Neurological disorders include a variety of conditions including Alzheimer’s, Motor Neuron and Parkinson’s disease, affecting longevity and quality of life and these have been associated with oxidative stress. Several of the chronic neurodegenerative pathologies of the central nervous system share some common features, such as oxidative stress, closely related to inflammation, synapse dysfunctions, protein misfolding, and defective autophagia. Sources of reactive oxygen species (ROS) that cause oxidative stress, relating oxidative damage with the pathogenesis of neurodegenerative disorders. Antioxidants can powerfully neutralise ROS and free radicals, decreasing oxidative damage. Antioxidant genes, like manganese superoxide dismutase (SOD-2) enzymes, can undergo epigenetic changes that reduce its expression, thus increasing oxidative stress in tissue or DNA can be altered by free radical damage. The epigenetic landscape of these genes can alter antioxidant function and can result in neurodegenerative disease. This imbalance of free radical production and antioxidant function increase the ROS that cause neuronal cell damage, often observed as an age-related event. Familial MND is associated with SOD-1 antioxidant gene polymorphism and function.
Increased antioxidant expression in mice is protective against ROS in neurons as is the exogenous supplementation of antioxidants. The associated manganese deficiency observed in Alzheimer’s suggests that this transition metal could be supplemented in deficient patients or SOD—2 therapy considered for age-related neurodegenerative disorders.
A new mimetic of SOD-2, Avasopasem manganese (GC4419 AVA), is described and suggested as putative treatment to reduce the oxidative stress that causes neurodegenerative diseases.
The free radical theory of aging (FRTA) is an established and accepted theory that proposes that oxidative damage caused by reactive oxygen species (ROS) is the primary cause of aging (1). The effects of ROS, with regard for neurogenerative disease, is well established with particular regard to Alzheimer’s (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Fredrich’s Ataxia (FA) Indeed, ROS have been shown to cause methylation of genes altering the epigenetic landscape of genes. Many chronic diseases are triggered by environmental exposures, such as ROS, that can give rise to aberrant changes in the epigenome. DNA methylation patterns can be remodelled by antioxidants and can remodel DNA methylation in chronic disease (2).
Genotypes of APOE4 that have been strongly associated with oxidative stress in the brain and recognised as a susceptibility genes for the AD phenotype and pathogenesis. ApoE4 is the least functional antioxidant of the ApoE family (ApoE1-4) (3)
ROS are atoms or groups of atoms that have odd, unpaired number of electrons, causing OS, and play a vital role in the pathophysiology of neurodegenerative disease. This can be exacerbated by mitochondrial dysfunction or reduced antioxidant gene expression (4) There are a number of examples of free radicals and these include, superoxide, oxygen radical, hydroxyl, alkoxy radical, peroxyl, nitric oxide and nitrogen dioxide. There are also nonradical reactive oxygen species, such as hydrogen peroxide, hypochlorous acid and several nitrogen compounds. OS biomarkers are available to investigate neurodegenerative disorders, such as, immunofluorescence (nitro-tyrosine, 4-hydrononeal, 8-hydroxiguanine in hippocampal slices (5,6). Other biomarkers could be protein carbonyls (5).
Refs
1. Anik MI, Mahmud N, Masud AA, Khan MI, Islam MN, Uddin S, Hossain MK. Role of Reactive Oxygen Species in Aging and Age-Related Diseases: A Review. ACS Appl Bio Mater. 2022 Aug 31. doi: 10.1021/acsabm.2c00411. Epub ahead of print. PMID: 36043942
2. Beetch, M, Harandi-Zadeh, S, Shen, K, et al. Dietary antioxidants remodel DNA methylation patterns in chronic disease. BrPharmacol. 2020; 177: 1382– 1408.
3. Butterfield DA, Mattson MP. Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease. Neurobiol Dis. 2020 May;138:104795. doi: 10.1016/j.nbd.2020.104795. Epub 2020 Feb 6. PMID: 32036033; PMCID: PMC7085980.).
4. https://doi.org/10.1111/bph.14888).
5. Islam MT. Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol Res. 2017 Jan;39(1):73-82. doi: 10.1080/01616412.2016.1251711. Epub 2016 Nov 3. PMID: 27809706).
It is clear that antioxidants can decrease the oxidative damage caused by free radicals in either an indirect way, by the inhibition of intra cellular activity, or expression of free radical generating enzymes, or by increasing the expression of intracellular enzymes or enhancing their activity. The ubiquitous family of enzymes that are superoxide dismutase’s (SOD) that catalyse the dismutation of superoxide anions and may be associated with copper, manganese, zinc and iron, depending on their function. The effects of antioxidant disfunction has been shown in SOD-2+/- mice experiments, where animals with low antioxidant capacity experienced direct damage to lipids, proteins and DNA, through OS, and caused behavioural impairments. OS makers in the cortex were shown to be increased in the hypothalamus and cortex. Indeed, over expression of SOD-2 in mice reduces hippocampal superoxide and prevents memory deficits. Indeed, a number of pathological phenotypes are associated with a loss of SOD-2 activity
Some evidence of age-related reduction of antioxidant gene expression was observed in the reduced expression of mRNAs coding for SOD-1, SOD-2 and catalase in the preovulatory follicles of women over the age of 38 years, indicating an age-related reduced defence against ROS.
1. Tatone C, Carbone MC, Falone S, Aimola P, Giardinelli A, Caserta D, Marci R, Pandolfi A, Ragnelli AM, Amicarelli F. Age-dependent changes in the expression of superoxide dismutases and catalase are associated with ultrastructural modifications in human granulosa cells. Mol Hum Reprod. 2006 Nov;12(11):655-60. doi: 10.1093/molehr/gal080. Epub 2006 Sep 27. PMID: 17005595.
2. J. Friedman, “Why is the nervous system vulnerable to oxidative stress?” in Oxidative Stress in Applied Basic Research and Clinical Practice, N. Gadoth and H. H. Gobel, Eds., pp. 19–27, Humana¨ Press, Totowa, NJ, USA, 2011).
3. Nakajima K, Kohsaka S. Microglia: activation and their significance in the central nervous system. J Biochem. 2001 Aug;130(2):169-75. doi: 10.1093/oxfordjournals.jbchem.a002969. PMID: 11481032).
4. Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M, Akbar MD. The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease: A Mini Review. Oxid Med Cell Longev. 2016;2016:8590578. doi: 10.1155/2016/8590578. Epub 2016 Dec 27. PMID: 28116038; PMCID: PMC5223034).
5. Wu YR, Chang KH, Chao CY, Lin CH, Chen YC, Liu TW, Lee-Chen GJ, Chen CM. Association of SOD2 p.V16A polymorphism with Parkinson's disease: A meta-analysis in Han Chinese. J Formos Med Assoc. 2021 Jan;120(1 Pt 2):501-507. doi: 10.1016/j.jfma.2020.06.023. Epub 2020 Jun 30. PMID: 32620460.
Antioxidant enzyme mimetic is already being trialled for diseases involving ROS, with some success, and some antioxidant molecules have been adapted to cross the BBB, Harald.
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