Generic placeholder image

Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Oxidative Status in Multiple Sclerosis and Off-Targets of Antioxidants: The Case of Edaravone

Author(s): Cristina Agresti, Rosella Mechelli, Stefania Olla, Caterina Veroni, Cecilia Eleuteri, Giovanni Ristori* and Marco Salvetti*

Volume 27, Issue 13, 2020

Page: [2095 - 2105] Pages: 11

DOI: 10.2174/0929867326666190124122752

Price: $65


Background: MS is a chronic inflammatory disease of the CNS leading to demyelination and neurodegeneration, with a complex and still to be clarified aetiology. Several data, coming from patients' samples and from animal models, show that Oxidative Status (OS) plays an important role in MS pathogenesis. Overproduction of reactive oxidative species by macrophages/microglia can bring about cellular injury and ensuing cell death by oxidizing cardinal cellular components. Oxidized molecules are present in active MS lesions and are associated with neurodegeneration.

Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature focusing on OS in MS. The contents of the selected papers were described in the context of a conceptual framework. A special emphasis was given to the results of our study in the field.

Results: The results of our three recent studies were put in the context and discussed taking into account the literature on the topic. Oxidative damage underpinned an imbalance shared by MS and neurodegenerative diseases such as Alzheimer and Parkinson diseases. In people with clinically isolated syndrome (an early phase of MS) oxidative stress proved to contribute to disease pathophysiology and to provide biomarkers that may help predict disease evolution. A drug screening platform based on multiple assays to test the remyelinating potential of library of approved compounds showed two anti-oxidants, edaravone and 5-methyl-7- methoxyisoflavone, as active drugs. Moreover, an analysis of 'structure activity relationship' showed off-targets sites of these compounds that accounted for their remyelinating activity, irrespective of their antioxidant action.

Conclusion: Overall, edaravone emerges as a candidate to treat complex disease such as MS, where inflammation, oxidative stress and neurodegeneration contribute to disease progression, together or individually, in different phases and disease types. Furthermore, approaches based on drug repositioning seem to maintain the promise of helping discover novel treatment for complex diseases, where molecular targets are largely unknown.

Keywords: Edaravone, antioxidant drug, multiple sclerosis, oxidative status, remyelination, chronic inflammatory disease.

