefore, vitamin C is essential for the maintenance of the SVZ cell populations required for normal activity of the SVZ neurogenic niche in the adult guinea pig brain. Based on our results from the guinea pig brain, we postulate that vitamin C deficiency could also affect neurogenesis in the human brain. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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Review

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22 pages, 2487 KiB

Open AccessReview

Bilirubin and Redox Stress in Age-Related Brain Diseases

by John Paul Llido, Sri Jayanti, Claudio Tiribelli and Silvia Gazzin

Antioxidants 2023, 12(8), 1525; https://doi.org/10.3390/antiox12081525 - 29 Jul 2023

Cited by 3 | Viewed by 2106

Abstract

Cellular redox status has a crucial role in brain physiology, as well as in pathologic conditions. Physiologic senescence, by dysregulating cellular redox homeostasis and decreasing antioxidant defenses, enhances the central nervous system’s susceptibility to diseases. The reduction of free radical accumulation through lifestyle changes, and the supplementation of antioxidants as a prophylactic and therapeutic approach to increase brain health, are strongly suggested. Bilirubin is a powerful endogenous antioxidant, with more and more recognized roles as a biomarker of disease resistance, a predictor of all-cause mortality, and a molecule that may promote health in adults. The alteration of the expression and activity of the enzymes involved in bilirubin production, as well as an altered blood bilirubin level, are often reported in neurologic conditions and neurodegenerative diseases (together denoted NCDs) in aging. These changes may predict or contribute both positively and negatively to the diseases. Understanding the role of bilirubin in the onset and progression of NCDs will be functional to consider the benefits vs. the drawbacks and to hypothesize the best strategies for its manipulation for therapeutic purposes. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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23 pages, 2503 KiB

Open AccessReview

Green Tea Catechins as Therapeutic Antioxidants for Glaucoma Treatment

by Tsz Kin Ng, Kai On Chu, Chi Chiu Wang and Chi Pui Pang

Antioxidants 2023, 12(7), 1320; https://doi.org/10.3390/antiox12071320 - 21 Jun 2023

Cited by 6 | Viewed by 4024

Abstract

Glaucoma is the leading cause of irreversible blindness and visual impairment, affecting more than 80 million individuals worldwide. Oxidative stress and inflammation-induced neurodegenerative insults to retinal ganglion cells are the main pathogenesis of glaucoma. Retinal ganglion cells, the retinal neurons transmitting the visual signals to the visual cortex in the brain, have very limited regeneration or recovery capacity after damages. Apart from intraocular pressure-lowering treatments, there is still no clinically effective treatment to rescue the degeneration of retinal ganglion cells in glaucoma. Dietary antioxidants are easily accessible and can be applied as supplements assisting in the clinical treatments. Catechins, a chemical family of flavonoids, are the phenolic compounds found in many plants, especially in green tea. The anti-oxidative and anti-inflammatory properties of green tea catechins in vitro and in vivo have been well proven. They could be a potential treatment ameliorating retinal ganglion cell degeneration in glaucoma. In this review, the chemistry, pharmacokinetics, and therapeutic properties of green tea catechins were summarized. Research updates on the biological effects of green tea catechins in cellular and animal experimental glaucoma models were reviewed. In addition, clinical potentials of green tea catechins for glaucoma treatment were also highlighted. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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34 pages, 635 KiB

Open AccessReview

New Directions to Approach Oxidative Stress Related to Physical Activity and Nutraceuticals in Normal Aging and Neurodegenerative Aging

by Manuela Violeta Bacanoiu, Mircea Danoiu, Ligia Rusu and Mihnea Ion Marin

Antioxidants 2023, 12(5), 1008; https://doi.org/10.3390/antiox12051008 - 26 Apr 2023

