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      Targeting Oxidative Stress Mechanisms to Treat Alzheimer's and Parkinson's Disease: A Critical Review

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          Abstract

          Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are becoming more frequent as the age increases. Contemporary therapies provide symptom resolution instead of targeting underlying pathological pathways. Consequently, there is considerable heterogeneity in response to treatment. Research has elucidated multiple potential of pathophysiological mechanisms contributing to neurodegenerative conditions, among which oxidative stress pathways appear to be suitable drug targets. The oxidative stress pathway has given rise to numerous novel pharmacological therapies that may provide a new avenue for neurodegenerative diseases. For example, SKQ (plastoquinone), MitoVitE, vitamin E, SOD mimic, MitoTEMPO (SOD mimetic), and bioactive molecules like curcumin and vitamin C have indeed been examined. To better understand how oxidative stress contributes to neurodegenerative diseases (such as Alzheimer's and Parkinson's), we analyzed the medicinal qualities of medicines that target markers in the cellular oxidative pathways. The specific pathway by which mitochondrial dysfunction causes neurodegeneration will require more investigation. An animal study should be carried out on medications that tackle cellular redox mechanisms but are not currently licensed for use in the management of neurodegenerative conditions.

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          Most cited references71

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          The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay.

          A simple, automated test measuring the ferric reducing ability of plasma, the FRAP assay, is presented as a novel method for assessing "antioxidant power." Ferric to ferrous ion reduction at low pH causes a colored ferrous-tripyridyltriazine complex to form. FRAP values are obtained by comparing the absorbance change at 593 nm in test reaction mixtures with those containing ferrous ions in known concentration. Absorbance changes are linear over a wide concentration range with antioxidant mixtures, including plasma, and with solutions containing one antioxidant in purified form. There is no apparent interaction between antioxidants. Measured stoichiometric factors of Trolox, alpha-tocopherol, ascorbic acid, and uric acid are all 2.0; that of bilirubin is 4.0. Activity of albumin is very low. Within- and between-run CVs are <1.0 and <3.0%, respectively, at 100-1000 micromol/liter. FRAP values of fresh plasma of healthy Chinese adults: 612-1634 micromol/liter (mean, 1017; SD, 206; n = 141). The FRAP assay is inexpensive, reagents are simple to prepare, results are highly reproducible, and the procedure is straightforward and speedy. The FRAP assay offers a putative index of antioxidant, or reducing, potential of biological fluids within the technological reach of every laboratory and researcher interested in oxidative stress and its effects.
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            How mitochondria produce reactive oxygen species

            The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2 •−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2 •− production within the matrix of mammalian mitochondria. The flux of O2 •− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2 •− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2 •− production is far lower. The generation of O2 •− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2 •− generation by mitochondria in vivo from O2 •−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2 •− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
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              Alpha-synuclein in Lewy bodies.

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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2022
                31 July 2022
                : 2022
                : 7934442
                Affiliations
                1Department of Chemistry, Mississippi State University, Starkville, USA
                2Department of Internal Medicine, Grant Government Medical College and Sir JJ Group of Hospitals, Mumbai, India
                3Harvard Medical School, Harvard University, Boston, MA, USA
                4Sumy State University, Ukraine
                5Mansoura Faculty of Medicine, Mansoura University, Egypt
                6MGM Medical College and Hospital, Aurangabad, India
                7Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA
                8Mayo Hospital Lahore, Pakistan
                9School of Medicine, Faculty of Health, Education, Medicine & Social Care, Anglia Ruskin University, Bishop Hall Lane, Chelmsford CM1 1SQ, UK
                10Tianjin Medical University, Tianjin, China
                11Leeds Medical School, University of Leeds, UK
                12University of Debrecen-Faculty of Medicine, Debrecen, Hungary
                13Norwich Medical School, University of East Anglia, Norwich, UK
                14University of the Philippines Manila, Philippines
                15Poltava State Medical University, Poltava, Ukraine
                16Municipal Enterprise “1 City Clinical Hospital of Poltava City Council”, Poltava, Ukraine
                17Institute of Applied Health Research, University of Birmingham, Birmingham, UK
                18West China School of Nursing/Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China
                19Novel Global Community Educational Foundation, Hebersham, 2770 NSW, Australia
                20AFNP Med Austria, 1010 Wien, Austria
                Author notes

                Academic Editor: Dragan Hrnčić

                Author information
                https://orcid.org/0000-0003-2516-5920
                https://orcid.org/0000-0002-3566-0389
                https://orcid.org/0000-0003-2380-2949
                https://orcid.org/0000-0002-0373-3168
                https://orcid.org/0000-0001-9060-6636
                https://orcid.org/0000-0001-5538-0010
                https://orcid.org/0000-0002-8813-2838
                https://orcid.org/0000-0002-2530-5148
                https://orcid.org/0000-0003-2226-0906
                https://orcid.org/0000-0001-8282-0691
                https://orcid.org/0000-0002-4604-1372
                https://orcid.org/0000-0003-4015-3995
                https://orcid.org/0000-0002-7198-5498
                https://orcid.org/0000-0001-8246-202X
                https://orcid.org/0000-0003-2899-1531
                https://orcid.org/0000-0002-2206-7236
                Article
                10.1155/2022/7934442
                9357807
                35958022
                f0184e54-bd10-48e8-8eb7-8bcc9bab2a39
                Copyright © 2022 Abdullahi Tunde Aborode et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 December 2021
                : 12 July 2022
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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