Koch, M.; Ramsaransing, G.S.; Arutjunyan, A.V.; Stepanov, M.; Teelken, A.; Heersema, D.J.; De Keyser, J. Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis. J. Neurol., 2006, 253(4), 483-487.
[] [PMID: 16283096]
Vladimirova, O.; O’Connor, J.; Cahill, A.; Alder, H.; Butunoi, C.; Kalman, B. Oxidative damage to DNA in plaques of MS brains. Mult. Scler., 1998, 4(5), 413-418.
[] [PMID: 9839301]
Hammann, K.P.; Hopf, H.C. Monocytes constitute the only peripheral blood cell population showing an increased burst activity in multiple sclerosis patients. Int. Arch. Allergy Appl. Immunol., 1986, 81(3), 230-234.
[] [PMID: 3095248]
Greco, A.; Minghetti, L.; Sette, G.; Fieschi, C.; Levi, G. Cerebrospinal fluid isoprostane shows oxidative stress in patients with multiple sclerosis. Neurology, 1999, 53(8), 1876-1879.
[] [PMID: 10563647]
Nikić, I.; Merkler, D.; Sorbara, C.; Brinkoetter, M.; Kreutzfeldt, M.; Bareyre, F.M.; Brück, W.; Bishop, D.; Misgeld, T.; Kerschensteiner, M. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med., 2011, 17(4), 495-499.
[] [PMID: 21441916]
van Horssen, J.; Witte, M.E.; Schreibelt, G.; de Vries, H.E. Radical changes in multiple sclerosis pathogenesis. Biochim. Biophys. Acta, 2011, 1812(2), 141-150.
[] [PMID: 20600869]
Haider, L. Inflammation, iron, energy failure, and oxidative stress in the pathogenesis of multiple sclerosis. Oxid. Med. Cell. Longev., 2015, 2015725370
[] [PMID: 26106458]
Gilgun-Sherki, Y.; Melamed, E.; Offen, D. Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology, 2001, 40(8), 959-975.
[] [PMID: 11406187]
van Horssen, J.; Schreibelt, G.; Drexhage, J.; Hazes, T.; Dijkstra, C.D.; van der Valk, P.; de Vries, H.E. Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic. Biol. Med., 2008, 45(12), 1729-1737.
[] [PMID: 18930811]
Haider, L.; Fischer, M.T.; Frischer, J.M.; Bauer, J.; Höftberger, R.; Botond, G.; Esterbauer, H.; Binder, C.J.; Witztum, J.L.; Lassmann, H. Oxidative damage in multiple sclerosis lesions. Brain, 2011, 134(Pt 7), 1914-1924.
[] [PMID: 21653539]
Polman, C.H.; Reingold, S.C.; Edan, G.; Filippi, M.; Hartung, H.P.; Kappos, L.; Lublin, F.D.; Metz, L.M.; McFarland, H.F.; O’Connor, P.W.; Sandberg-Wollheim, M.; Thompson, A.J.; Weinshenker, B.G.; Wolinsky, J.S. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol., 2005, 58(6), 840-846.
[] [PMID: 16283615]
Miller, D.; Barkhof, F.; Montalban, X.; Thompson, A.; Filippi, M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol., 2005, 4(5), 281-288.
[] [PMID: 15847841]
Swanton, J.K.; Rovira, A.; Tintore, M.; Altmann, D.R.; Barkhof, F.; Filippi, M.; Huerga, E.; Miszkiel, K.A.; Plant, G.T.; Polman, C.; Rovaris, M.; Thompson, A.J.; Montalban, X.; Miller, D.H. MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study. Lancet Neurol., 2007, 6(8), 677-686.
[] [PMID: 17616439]
Brex, P.A.; Ciccarelli, O.; O’Riordan, J.I.; Sailer, M.; Thompson, A.J.; Miller, D.H. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N. Engl. J. Med., 2002, 346(3), 158-164.
[] [PMID: 11796849]
Alimonti, A.; Ristori, G.; Giubilei, F.; Stazi, M.A.; Pino, A.; Visconti, A.; Brescianini, S.; Sepe Monti, M.; Forte, G.; Stanzione, P.; Bocca, B.; Bomboi, G.; D’Ippolito, C.; Annibali, V.; Salvetti, M.; Sancesario, G. Serum chemical elements and oxidative status in Alzheimer’s disease, Parkinson disease and multiple sclerosis. Neurotoxicology, 2007, 28(3), 450-456.
[] [PMID: 17267042]
Ristori, G.; Brescianini, S.; Pino, A.; Visconti, A.; Vittori, D.; Coarelli, G.; Cotichini, R.; Bocca, B.; Forte, G.; Pozzilli, C.; Pestalozza, I.; Stazi, M.A.; Alimonti, A.; Salvetti, M. Serum elements and oxidative status in clinically isolated syndromes: imbalance and predictivity. Neurology, 2011, 76(6), 549-555.
