{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:50:06Z","timestamp":1791946206305,"version":"4.3.4"},"reference-count":110,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:00:00Z","timestamp":1629936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1A2C2006703"],"award-info":[{"award-number":["NRF-2020R1A2C2006703"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) and Lou Gehrig\u2019s disease, is characterized by a loss of the lower motor neurons in the spinal cord and the upper motor neurons in the cerebral cortex. Due to the complex and multifactorial nature of the various risk factors and mechanisms that are related to motor neuronal degeneration, the pathological mechanisms of ALS are not fully understood. Oxidative stress is one of the known causes of ALS pathogenesis. This has been observed in patients as well as in cellular and animal models, and is known to induce mitochondrial dysfunction and the loss of motor neurons. Numerous therapeutic agents have been developed to inhibit oxidative stress and neuroinflammation. In this review, we describe the role of oxidative stress in ALS pathogenesis, and discuss several anti-inflammatory and anti-oxidative agents as potential therapeutics for ALS. Although oxidative stress and antioxidant fields are meaningful approaches to delay disease progression and prolong the survival in ALS, it is necessary to investigate various animal models or humans with different subtypes of sporadic and familial ALS.<\/jats:p>","DOI":"10.3390\/diagnostics11091546","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T09:27:57Z","timestamp":1629970077000},"page":"1546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Oxidative Stress as a Therapeutic Target in Amyotrophic Lateral Sclerosis: Opportunities and Limitations"],"prefix":"10.3390","volume":"11","author":[{"given":"Hee Ra","family":"Park","sequence":"first","affiliation":[{"name":"KM Medicine Science Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon 34054, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Jin","family":"Yang","sequence":"additional","affiliation":[{"name":"KM Medicine Science Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon 34054, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,26]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Amyotrophic lateral sclerosis and environmental factors","volume":"31","author":"Bozzoni","year":"2016","journal-title":"Funct. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1007\/s00234-021-02681-3","article-title":"Age at symptom onset influences cortical thinning distribution and survival in amyotrophic lateral sclerosis","volume":"63","author":"Ferraro","year":"2021","journal-title":"Neuroradiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/ana.25443","article-title":"Smoking and amyotrophic lateral sclerosis: A mendelian randomization study","volume":"85","author":"Zhan","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.bbadis.2014.08.010","article-title":"Sporadic and hereditary amyotrophic lateral sclerosis (ALS)","volume":"1852","author":"Siddique","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"418","DOI":"10.4103\/ijp.IJP_823_19","article-title":"Novel therapeutic targets for amyotrophic lateral sclerosis","volume":"51","author":"Batra","year":"2019","journal-title":"Indian J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"622","DOI":"10.3389\/fnins.2018.00622","article-title":"Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis","volume":"12","author":"Brambilla","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1089\/ars.2017.7271","article-title":"Neuroinflammation in Amyotrophic Lateral Sclerosis: Role of Redox (dys)Regulation","volume":"29","author":"Cozzolino","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"653688","DOI":"10.3389\/fncel.2021.653688","article-title":"The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS","volume":"15","author":"Dafinca","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Granatiero, V., and Manfredi, G. (2019). Mitochondrial Transport and Turnover in the Pathogenesis of Amyotrophic Lateral Sclerosis. Biology, 8.","DOI":"10.3390\/biology8020036"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7395","DOI":"10.1002\/jcp.27498","article-title":"Characterizing the multiple roles of FGF-2 in SOD1(G93A) ALS mice in vivo and in vitro","volume":"234","author":"Kefalakes","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"105281","DOI":"10.1016\/j.phrs.2020.105281","article-title":"Challenges of BDNF-based therapies: From common to rare diseases","volume":"162","author":"Tanqueiro","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"136039","DOI":"10.1016\/j.neulet.2021.136039","article-title":"Cortical hyperexcitability: Diagnostic and pathogenic biomarker of ALS","volume":"759","author":"Vucic","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Piancone, F., La Rosa, F., Marventano, I., Saresella, M., and Clerici, M. (2021). The Role of the Inflammasome in Neurodegenerative. Dis. Mol., 26.","DOI":"10.3390\/molecules26040953"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.7901908","article-title":"Oxidative stress, glutamate, and neurodegenerative disorders","volume":"262","author":"Coyle","year":"1993","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8867701","DOI":"10.1155\/2020\/8867701","article-title":"Dual and Opposite Roles of Reactive Oxygen Species (ROS) in Chagas Disease: Beneficial on the Pathogen and Harmful on the Host","volume":"2020","author":"Maldonado","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1600-051X.1997.tb00760.x","article-title":"Reactive oxygen species and antioxidants in inflammatory diseases","volume":"24","author":"Chapple","year":"1997","journal-title":"J. Clin. Periodontol."