Cited by 2 | Viewed by 1944

Abstract

Oxidative stress (OS) plays, perhaps, the most important role in the advanced aging process, cognitive impairment and pathogenesis of neurodegenerative disorders. The process generates tissue damage via specific mechanisms on proteins, lipids and nucleic acids of the cells. An imbalance between the excessive production of oxygen- and nitrogen-reactive species and antioxidants leads to a progressive decline in physiological, biological and cognitive functions. Accordingly, we need to design and develop favourable strategies for stopping the early aging process as well as the development of neurodegenerative diseases. Exercise training and natural or artificial nutraceutical intake are considered therapeutic interventions that reduce the inflammatory process, increase antioxidant capacities and promote healthy aging by decreasing the amount of reactive oxygen species (ROS). The aim of our review is to present research results in the field of oxidative stress related to physical activity and nutraceutical administration for the improvement of the aging process, but also related to reducing the neurodegeneration process based on analysing the beneficial effects of several antioxidants, such as physical activity, artificial and natural nutraceuticals, as well as the tools by which they are evaluated. In this paper, we assess the recent findings in the field of oxidative stress by analysing intervention antioxidants, anti-inflammatory markers and physical activity in healthy older adults and the elderly population with dementia and Parkinson’s disease. By searching for studies from the last few years, we observed new trends for approaching the reduction in redox potential using different tools that evaluate regular physical activity, as well as antioxidant and anti-inflammatory markers preventing premature aging and the progress of disabilities in neurodegenerative diseases. The results of our review show that regular physical activity, supplemented with vitamins and oligomolecules, results in a decrease in IL-6 and an increase in IL-10, and has an influence on the oxidative metabolism capacity. In conclusion, physical activity provides an antioxidant-protective effect by decreasing free radicals and proinflammatory markers. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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17 pages, 1410 KiB

Open AccessReview

A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies

by Juan Segura-Aguilar and Bengt Mannervik

Antioxidants 2023, 12(3), 673; https://doi.org/10.3390/antiox12030673 - 9 Mar 2023

Cited by 7 | Viewed by 1967

Abstract

Investigations of the effect of antioxidants on idiopathic Parkinson’s disease have been unsuccessful because the preclinical models used to propose these clinical studies do not accurately represent the neurodegenerative process of the disease. Treatment with certain exogenous neurotoxins induces massive and extremely rapid degeneration; for example, MPTP causes severe Parkinsonism in just three days, while the degenerative process of idiopathic Parkinson´s disease proceeds over many years. The endogenous neurotoxin aminochrome seems to be a good alternative target since it is formed in the nigrostriatal system neurons where the degenerative process occurs. Aminochrome induces all the mechanisms reported to be involved in the degenerative processes of idiopathic Parkinson’s disease. The presence of neuromelanin-containing dopaminergic neurons in the postmortem brain of healthy elderly people suggests that neuromelanin synthesis is a normal and harmless process despite the fact that it requires oxidation of dopamine to three ortho-quinones that are potentially toxic, especially aminochrome. The apparent contradiction that neuromelanin synthesis is harmless, despite its formation via neurotoxic ortho-quinones, can be explained by the protective roles of DT-diaphorase and glutathione transferase GSTM2-2 as well as the neuroprotective role of astrocytes secreting exosomes loaded with GSTM2-2. Increasing the expression of DT-diaphorase and GSTM2-2 may be a therapeutic goal to prevent the degeneration of new neuromelanin-containing dopaminergic neurons. Several phytochemicals that induce DT-diaphorase have been discovered and, therefore, an interesting question is whether these phytochemical KEAP1/NRF2 activators can inhibit or decrease aminochrome-induced neurotoxicity. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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13 pages, 677 KiB

Open AccessReview

Mitochondria in Cell-Based Therapy for Stroke

by Molly Monsour, Jonah Gordon, Gavin Lockard, Adam Alayli and Cesar V. Borlongan

Antioxidants 2023, 12(1), 178; https://doi.org/10.3390/antiox12010178 - 12 Jan 2023

Cited by 6 | Viewed by 2334

Abstract

Despite a relatively developed understanding of the pathophysiology underlying primary and secondary mechanisms of cell death after ischemic injury, there are few established treatments to improve stroke prognoses. A major contributor to secondary cell death is mitochondrial dysfunction. Recent advancements in cell-based therapies suggest that stem cells may be revolutionary for treating stroke, and the reestablishment of mitochondrial integrity may underlie these therapeutic benefits. In fact, functioning mitochondria are imperative for reducing oxidative damage and neuroinflammation following stroke and reperfusion injury. In this review, we will discuss the role of mitochondria in establishing the anti-oxidative effects of stem cell therapies for stroke. Full article

(This article belongs to the Special Issue Novel Therapies of Oxidative Stress-Induced Age-Related Neurodegenerative Diseases)

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