[] [PMID: 21300970]
Simpson, E.P.; Henry, Y.K.; Henkel, J.S.; Smith, R.G.; Appel, S.H. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology, 2004, 62(10), 1758-1765.
[] [PMID: 15159474]
Watanabe, K.; Tanaka, M.; Yuki, S.; Hirai, M.; Yamamoto, Y. How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J. Clin. Biochem. Nutr., 2018, 62(1), 20-38.
[] [PMID: 29371752]
Edaravone Acute Infarction Study Group. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc. Dis., 2003, 15(3), 222-229.
[] [PMID: 12715790]
Ikawa, M.; Okazawa, H.; Tsujikawa, T.; Matsunaga, A.; Yamamura, O.; Mori, T.; Hamano, T.; Kiyono, Y.; Nakamoto, Y.; Yoneda, M. Increased oxidative stress is related to disease severity in the ALS motor cortex: A PET study. Neurology, 2015, 84(20), 2033-2039.
[] [PMID: 25904686]
Rosen, D.R.; Siddique, T.; Patterson, D.; Figlewicz, D.A.; Sapp, P.; Hentati, A.; Donaldson, D.; Goto, J.; O’Regan, J.P.; Deng, H.X. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 1993, 362(6415), 59-62.
[] [PMID: 8446170]
Mondola, P.; Damiano, S.; Sasso, A.; Santillo, M. The Cu, Zn superoxide dismutase: not only a dismutase enzyme. Front. Physiol., 2016, 7, 594.
[] [PMID: 27965593]
Yoshino, H.; Kimura, A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph. Lateral Scler., 2006, 7(4), 241-245.
[] [PMID: 17127563]
Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well-defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol., 2017, 16(7), 505-512.
[] [PMID: 28522181]
Hauser, D.N.; Hastings, T.G. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol. Dis., 2013, 51, 35-42.
[] [PMID: 23064436]
Jenner, P. Oxidative stress in Parkinson’s disease. Ann. Neurol., 2003, 53(Suppl. 3), S26-S36.
[] [PMID: 12666096]
Olanow, C.W.; Jenner, P.; Brooks, D. Dopamine agonists and neuroprotection in Parkinson’s disease. Ann. Neurol., 1998, 44(3)(Suppl. 1), S167-S174.
[] [PMID: 9749590]
Monti, D.A.; Zabrecky, G.; Kremens, D.; Liang, T.W.; Wintering, N.A.; Cai, J.; Wei, X.; Bazzan, A.J.; Zhong, L.; Bowen, B.; Intenzo, C.M.; Iacovitti, L.; Newberg, A.B. N-Acetyl cysteine may support dopamine neurons in parkinson’s disease: preliminary clinical and cell line data. PLoS One, 2016, 11(6)e0157602
[] [PMID: 27309537]
Zhu, Z.G.; Sun, M.X.; Zhang, W.L.; Wang, W.W.; Jin, Y.M.; Xie, C.L. The efficacy and safety of coenzyme Q10 in Parkinson’s disease: a meta-analysis of randomized controlled trials. Neurol. Sci., 2017, 38(2), 215-224.
[] [PMID: 27830343]
Yuan, W.J.; Yasuhara, T.; Shingo, T.; Muraoka, K.; Agari, T.; Kameda, M.; Uozumi, T.; Tajiri, N.; Morimoto, T.; Jing, M.; Baba, T.; Wang, F.; Leung, H.; Matsui, T.; Miyoshi, Y.; Date, I. Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons. BMC Neurosci., 2008, 9, 75.
[] [PMID: 18671880]
Clark, T.A.; Lee, H.P.; Rolston, R.K.; Zhu, X.; Marlatt, M.W.; Castellani, R.J.; Nunomura, A.; Casadesus, G.; Smith, M.A.; Lee, H.G.; Perry, G. Oxidative stress and its implications for future treatments and management of Alzheimer disease. Int. J. Biomed. Sci., 2010, 6(3), 225-227.
[PMID: 21765811]
Mattson, M.P. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev., 1997, 77(4), 1081-1132.
[] [PMID: 9354812]
Huang, X.; Atwood, C.S.; Hartshorn, M.A.; Multhaup, G.; Goldstein, L.E.; Scarpa, R.C.; Cuajungco, M.P.; Gray, D.N.; Lim, J.; Moir, R.D.; Tanzi, R.E.; Bush, A.I. The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry, 1999, 38(24), 7609-7616.
[] [PMID: 10386999]
Feng, Y.; Wang, X. Antioxidant therapies for Alzheimer’s disease. Oxid. Med. Cell. Longev., 2012, 2012472932
[] [PMID: 22888398]