},{"key":"ref_17","first-page":"5","article-title":"Oxygen-derived species: Their relation to human disease and environmental stress","volume":"102","author":"Halliwell","year":"1994","journal-title":"Environ. Health Perspect."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1080\/14660820310011278","article-title":"Relevance of oxidative injury in the pathogenesis of motor neuron diseases","volume":"4","author":"Agar","year":"2003","journal-title":"Amyotroph. Lateral Scler. Other Mot. Neuron Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1046\/j.1471-4159.1997.69052064.x","article-title":"Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis","volume":"69","author":"Ferrante","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1002\/mus.24223","article-title":"Skeletal muscle oxidative capacity in amyotrophic lateral sclerosis","volume":"50","author":"Ryan","year":"2014","journal-title":"Muscle Nerve"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.abb.2019.01.024","article-title":"Dysregulated mitochondrial Ca(2+) and ROS signaling in skeletal muscle of ALS mouse model","volume":"663","author":"Zhou","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/0304-3940(95)12039-7","article-title":"Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis","volume":"199","author":"Abe","year":"1995","journal-title":"Neurosci. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/ana.410420416","article-title":"Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis","volume":"42","author":"Beal","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1212\/WNL.62.10.1758","article-title":"Increased lipid peroxidation in sera of ALS patients: A potential biomarker of disease burden","volume":"62","author":"Simpson","year":"2004","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/ana.410440419","article-title":"Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis","volume":"44","author":"Smith","year":"1998","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1017\/cjn.2016.284","article-title":"Panel of Oxidative Stress and Inflammatory Biomarkers in ALS: A Pilot Study","volume":"44","author":"Blasco","year":"2017","journal-title":"Can. J. Neurol Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1080\/00365510310001771","article-title":"Total antioxidant status is increased in the serum of amyotrophic lateral sclerosis patients","volume":"63","author":"Ilzecka","year":"2003","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/362059a0","article-title":"Mutations in Cu\/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis","volume":"362","author":"Rosen","year":"1993","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1126\/science.8209258","article-title":"Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation","volume":"264","author":"Gurney","year":"1994","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.tox.2006.09.011","article-title":"Metallothionein proteins expression, copper and zinc concentrations, and lipid peroxidation level in a rodent model for amyotrophic lateral sclerosis","volume":"229","author":"Tokuda","year":"2007","journal-title":"Toxicology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1046\/j.0022-3042.2001.00720.x","article-title":"Increased mitochondrial antioxidative activity or decreased oxygen free radical propagation prevent mutant SOD1-mediated motor neuron cell death and increase amyotrophic lateral sclerosis-like transgenic mouse survival","volume":"80","author":"Liu","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105090","DOI":"10.1016\/j.phrs.2020.105090","article-title":"Map kinase signaling as therapeutic target for neurodegeneration","volume":"160","author":"Ahmed","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.nbd.2006.12.023","article-title":"Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death","volume":"26","author":"Dewil","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.mcn.2005.09.009","article-title":"Activation of the p38MAPK cascade is associated with upregulation of TNF alpha receptors in the spinal motor neurons of mouse models of familial ALS","volume":"31","author":"Veglianese","year":"2006","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/S1044-7431(03)00022-8","article-title":"Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression","volume":"23","author":"Tortarolo","year":"2003","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/ana.410390119","article-title":"SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis","volume":"39","author":"Rouleau","year":"1996","journal-title":"Ann. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.nbd.2017.02.004","article-title":"Neurobiology of axonal transport defects in motor neuron diseases: Opportunities for translational research?","volume":"105","author":"Hafezparast","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Morfini, G.A., Bosco, D.A., Brown, H., Gatto, R., Kaminska, A., Song, Y., Molla, L., Baker, L., Marangoni, M.N., and Berth, S. (2013). Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065235"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-018-0624-8","article-title":"Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS","volume":"9","author":"Gibbs","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.stemcr.2017.02.019","article-title":"Genetic Correction of SOD1 Mutant iPSCs 1Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis","volume":"8","author":"Bhinge","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-00091-1","article-title":"ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation","volume":"7","author":"Sama","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.1165942","article-title":"Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6","volume":"323","author":"Vance","year":"2009","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1126\/science.1166066","article-title":"Mutations in the FUS\/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis","volume":"323","author":"Kwiatkowski","year":"2009","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Jaganjac, M., Milkovic, L., Sunjic, S.B., and Zarkovic, N. (2020). The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies. Antioxidants, 9.","DOI":"10.3390\/antiox9111151"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s12265-020-10083-8","article-title":"NRF2 in Cardiovascular Diseases: A Ray of Hope!","volume":"14","author":"Vashi","year":"2021","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111817","DOI":"10.1016\/j.fct.2020.111817","article-title":"Flavonoids targeting NRF2 in neurodegenerative disorders","volume":"146","author":"Khan","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1093\/brain\/awh503","article-title":"Mutant SOD1 alters the motor neuronal transcriptome: Implications for familial ALS","volume":"128","author":"Kirby","year":"2005","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1097\/NEN.0b013e31818b4906","article-title":"Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis","volume":"67","author":"Sarlette","year":"2008","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/labinvest.2013.73","article-title":"The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model","volume":"93","author":"Guo","year":"2013","journal-title":"Lab. Investig."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.neuron.2014.01.013","article-title":"Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis","volume":"81","author":"Frakes","year":"2014","journal-title":"Neuron"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Crosio, C., Valle, C., Casciati, A., Iaccarino, C., and Carri, M.T. (2011). Astroglial inhibition of NF-kappaB does not ameliorate disease onset and progression in a mouse model for amyotrophic lateral sclerosis (ALS). PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017187"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5137","DOI":"10.1523\/JNEUROSCI.0536-20.2020","article-title":"Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling","volume":"40","author":"Dutta","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kallstig, E., McCabe, B.D., and Schneider, B.L. (2021). The Links between ALS and NF-kappaB. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083875"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1038\/s41593-020-00718-z","article-title":"Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival","volume":"23","author":"Chiot","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s13311-020-00953-z","article-title":"A Nitroalkene Benzoic Acid Derivative Targets Reactive Microglia and Prolongs Survival in an Inherited Model of ALS via NF-kappaB Inhibition","volume":"18","author":"Ibarburu","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.3389\/fimmu.2019.01043","article-title":"Cellular Specificity of NF-kappaB Function in the Nervous System","volume":"10","author":"Dresselhaus","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_57","first-page":"185","article-title":"Riluzole and ALS therapy","volume":"146","author":"Hugon","year":"1996","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1006\/nbdi.2000.0297","article-title":"A novel neuroprotective mechanism of riluzole: Direct inhibition of protein kinase C","volume":"7","author":"Noh","year":"2000","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"438","DOI":"10.9758\/cpn.2019.17.3.438","article-title":"Riluzole Selective Antioxidant Effects in Cell Models Expressing Amyotrophic Lateral Sclerosis Endophenotypes","volume":"17","author":"Sala","year":"2019","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Shen, C., Ma, W., Zheng, W., Huang, H., Xia, R., Li, C., and Zhu, X. (2017). The antioxidant effects of riluzole on the APRE-19 celll model injury-induced by t-BHP. BMC Ophthalmol., 17.","DOI":"10.1186\/s12886-017-0614-0"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.biopha.2016.12.067","article-title":"Riluzole ameliorates learning and memory deficits in Abeta25-35-induced rat model of Alzheimer\u2019s disease and is independent of cholinoceptor activation","volume":"87","author":"Mokhtari","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S1474-4422(18)30054-1","article-title":"Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: A retrospective analysis of data from a dose-ranging study","volume":"17","author":"Fang","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_63","first-page":"1","article-title":"Riluzole for amyotrophic lateral sclerosis (ALS)\/motor neuron disease (MND)","volume":"14","author":"Miller","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/S0006-8993(97)00490-3","article-title":"Delayed neuronal death prevented by inhibition of increased hydroxyl radical formation in a transient cerebral ischemia","volume":"762","author":"Yamamoto","year":"1997","journal-title":"Brain Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.ibror.2020.04.003","article-title":"Edaravone protects rat astrocytes from oxidative or neurotoxic inflammatory insults by restoring Akt\/Bcl-2\/Caspase-3 signaling axis","volume":"8","author":"Guo","year":"2020","journal-title":"IBRO Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.neuint.2015.07.024","article-title":"Edaravone leads to proteome changes indicative of neuronal cell protection in response to oxidative stress","volume":"90","author":"Jami","year":"2015","journal-title":"Neurochem. Int."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"116906","DOI":"10.1016\/j.jns.2020.116906","article-title":"Improvement of a decreased anti-oxidative activity by edaravone in amyotrophic lateral sclerosis patients","volume":"415","author":"Ohta","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"ref_68","first-page":"104","article-title":"Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration","volume":"21","author":"Nagase","year":"2016","journal-title":"Redox Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ejphar.2016.08.003","article-title":"Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippocampus","volume":"791","author":"Jangra","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1002\/jnr.24368","article-title":"Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis","volume":"97","author":"Ohta","year":"2019","journal-title":"J. Neurosci. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.lfs.2019.02.025","article-title":"Edaravone reduces Abeta-induced oxidative damage in SH-SY5Y cells by activating the Nrf2\/ARE signaling pathway","volume":"221","author":"Zhang","year":"2019","journal-title":"Life Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1111\/bph.15221","article-title":"Protein kinase inhibitors for amyotrophic lateral sclerosis therapy","volume":"178","author":"Palomo","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e123249","DOI":"10.1172\/jci.insight.123249","article-title":"Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS","volume":"3","author":"Trias","year":"2018","journal-title":"JCI Insight"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/21678421.2019.1632346","article-title":"Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: A randomized clinical trial","volume":"21","author":"Mora","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"979730","DOI":"10.1155\/2014\/979730","article-title":"Recent updates in the treatment of neurodegenerative disorders using natural compounds","volume":"2014","author":"Rasool","year":"2014","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Truzzi, F., Tibaldi, C., Zhang, Y., Dinelli, G., and D\u2032Amen, E. (2021). An Overview on Dietary Polyphenols and Their Biopharmaceutical Classification System (BCS). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115514"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"324256","DOI":"10.1155\/2012\/324256","article-title":"Therapeutic approach to neurodegenerative diseases by medical gases: Focusing on redox signaling and related antioxidant enzymes","volume":"2012","author":"Fujita","year":"2012","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.neulet.2014.02.058","article-title":"7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis","volume":"566","author":"Korkmaz","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.neuroscience.2018.03.008","article-title":"Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK","volume":"379","author":"Wang","year":"2018","journal-title":"Neuroscience"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S0022-510X(00)00317-8","article-title":"Increased reactive oxygen species in familial amyotrophic lateral sclerosis with mutations in SOD1","volume":"176","author":"Hung","year":"2000","journal-title":"J. Neurol. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"111119","DOI":"10.1016\/j.biopha.2020.111119","article-title":"The role of curcumin in aging and senescence: Molecular mechanisms","volume":"134","author":"Zia","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.bbapap.2015.01.014","article-title":"Curcumin binds to the pre-fibrillar aggregates of Cu\/Zn superoxide dismutase (SOD1) and alters its amyloidogenic pathway resulting in reduced cytotoxicity","volume":"1854","author":"Bhatia","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.neuroscience.2014.04.032","article-title":"Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS","volume":"272","author":"Dong","year":"2014","journal-title":"Neuroscience"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.neuro.2018.11.009","article-title":"Resveratrol treatment reduces the vulnerability of SH-SY5Y cells and cortical neurons overexpressing SOD1-G93A to Thimerosal toxicity through SIRT1\/DREAM\/PDYN pathway","volume":"71","author":"Laudati","year":"2019","journal-title":"Neurotoxicology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"12875","DOI":"10.1038\/s41598-018-30659-4","article-title":"Acetylation state of RelA modulated by epigenetic drugs prolongs survival and induces a neuroprotective effect on ALS murine model","volume":"8","author":"Schiaffino","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1089\/jmf.2009.0243","article-title":"A single-dose resveratrol treatment in a mouse model of amyotrophic lateral sclerosis","volume":"13","author":"Markert","year":"2010","journal-title":"J. Med. Food"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"626010","DOI":"10.3389\/fphar.2021.626010","article-title":"Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders","volume":"12","author":"Navarrete","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Melas, P.A., Scherma, M., Fratta, W., Cifani, C., and Fadda, P. (2021). Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041863"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S1474-4422(18)30406-X","article-title":"Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): A multicentre, double-blind, randomised, placebo-controlled, phase 2 trial","volume":"18","author":"Riva","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1111\/cns.12262","article-title":"Changes in endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice and evaluation of a Sativex((R))-like combination of phytocannabinoids: Interest for future therapies in amyotrophic lateral sclerosis","volume":"20","year":"2014","journal-title":"CNS Neurosci. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1002\/jcb.25757","article-title":"Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked with Amyotrophic Lateral Sclerosis","volume":"118","author":"Rajan","year":"2017","journal-title":"J. Cell Biochem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1111\/bph.15386","article-title":"Targeting the CB2 receptor and other endocannabinoid elements to delay disease progression in amyotrophic lateral sclerosis","volume":"178","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1089\/ars.2017.7144","article-title":"Neuroprotection in Oxidative Stress-Related Neurodegenerative Diseases: Role of Endocannabinoid System Modulation","volume":"29","author":"Paloczi","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1111\/j.1471-4159.2004.02544.x","article-title":"Endocannabinoids accumulate in spinal cord of SOD1 G93A transgenic mice","volume":"89","author":"Witting","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Rodriguez-Cueto, C., Gomez-Almeria, M., Garcia Toscano, L., Romero, J., Hillard, C.J., de Lago, E., and Fernandez-Ruiz, J. (2021). Inactivation of the CB2 receptor accelerated the neuropathological deterioration in TDP-43 transgenic mice, a model of amyotrophic lateral sclerosis. Brain Pathol., e12972.","DOI":"10.1111\/bpa.12972"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1111\/bph.14216","article-title":"Targeting glial cannabinoid CB2 receptors to delay the progression of the pathological phenotype in TDP-43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis","volume":"176","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ejphar.2006.05.025","article-title":"AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis","volume":"542","author":"Kim","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_98","first-page":"551","article-title":"Upregulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis","volume":"10","author":"Coates","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/nrn1971","article-title":"Molecular biology of amyotrophic lateral sclerosis: Insights from genetics","volume":"7","author":"Pasinelli","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1007\/s00415-014-7470-0","article-title":"NADPH oxidase (NOX2) activity is a modifier of survival in ALS","volume":"261","author":"Marrali","year":"2014","journal-title":"J. Neurol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.freeradbiomed.2016.05.016","article-title":"Evaluation of NADPH oxidases as drug targets in a mouse model of familial amyotrophic lateral sclerosis","volume":"97","author":"Seredenina","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"12132","DOI":"10.1073\/pnas.0603670103","article-title":"The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice","volume":"103","author":"Wu","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","first-page":"659","article-title":"SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model","volume":"118","author":"Harraz","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s12031-015-0695-2","article-title":"Multifactorial Gene Therapy Enhancing the Glutamate Uptake System and Reducing Oxidative Stress Delays Symptom Onset and Prolongs Survival in the SOD1-G93A ALS Mouse Model","volume":"58","author":"Benkler","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1093\/aje\/kwq416","article-title":"Vitamin E intake and risk of amyotrophic lateral sclerosis: A pooled analysis of data from 5 prospective cohort studies","volume":"173","author":"Wang","year":"2011","journal-title":"Am. J. Epidemiol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/ana.410390203","article-title":"Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis","volume":"39","author":"Gurney","year":"1996","journal-title":"Ann. Neurol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.mam.2007.01.004","article-title":"Vitamin E and neurodegenerative diseases","volume":"28","author":"Ricciarelli","year":"2007","journal-title":"Mol. Asp. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1002\/ana.20316","article-title":"Vitamin E intake and risk of amyotrophic lateral sclerosis","volume":"57","author":"Ascherio","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1080\/146608201300079364","article-title":"A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group","volume":"2","author":"Desnuelle","year":"2001","journal-title":"Amyotroph. Lateral Scler. Other Mot. Neuron Disord."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"246","DOI":"10.3109\/21678421.2012.745570","article-title":"Vitamin E serum levels and controlled supplementation and risk of amyotrophic lateral sclerosis","volume":"14","author":"Kuncl","year":"2013","journal-title":"Amyotroph. Lateral Scler. Front. Degener."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/11\/9\/1546\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:52:31Z","timestamp":1760165551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/11\/9\/1546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,26]]},"references-count":110,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["diagnostics11091546"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics11091546","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,26]]}}}