Jiao, S.S.; Yao, X.Q.; Liu, Y.H.; Wang, Q.H.; Zeng, F.; Lu, J.J.; Liu, J.; Zhu, C.; Shen, L.L.; Liu, C.H.; Wang, Y.R.; Zeng, G.H.; Parikh, A.; Chen, J.; Liang, C.R.; Xiang, Y.; Bu, X.L.; Deng, J.; Li, J.; Xu, J.; Zeng, Y.Q.; Xu, X.; Xu, H.W.; Zhong, J.H.; Zhou, H.D.; Zhou, X.F.; Wang, Y.J. Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits. Proc. Natl. Acad. Sci. USA, 2015, 112(16), 5225-5230.
[] [PMID: 25847999]
Patani, R.; Balaratnam, M.; Vora, A.; Reynolds, R. Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol. Appl. Neurobiol., 2007, 33(3), 277-287.
[] [PMID: 17442065]
Patrikios, P.; Stadelmann, C.; Kutzelnigg, A.; Rauschka, H.; Schmidbauer, M.; Laursen, H.; Sorensen, P.S.; Brück, W.; Lucchinetti, C.; Lassmann, H. Remyelination is extensive in a subset of multiple sclerosis patients. Brain, 2006, 129(Pt 12), 3165-3172.
[] [PMID: 16921173]
Goldschmidt, T.; Antel, J.; König, F.B.; Brück, W.; Kuhlmann, T. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology, 2009, 72(22), 1914-1921.
[] [PMID: 19487649]
Piaton, G.; Williams, A.; Seilhean, D.; Lubetzki, C. Remyelination in multiple sclerosis. Prog. Brain Res., 2009, 175, 453-464.
[] [PMID: 19660673]
Kuhlmann, T.; Miron, V.; Cui, Q.; Wegner, C.; Antel, J.; Brück, W. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain, 2008, 131(Pt 7), 1749-1758.
[] [PMID: 18515322]
Hagemeier, K.; Brück, W.; Kuhlmann, T. Multiple sclerosis - remyelination failure as a cause of disease progression. Histol. Histopathol., 2012, 27(3), 277-287.
[PMID: 22237705]
Eleuteri, C.; Olla, S.; Veroni, C.; Umeton, R.; Mechelli, R.; Romano, S.; Buscarinu, M.C.; Ferrari, F.; Calò, G.; Ristori, G.; Salvetti, M.; Agresti, C. A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials. Sci. Rep., 2017, 7, 45780.
[] [PMID: 28387380]
Takase, H.; Liang, A.C.; Miyamoto, N.; Hamanaka, G.; Ohtomo, R.; Maki, T.; Pham, L.D.; Lok, J.; Lo, E.H.; Arai, K. Protective effects of a radical scavenger edaravone on oligodendrocyte precursor cells against oxidative stress. Neurosci. Lett., 2018, 668, 120-125.
[] [PMID: 29337010]
Deshmukh, V.A.; Tardif, V.; Lyssiotis, C.A.; Green, C.C.; Kerman, B.; Kim, H.J.; Padmanabhan, K.; Swoboda, J.G.; Ahmad, I.; Kondo, T.; Gage, F.H.; Theofilopoulos, A.N.; Lawson, B.R.; Schultz, P.G.; Lairson, L.L. A regenerative approach to the treatment of multiple sclerosis. Nature, 2013, 502(7471), 327-332.9.
Mei, F.; Fancy, S.P.J.; Shen, Y.A.; Niu, J.; Zhao, C.; Presley, B.; Miao, E.; Lee, S.; Mayoral, S.R.; Redmond, S.A.; Etxeberria, A.; Xiao, L.; Franklin, R.J.M.; Green, A.; Hauser, S.L.; Chan, J.R. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med., 2014, 20(8), 954-960.
[] [PMID: 24997607]
Najm, F.J.; Madhavan, M.; Zaremba, A.; Shick, E.; Karl, R.T.; Factor, D.C.; Miller, T.E.; Nevin, Z.S.; Kantor, C.; Sargent, A.; Quick, K.L.; Schlatzer, D.M.; Tang, H.; Papoian, R.; Brimacombe, K.R.; Shen, M.; Boxer, M.B.; Jadhav, A.; Robinson, A.P.; Podojil, J.R.; Miller, S.D.; Miller, R.H.; Tesar, P.J. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature, 2015, 522(7555), 216-220.
[] [PMID: 25896324]
Dolgin, E. Nonprofit disease groups earmark grants for drug repositioning. Nat. Med., 2011, 17(9), 1027.
[] [PMID: 21900904]
Reed, J.C.; White, E.L.; Aubé, J.; Lindsley, C.; Li, M.; Sklar, L.; Schreiber, S. The NIH’s role in accelerating translational sciences. Nat. Biotechnol., 2012, 30(1), 16-19.
[] [PMID: 22231085]
Nosengo, N. Can you teach old drugs new tricks? Nature, 2016, 534(7607), 314-316.
[] [PMID: 27306171]
Medina-Franco, J.L.; Giulianotti, M.A.; Welmaker, G.S.; Houghten, R.A. Shifting from the single to the multitarget paradigm in drug discovery. Drug Discov. Today, 2013, 18(9-10), 495-501.
[] [PMID: 23340113]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy