Mitochondria-targeted Antioxidants as a Prospective ...

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Current Medicinal Chemistry, 2017, 24, 2086-2114

REVIEW ARTICLE

Mitochondria-targeted Antioxidants as a Prospective Therapeutic Strategy for Multiple Sclerosis Elena Fetisova, Boris Chernyak*, Galina Korshunova, Maria Muntyan* and Vladimir Skulachev Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie gory, 119991 Moscow, Russian Federation

ARTICLE HISTORY Received: October 10, 2016 Revised: February 24, 2017 Accepted: March 08, 2017 DOI: 10.2174/092986732466617031 6114452

Abstract: Background: Multiple sclerosis (MS) is one of the most widespread chronic neurological diseases that manifests itself by progressive demyelination in the central nervous system. The study of MS pathogenesis begins with the onset of the relapsing–remitting phase of the disease, which becomes apparent due to microglia activation, neuroinflammation and demyelination/remyelination in the white matter. The following progressive phase is accompanied by severe neurological symptoms when demyelination and neurodegeneration are spread to both gray and white matter. In this review, we discuss a possible role of mitochondrial reactive oxygen species (mtROS) in MS pathogenesis, mechanisms of mtROS generation and effects of some mitochondria-targeted antioxidants as potential components of MS therapy. Results: In the early phase of MS, mtROS stimulate NLRP3 inflammasomes, which is critical for the formation of local inflammatory lesions. Later, mtROS contribute to blood-brain barrier disruption induced by mediators of inflammation, followed by infiltration of leukocytes. ROS generated by leukocytes and activated microglia promote mitochondrial dysfunction and oligodendrocyte cell death. In the progressive phase, neurodegeneration also depends on excessive mtROS generation. Currently, only a few immunomodulatory drugs are approved for treatment of MS. These drugs mainly reduce the number of relapses but do not stop MS progression. Certain dietary and synthetic antioxidants have demonstrated encouraging results in animal models of MS but were ineffective in the completed clinical trials. Conclusion: Novel mitochondria-targeted antioxidants could be promising components of combined programs for MS therapy considering that they can be applied at extremely low doses and concurrently demonstrate anti-inflammatory and neuroprotective activities.

Keywords: Multiple sclerosis, oligodendrocytes, demyelination, inflammasome, mitochondria, reactive oxygen species, mitochondria-targeted antioxidants, neuroprotection 1. INTRODUCTION Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that affects more than 2.5 million people around the world. Its pathogenesis is not clear, as it is associated with inflammatory and possibly autoimmune processes [1-3]. The initial sharp onset of the disease *Address correspondence to these authors at Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russian Federation; Tel: +7 495 939-5550 and +7 495 939-5360; Fax: +7 495 939-3181; E-mails: [email protected] and [email protected] 0929-8673/17 $58.00+.00

with alternating nerve fiber demyelination and remyelination is a typical manifestation of MS pathology in the so-called relapsing-remitting form of MS (RRMS), which is accompanied by neurological symptoms and characterized by activation of microglia and the presence of cellular infiltrates in the CNS [4,5]. Atrophy of the cerebrum and spinal cord including gray matter is typical at the earliest stages of the disease [6]. Unlike RRMS, the two chronic progressive forms of MS, primary and secondary, are marked by continuous neurological worsening devoid of relapsing-remitting periods. Lingering RRMS (19-28 years) has a high probability to progress to the next disease stage, secondary © 2017 Bentham Science Publishers

Current Medicinal Chemistry, 2017, Vol. 24, No. 19 2105

Mitochondrial Antioxidants in Multiple Sclerosis

MTP

=

Mitochondrial permeability transition pore

[4]

SOD2

=

Mitochondrial superoxide dismutase

[5]

MAO

=

Mitochondria-targeted antioxidants

MS

=

Multiple sclerosis

MBP

=

Myelin basic protein

MOG

=

Myelin oligodendrocyte glycoprotein

Nrf2

=

Nuclear E2-related factor

NLRP3

=

Nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3

PD

=

Parkinson's disease

PPMS

=

Primary progressive MS

PDH

=

Pyruvate dehydrogenase

RRMS

=

Relapsing-remitting MS

SPMS

=

Secondary progressive MS

TRX

=

Thioredoxin

VGK

=

Voltage-gated potassium channel

VGNa

=

Voltage-gated sodium channel

RRMS

=

Relapsing-remitting MS

[6] [7]

[8] [9] [10]

[11]

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CONFLICT OF INTEREST

[13]

The authors confirm that this article content has no conflict of interest.

[14]

ACKNOWLEDGEMENTS The completion of this review was supported in part by the Russian Scientific Foundation grants 14-5000029 (sections “Experimental models of MS”, “Inflammation in MS” and “Oxidative damage in MS pathogenesis”) and 14-24-00107 (sections “Participation of mitochondria in MS pathogenesis” and “Mitochondria-targeted antioxidants”) and the Russian Foundation for Basic Research grant 17-04-02173 (section “Mitochondrial ROS generators”).

[15] [16] [17]

[18]

REFERENCES [1] [2] [3]

Waksman, B.H.; Reynolds, W.E. Multiple sclerosis as a disease of immune regulation. Exp. Biol. Med., 1984, 175(3), 282-294. Hafler, D.A.; Weiner, H.L. T cells in multiple sclerosis and inflammatory central nervous system diseases. Immunol. Rev., 1987, 100(1), 307-332. Ransohoff, R.M.; Hafler, D.A.; Lucchinetti, C.F. Multiple sclerosis - a quiet revolution. Nat. Rev. Neurol., 2015, 11(3), 134-142.

[19] [20]

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. Herranz, E.; Giannì, C.; Louapre, C.; Treaba, C.A.; Govindarajan, S.T.; Ouellette, R.;, Loggia, M.L.; Sloane, J.A.; Madigan, N.; Izquierdo-Garcia, D.; Ward, N.; Mangeat, G.; Granberg, T.; Klawiter, E.C.; Catana, C.; Hooker, J.M.; Taylor, N.; Ionete, C.; Kinkel, R.P.; Mainero, C. Neuroinflammatory component of gray matter pathology in multiple sclerosis. Ann. Neurol., 2016, 80(5), 776-790. Friese, M.A.; Schattling, B.; Fugger, L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat. Rev. Neurol., 2014, 10(4), 225-238. Scalfari, A.; Neuhaus, A.; Daumer, M.; Muraro, P.A.; Ebers, G.C. Onset of secondary progressive phase and longterm evolution of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry, 2014, 85(1), 67-75. van der Valk, P.; Amor, S. Preactive lesions in multiple sclerosis. Curr. Opin. Neurol., 2009, 22(3), 207-213. Mao, P.; Reddy, P.H. Is multiple sclerosis a mitochondrial disease? Biochim. Biophys. Acta, 2010, 1802(1), 66-79. Singh, S.; Metz, I.; Amor, S.; van der Valk, P.; Stadelmann, C.; Brück, W. Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. Acta Neuropathol., 2013, 125(4), 595-608. Bsibsi, M.; Peferoen, L.A.; Holtman, I.R.; Nacken, P.J.; Gerritsen, W.H.; Witte, M.E.; van Horssen J.; Eggen B.J.L.; van der Valk P.; Amor S.; van Noort, J.M. Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-γ and alpha Bcrystallin. Acta Neuropathol., 2014, 128(2), 215-229. Filippini, G.; Munari, L.; Incorvaia, B.; Ebers, G.C.; Polman, C.; D'Amico, R.; Rice, G.P. Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet, 2003, 361(9357), 545-552. Bornstein, M.B.; Murray, M.R. Serial observations on patterns of growth, myelin formation, maintenance and degeneration in cultures of new-born rat and kitten cerebellum. J. Biophys. Biochem. Cytol., 1958, 4(5), 499-504. Thomson, C.E.; Anderson, T.J.; McCulloch, M.C.; Dickinson, P.; Vouyiouklis, D.A.; Griffiths, I.R. The early phenotype associated with the jimpy mutation of the proteolipid protein gene. J. Neurocytol., 1999, 28(3), 207-221. Mattson, M.P. Human fetal brain cell culture. In: Human Cell Culture Protocols. Methods in Molecular Medicine; Jones, Ed.; Humana Press: Totowa, 1996; pp. 53-62. McCarthy, K.D.; De Vellis, J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J. Cell Biol., 1980, 85(3), 890-902. Victorov, I.V.; Khaspekov, L.G.; Shashkova, N.A. Cultivation of tissue and cells of the central nervous system. In: Guide culturing neural tissue. Methods. Equipment. Problems (In Russ.), 2nd ed.; Veprintsev, Victorov, Vil'ner, Eds.; Nauka: Moscow, 1988; pp. 141-166. Khalansky, A.S. Neuroglia and subsidiary cells in culture. In: Guide culturing neural tissue. Methods. Equipment. Problems (In Russ.), 2nd ed.; Veprintsev, Victorov, Vil'ner, Eds.; Nauka: Moscow, 1988; pp. 217-232. Raine, C.S. The Norton Lecture: a review of the oligodendrocyte in the multiple sclerosis lesion. J. Neuroimmunol., 1997, 77(2), 135-152. Kaneko, S.; Wang, J.; Kaneko, M.; Yiu, G.; Hurrell, J.M.; Chitnis, T.; Khoury, S.J.; He, Z. Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models. J. Neurosci., 2006, 26(38), 9794-9804.

2106 Current Medicinal Chemistry, 2017, Vol. 24, No. 19 [21] [22]

[23]

[24]

[25] [26]

[27]

[28]

[29]

[30]

[31]

[32]

[33] [34]

[35]

[36]

Mitrovic, B.; Parkinson, J.; Merrill, J.E. An in vitro model of oligodendrocyte destruction by nitric oxide and its relevance to multiple sclerosis. Methods, 1996, 10(3), 501-513. Lehnardt, S.; Massillon, L.; Follett, P.; Jensen, F.E.; Ratan, R.; Rosenberg, P.A.; Volpe, J.J.; Vartanian, T. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc. Natl. Acad. Sci. USA, 2003, 100(14), 8514-8519. Pitt, D.; Nagelmeier, I.E.; Wilson, H.C.; Raine, C.S. Glutamate uptake by oligodendrocytes. Implications for excitotoxicity in multiple sclerosis. Neurology, 2003, 61(8), 11131120. Vartanian, T.; Li, Y.; Zhao, M.; Stefansson, K. Interferongamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis. Mol. Med., 1995, 1(7), 732. Louis, J.C.; Magal, E.; Takayama, S.; Varon, S. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science, 1993, 259, 689-689. Lehnardt, S.; Lachance, C.; Patrizi, S.; Lefebvre, S.; Follett, P.L.; Jensen, F.E.; Rosenberg, P.A.; Volpe, J.J.; Vartanian, T. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J. Neurosci., 2002, 22(7), 2478-2486. Elliott, C.; Lindner, M.; Arthur, A.; Brennan, K.; Jarius, S.; Hussey, J.; Chan, A.; Stroet, A.; Olsson, T.; Willison, H.; Barnett, S.C.; Meinl, E.; Linington, C. Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain, 2012, 135(6), 1819-1833. Bénardais, K.; Kotsiari, A.; Škuljec, J.; Koutsoudaki, P.N.; Gudi, V.; Singh, V.; Vulinović, F.; Skripuletz, T.; Stangel, M. Cuprizone [bis (cyclohexylidenehydrazide)] is selectively toxic for mature oligodendrocytes. Neurotox. Res., 2013, 24(2), 244-250. Faizi, M.; Salimi, A.; Seydi, E.; Naserzadeh, P.; Kouhnavard, M.; Rahimi, A.; Pourahmad, J. Toxicity of cuprizone a Cu2+ chelating agent on isolated mouse brain mitochondria: a justification for demyelination and subsequent behavioral dysfunction. Toxicol. Mech. Methods, 2016, 26(4), 276-283. Felts, P.A.; Woolston, A.M.; Fernando, H.B.; Asquith, S.; Gregson, N.A.; Mizzi, O.J.; Smith, K.J. Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide. Brain, 2005, 128(7), 1649-1666. Raine, C.S.; Bornstein, M.B. Experimental allergic encephalomyelitis: an ultrastructural study of experimental demyelination in vitro. J. Neuropathol. Exp. Neurol., 1970, 29(2), 177-191. Saida, T.; Saida, K.; Silberberg, D.H. Demyelination produced by experimental allergic neuritis serum and antigalactocerebroside antiserum in CNS cultures. Acta Neuropathol., 1979, 48(1), 19-25. Baxter, A.G. The origin and application of experimental autoimmune encephalomyelitis. Nat. Rev. Immunol., 2007, 7(11), 904-912. Gold, R.; Linington, C.; Lassmann, H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain, 2006, 129(Pt 8), 1953-1971. Qi, X.; Lewin, A.S.; Sun, L.; Hauswirth, W.W.; Guy, J. Suppression of mitochondrial oxidative stress provides long-term neuroprotection in experimental optic neuritis. Invest. Ophthalmol. Vis. Sci., 2007, 48(2), 681-691. Forte, M.; Gold, B.G.; Marracci, G.; Chaudhary, P.; Basso, E.; Johnsen, D.; Yu, X.; Fowlkes, J.; Rahder, M.; Stem, K.; Bernardi, P.; Bourdette, D. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis,

Fetisova et al.

[37] [38]

[39]

[40]

[41] [42]

[43] [44]

[45] [46]

[47] [48]

[49]

[50] [51] [52] [53]

an animal model of multiple sclerosis. Proc. Natl. Acad. Sci. USA, 2007, 104(18), 7558-7563. Su, K.; Bourdette, D.; Forte, M. Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front. Physiol., 2013, 4, 00169. Singhal, G.; Jaehne, E.J.; Corrigan, F.; Toben, C.; Baune, B.T. Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front. Neurosci., 2014, 8, 315. Goodin, D.S.; Reder, A.T.; Bermel, R.A.; Cutter, G.R.; Fox, R.J.; John, G.R.; Lublin, F.D.; Lucchinetti, C.F.; Miller, A.E.; Pelletier, D.; Racke, M.K.; Trapp, B.D.; Vartanian, T.; Waubant, E. Relapses in multiple sclerosis: relationship to disability. Mult. Scler. Relat. Disord., 2016, 6, 10-20. Yamasaki, R.; Lu, H.; Butovsky, O.; Ohno, N.; Rietsch, A.M.; Cialic, R.; Wu, P.M.; Doykan, C.E.; Lin, J.; Cotleur, A.C.; Kidd, G.; Zorlu, M.M.; Sun, N.; Hu, W.; Liu, L.P.; Lee, J.-C.; Taylor, S.E.; Uehlein, L.Y.; Dixon, D.; Gu, J.; Floruta, C.M.; Zhu, M.; Charo, I.F.; Weiner, H.L.; Ransohoff, R.M. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med., 2014, 211(8), 1533-1549. Colton, C.A.; Gilbert, D.L. Microglia, an in vivo source of reactive oxygen species in the brain. Adv. Neurol., 1993, 59, 321-326. Meda, L.; Cassatella, M.A.; Szendrei, G.I.; Otvos, L.; Baron, P.; Villalba, M.; Ferrari D.; Rossi, F. Activation of microglial cells by β-amyloid protein and interferon-γ. Nature, 1995, 374(6523), 647-650. Inoue, M.; Shinohara, M.L. Nlrp3 inflammasome and MS/EAE. Autoimmune Dis., 2013, 2013, 859145. Available: http://dx.doi.org/10.1155/2013/859145. Bulua, A.C.; Simon, A.; Maddipati, R.; Pelletier, M.; Park, H.; Kim, K.Y.; Sack, M.N.; Kastner, D.L.; Siegel, R.M. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1associated periodic syndrome (TRAPS). J. Exp. Med., 2011, 208(3), 519-533. Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature, 2011, 469(7329), 221-225. Abais, J.M.; Xia, M.; Zhang, Y.; Boini, K.M.; Li, P.L. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid. Redox Signal., 2015, 22(13), 11111129. Elliott, E.I.; Sutterwala, F.S. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol. Rev., 2015, 265(1), 35-52. Zhou, R.; Tardivel, A.; Thorens, B.; Choi, I.; Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol., 2010, 11(2), 136140. Frischer, J.M.; Bramow, S.; Dal-Bianco, A.; Lucchinetti, C.F.; Rauschka, H.; Schmidbauer, M.; Laursen H.; Sorensen P.S.; Lassmann, H. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain, 2009, 132(5), 1175-1189. Owens, T.; Bechmann, I.; Engelhardt, B. Perivascular spaces and the two steps to neuroinflammation. J. Neuropathol. Exp. Neurol., 2008, 67(12), 1113-1121. Garden, G.A.; Möller, T. Microglia biology in health and disease. J. Neuroimmune Pharmacol., 2006, 1(2), 127-137. Volk, T.; Kox, W.J. Endothelium function in sepsis. Inflamm. Res., 2000, 49(5), 185-198. Ye, X.; Ding, J.; Zhou, X.; Chen, G.; Liu, S.F. Divergent roles of endothelial NF-kappaB in multiple organ injury and bacterial clearance in mouse models of sepsis. J. Exp. Med., 2008, 205(6), 1303-1315.


Mitochondrial Antioxidants in Multiple Sclerosis [54]

[55] [56]

[57]

[58]

[59]

[60] [61] [62] [63] [64]

[65]

[66] [67]

[68] [69]

Ding, J.; Song, D.; Ye, X.; Liu, S.F. A pivotal role of endothelial-specific NF-κB signaling in the pathogenesis of septic shock and septic vascular dysfunction. Nature, 2009, 183(6), 4031-4038. Davidson, S.M.; Duchen, M.R. Endothelial mitochondria: contributing to vascular function and disease. Circ. Res., 2007, 100(8), 1128-1141. Zinovkin, R.A.; Romaschenko, V.P.; Galkin, I.I.; Zakharova, V.V.; Pletjushkina, O.Y.; Chernyak, B.V.; Popova, E.N. Role of mitochondrial reactive oxygen species in agerelated inflammatory activation of endothelium. Aging (Albany NY), 2014, 6(8), 661-674. Zang, Q.S.; Sadek, H.; Maass, D.L.; Martinez, B.; Ma, L.; Kilgore, J.A.; Williams, N.S.; Frantz, D.E.; Wigginton, J.G.; Nwariaku, F.E.; Wolf, S.E.; Minei, J.P. Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumoniarelated sepsis model. Am. J. Physiol. Heart Circ. Physiol., 2012, 302(9), H1847-H1859. Lowes, D.A.; Webster, N.R.; Murphy, M.P.; Galley, H.F. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br. J. Anaesth., 2013, 110(3), 472480. van der Goes, A.; Brouwer, J.; Hoekstra, K.; Roos, D.; van den Berg, T.K.; Dijkstra, C.D. Reactive oxygen species are required for the phagocytosis of myelin by macrophages. J. Neuroimmunol., 1998, 92(1-2), 67-75. Hendriks, J.J.; Teunissen, C.E.; de Vries, H.E.; Dijkstra, C.D. Macrophages and neurodegeneration. Brain Res. Rev., 2005, 48(2), 185-195. Chen, W.W.; Zhang, X.; Huang, W.J. Role of neuroinflammation in neurodegenerative diseases. Mol. Med. Rep., 2016, 13(4), 3391-3396. French, H.M.; Reid, M.; Mamontov, P.; Simmons, R.A.; Grinspan, J.B. Oxidative stress disrupts oligodendrocyte maturation. J. Neurosci. Res., 2009, 87(14), 3076-3087. Nonneman, A.; Robberecht, W.; Van Den Bosch, L.V. The role of oligodendroglial dysfunction in amyotrophic lateral sclerosis. Neurodegen. Dis. Manag., 2014, 4(3), 223-239. Calkins, M.J.; Johnson, D.A.; Townsend, J.A.; Vargas, M.R.; Dowell, J.A.; Williamson, T.P.; Kraft, A.D.; Lee, J.M.; Li, J.; Johnson, J.A. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid. Redox Signal., 2009, 11(3), 497-508. Lu, F.; Selak, M.; O’Connor, J.; Croul, S.; Lorenzana, C.; Butunoi, C.; Kalman, B. Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J. Neurol. Sci., 2000, 177(2), 95-103. Kharel, P.; McDonough, J.; Basu, S. Evidence of extensive RNA oxidation in normal appearing cortex of multiple sclerosis brain. Neurochem. Int., 2016, 92, 43-48. 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 Rad. Biol. Med., 2008, 45(12), 1729-1737. 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, 413-418. Polachini, C.R.N.; Spanevello, R.M.; Zanini, D.; Baldissarelli, J.; Pereira, L.B.; Schetinger, M.R.C.; da Cruz I.B.; Assmann C.E.; Bagatini M.D.; Morsch, V.M. Evaluation of delta-aminolevulinic dehydratase activity, oxidative stress biomarkers, and vitamin D levels in patients with multiple sclerosis. Neurotox. Res., 2016, 29(2), 230-242.

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79] [80] [81]

[82]

[83]

[84]

Campbell, G.R.; Ziabreva, I.; Reeve, A.K.; Krishnan, K.J.;, Reynolds, R.; Howell, O.; Lassmann, H.; Turnbull, D.M.; Mahad, D.J. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann. Neurol., 2011, 69(3), 481-492. Bizzozero, O.A.; DeJesus, G.; Callahan, K.; Pastuszyn, A. Elevated protein carbonylation in the brain white matter and gray matter of patients with multiple sclerosis. J. Neurosci. Res., 2005, 81(5), 687-695. Dasgupta, A.; Zheng, J.; Perrone-Bizzozero, N.I.; Bizzozero, O.A. Increased carbonylation, protein aggregation and apoptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis. ASN Neuro, 2013, 5(2), e00111. Bizzozero, O.A.; DeJesus, G.; Bixler, H.A.; Pastuszyn, A. Evidence of nitrosative damage in the brain white matter of patients with multiple sclerosis. Neurochem. Res., 2005, 30(1), 139-149. Calabrese, V.; Cornelius, C.; Rizzarelli, E.; Owen, J.B.; Dinkova-Kostova, A.T.; Butterfield, D.A. Nitric oxide in cell survival: a janus molecule. Antioxid. Redox Signal., 2009, 11(11), 2717-2739. Qi, X.; Lewin, A.S.; Sun, L.; Hauswirth, W.W.; Guy, J. Mitochondrial protein nitration primes neurodegeneration in experimental autoimmune encephalomyelitis. J. Biol. Chem., 2006, 281, 31950-31962. Sadeghian, M.; Mastrolia, V.; Haddad, A.R.; Mosley, A.; Mullali, G.; Schiza, D.; Sajic, M.; Hargreaves, I.; Heales, S.; Duchen, M.R.; Smith, K.J. Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis. Sci. Rep., 2016, 6, 33249. Sands, S.A.; Williams, R.; Marshall, S. 3rd; LeVine, S.M. Perivascular iron deposits are associated with protein nitration in cerebral experimental autoimmune encephalomyelitis. Neurosci. Lett., 2014, 582, 133-138. Ferretti, G.; Bacchetti, T.; Principi, F.; Di Ludovico, F.; Viti, B.; Angeleri, V. A.; Danni, M.; Provinciali, L. Increased levels of lipid hydroperoxides in plasma of patients with multiple sclerosis: a relationship with paraoxonase activity. Mult. Scler., 2005, 11, 677-682. Reale, M.; Sánchez-Ramón, S. Lipids at the cross-road of autoimmunity in multiple sclerosis. Curr. Med. Chem., 2017, 24(2), 176-192. Tully, M.; Shi, R. New insights in the pathogenesis of multiple sclerosis - role of acrolein in neuronal and myelin damage. Int. J. Mol. Sci., 2013, 14(10), 20037-20047. Naidoo, R.; Knapp, M.L. Studies of lipid peroxidation products in cerebrospinal fluid and serum in multiple sclerosis and other conditions. Clin. Chem., 1992, 38, 24492454. Gard, A.L.; Solodushko, V.G.; Waeg, G.; Majic, T. 4Hydroxynonenal, a lipid peroxidation byproduct of spinal cord injury, is cytotoxic for oligodendrocyte progenitors and inhibits their responsiveness to PDGF. Microsc. Res. Tech., 2001, 52, 709-718. Ayala, A.; Muñoz, M.F.; Argüelles, S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid. Med. Cell. Longev., 2014, 2014, 360438. Zarrouk, A.; Nury, T.; Karym, E.M.; Vejux, A.; Sghaier, R.; Gondcaille, C.; Andreoletti, P.; Trompier, D.; Savary, S.; Cherkaoui-Malki, M.; Debbabi, M.; Fromont, A.; Riedinger, J.-M.; Moreau, T.; Lizard, G. Attenuation of 7ketocholesterol-induced overproduction of reactive oxygen species, apoptosis, and autophagy by dimethyl fumarate on 158N murine oligodendrocytes. J. Steroid Biochem. Mol. Biol., 2016. Available: http://dx.doi.org/10.1016/ j.jsbmb.2016.02.024

2108 Current Medicinal Chemistry, 2017, Vol. 24, No. 19 [85]

Wang, P.; Xie, K.; Wang, C.; Bi, J. Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. Eur. Neurol., 2014, 72(3-4), 249-254. [86] Long, J.; Liu, C.; Sun, L.; Gao, H.; Liu, J. Neuronal mitochondrial toxicity of malondialdehyde: inhibitory effects on respiratory function and enzyme activities in rat brain mitochondria. Neurochem. Res., 2009, 34(4), 786-794. [87] Morel, A.; Miller, E.; Bijak, M.; Saluk, J. The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients. Mol. Cell. Biochem., 2016, 420(1-2), 85-94. [88] Usatyuk, P. V.; Parinandi, N. L.; Natarajan, V. Redox regulation of 4-Hydroxy-2-nonenal-mediated endothelial barrier dysfunction by focal adhesion, adherens, and tight junction proteins. J. Biol. Chem., 2006, 281, 35554-35566. [89] Hulet, S.W.; Powers, S.; Connor, J.R. Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brain. J. Neurol. Sci., 1999, 165, 48-55. [90] Stephenson, E.; Nathoo, N.; Mahjoub, Y.; Dunn, J.F.; Yong, V.W. Iron in multiple sclerosis: roles in neurodegeneration and repair. Nat. Rev. Neurol., 2014, 10(8), 459-468. [91] Lassmann, H.; van Horssen, J.; Mahad, D. Progressive multiple sclerosis: pathology and pathogenesis. Nat. Rev. Neurol., 2012, 8(11), 647-656. [92] Hametner, S.; Wimmer, I.; Haider, L.; Pfeifenbring, S.; Brück, W.; Lassmann, H. Iron and neurodegeneration in the multiple sclerosis brain. Ann. Neurol., 2013, 74(6), 848861. [93] Wang, Q.; Chuikov, S.; Taitano, S.; Wu, Q.; Rastogi, A.; Tuck, S.J.; Corey J.M.; Lundy S.K.; Mao-Draayer, Y. Dimethyl fumarate protects neural stem/progenitor cells and neurons from oxidative damage through Nrf2-ERK1/2 MAPK pathway. Int. J. Mol. Sci., 2015, 16(6), 1388513907. [94] Aboul-Enein, F.; Rauschka, H.; Kornek, B.; Stadelmann, C.; Stefferl, A.; Brück, W.; Lucchinetti, C.; Schmidbauer, M.; Jellinger, K.; Lassmann, H. Preferential loss of myelinassociated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J. Neuropathol. Exp. Neurol., 2003, 62(1), 25-33. [95] Brooks, D.J.; Leenders, K.L.; Head, G.; Marshall, J.; Legg, N.J.; Jones, T. Studies on regional cerebral oxygen utilisation and cognitive function in multiple sclerosis. J. Neurol. Neurosurg. Psychiatr., 1984, 47(11), 1182-1191. [96] Johnson, T.W.; Wu, Y.; Nathoo, N.; Rogers, J.A.; Yong V.W.; Dunn, J.F. Gray matter hypoxia in the brain of the experimental autoimmune encephalomyelitis model of multiple sclerosis. PLoS One, 2016, 11(12), e0167196. [97] Klimova T.; Chandel, N.S. Mitochondrial complex III regulates hypoxic activation of HIF. Cell. Death Differ., 2008, 15(4), 660-666. [98] Cummins, E.P.; Keogh, C.E.; Crean, D.; Taylor, C.T. The role of HIF in immunity and inflammation. Mol. Aspects Med., 2016, 47, 24-34. [99] Yousefi, B.; Ahmadi, Y.; Ghorbanihaghjo, A.; Faghfoori, Z.; Irannejad V.S. Serum arsenic and lipid peroxidation levels in patients with multiple sclerosis. Biol. Trace Elem. Res., 2014, 158(3), 276-279. [100] Poser, C.M. The multiple sclerosis trait and the development of multiple sclerosis: genetic vulnerability and environmental effect. Clin. Neurol. Neurosurg., 2006, 108(3), 227-233. [101] Leung, G.; Sun, W.; Zheng, L.; Brookes, S.; Tully, M.; Shi, R. Anti-acrolein treatment improves behavioral outcome and alleviates myelin damage in experimental autoimmune enchephalomyelitis mouse. Neuroscience, 2011, 173, 150155.

Fetisova et al. [102] Drukarch, B.; van Muiswinkel, F.L. Neuroprotection for Parkinson’s disease: a new approach for a new millennium. Expert Opin. Invest. Drugs, 2001, 10(10), 1855-1868. [103] van Muiswinkel, F.L.; Kuiperij, H.B. The Nrf2-ARE Signalling pathway: promising drug target to combat oxidative stress in neurodegenerative disorders. Curr. Drug Targets CNS Neurol. Disord., 2005, 4(3), 267-281. [104] Schreibelt, G.; van Horssen, J.; van Rossum, S.; Dijkstra, C.D.; Drukarch, B.; de Vries, H.E. Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology. Brain Res. Rev., 2007, 56(2), 322-330. [105] Liu, J.S.; Zhao, M.L.; Brosnan, C.F.; Lee, S.C. Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am. J. Pathol., 2001, 158(6), 20572066. [106] Schreibelt, G.; van Horssen, J.; Haseloff, R.F.; Reijerkerk, A.; van der Pol, S.M.; Nieuwenhuizen, O.; Krause, E.; Blasig, I.E.; Dijkstra, C.D.; Ronken, E.; de Vries, H.E. Protective effects of peroxiredoxin-1 at the injured blood–brain barrier. Free Radic. Biol. Med., 2008, 45(3), 256-264. [107] Emamgholipour, S.; Hossein-Nezhad, A.; Sahraian, M.A.; Askarisadr, F.; Ansari, M. Evidence for possible role of melatonin in reducing oxidative stress in multiple sclerosis through its effect on SIRT1 and antioxidant enzymes. Life Sci., 2016, 145, 34-41. [108] Murphy, T.H.; Yu, J.; Ng, R.; Johnson, D.A.; Shen, H.; Honey, C.R.; Johnson, J.A. Preferential expression of antioxidant response element mediated gene expression in astrocytes. J. Neurochem., 2001, 76(6), 1670-1678. [109] Ruuls, S.R.; Bauer, J.; Sontrop, K.; Huitinga, I.; 't Hart, B.A.; Dijkstra, C.D. Reactive oxygen species are involved in the pathogenesis of experimental allergic encephalomyelitis in Lewis rats. J. Neuroimmunol., 1995, 56(2), 207-217. [110] Delacourte, A.; Defossez, A.; Ceballos, I.; Nicole, A.; Sinet, P.M. Preferential localization of copper zinc superoxide dismutase in the vulnerable cortical neurons in Alzheimer's disease. Neurosci. Lett., 1988, 92(3), 247-253. [111] SantaCruz, K.S.; Yazlovitskaya, E.; Collins, J.; Johnson, J.; DeCarli, C. Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer's disease. Neurobiol. Aging, 2004, 25(1), 63-69. [112] van Muiswinkel, F.L.; de Vos, R.A.; Bol, J.G.; Andringa, G.; Steur, E.J.; Ross, D.; Siegel, D.; Drukarch, B. Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol. Aging, 2004, 25(9), 1253-1262. [113] Miller, E.; Mrowicka, M.; Malinowska, K.; Zolynski, K.; Kedziora, J. Effects of the whole-body cryotherapy on a total antioxidative status and activities of some antioxidative enzymes in blood of patients with multiple sclerosispreliminary study. J. Med. Invest., 2010, 57(1-2), 168-173. [114] Ljubisavljevic, S.; Stojanovic, I.; Cvetkovic, T.; Vojinovic, S.; Stojanov, D.; Stojanovic, D.; Stefanovic N.; Pavlovic, D. Erythrocytes' antioxidative capacity as a potential marker of oxidative stress intensity in neuroinflammation. J. Neurol. Sci., 2014, 337(1), 8-13. [115] Dǔračkova, Z. Free radicals and antioxidants for nonexperts. In: Systems Biology of Free Radicals and Antioxidants; Laher, Ed.; Springer-Verlag: Berlin Heidelberg, 2014; Vol. 1, pp. 3-38. [116] Witte, M.E.; Geurts, J.J.; de Vries, H.E.; van der Valk, P.; van Horssen, J. Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion, 2010, 10(5), 411-418. [117] Dutta, R.; McDonough, J.; Yin, X.; Peterson, J.; Chang, A.; Torres, T.; Gudz, T.; Macklin, W.B.; Lewis, D.A.; Fox, R.J.; Rudick, R.; Mirnics, K.; Trapp, B.D. Mitochondrial



[118]

[119]

[120] [121] 122]

[123] [124]

[125] [126] [127] [128]

[129]

[130]

[131]

[132]

[133]

dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol., 2006, 59(3) 478-489. Falabella, M.; Forte, E.; Magnifico, M.C.; Santini, P.; Arese, M.; Giuffrè, A.; Radić K.; Chessa L.; Coarelli G.; Buscarinu M.C.; Mechelli R.; Salvetti M.; Sarti P. Evidence for detrimental cross interactions between reactive oxygen and nitrogen species in Leber’s hereditary optic neuropathy cells. Oxid. Med. Cell. Longev., 2016, 2016, 3187560. Available: http://dx.doi.org/10.1155/2016/3187560. Matthews, L.; Enzinger, C.; Fazekas, F.; Rovira, A.; Ciccarelli, O.; Dotti, M.T.; Filippi M.; Frederiksen J.L.; Giorgio A.;, Küker W.; Lukas C.; Rocca M.A.; De Stefano N.; Toosy A.; Yousry T.; Palace J. MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis. J. Neurol. Neurosurg. Psychiatry, 2015, 86(5), 537-542. Mahad, D.; Ziabreva, I.; Lassmann, H.; Turnbull, D. Mitochondrial defects in acute multiple sclerosis lesions. Brain, 2008, 131(7), 1722-1735. Beal, M.F. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol., 1995, 38(3), 357-366. Errea, O.; Moreno, B.; Gonzalez-Franquesa, A.; GarciaRoves, P.M.; Villoslada, P. The disruption of mitochondrial axonal transport is an early event in neuroinflammation. J. Neuroinflammation, 2015, 12(1), 152. Waxman, S.G. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat. Rev. Neurosci., 2006, 7(12), 932-941. Pletjushkina, O.Y.; Lyamzaev, K.G.; Popova, E.N.; Nepryakhina, O.K.; Ivanova, O.Y.; Domnina, L.V.; Chernyak, B.V.; Skulachev, V.P. Effect of oxidative stress on dynamics of mitochondrial reticulum. Biochim. Biophys. Acta, 2006, 1757(5-6), 518-524. Förstermann, U.; Sessa, W.C. Nitric oxide synthases: regulation and function. Eur. Heart J., 2012, 33(7), 829-837. Daff, S. NO synthase: structures and mechanisms. Nitric oxide, 2010, 23(1), 1-11. Schapira, A.H. Targeting mitochondria for neuroprotection in Parkinson's disease. Antioxid. Redox Signal., 2012, 16(9), 965-973. Leuner, K.; Schütt, T.; Kurz, C.; Eckert., S.H.; Schiller., C.; Occhipinti, A.; Mai, S.; Jendrach, M.; Eckert, G.P.; Kruse, S.E.; Palmiter, R.D.; Brandt, U.; Dröse, S.; Wittig, I.; Willem, M.; Haass, C.; Reichert, A.S.; Müller, W.E. Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid. Redox Signal., 2012, 16(12), 1421-1433. Li, Q.; Vande Velde, C.; Israelson, A.; Xie, J.; Bailey, A.O.; Dong, M.Q.; Chun, S.J.; Roy, T.; Winer, L.; Yates, J.R.; Capaldi, R.A.; Cleveland, D.W.; Miller, T.M. ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import. Proc. Natl. Acad. Sci. USA, 2010, 107(49), 21146-21151. Ghiasi, P.; Hosseinkhani, S.; Noori, A.; Nafissi, S.; Khajeh, K. Mitochondrial complex I deficiency and ATP/ADP ratio in lymphocytes of amyotrophic lateral sclerosis patients. Neurol. Res., 2012, 34(3), 297-303. Talla, V.; Yu, H.; Chou, T.H.; Porciatti, V.; Chiodo, V.; Boye, S.L.; Hauswirth, W.W.; Lewin, A.S.; Guy, J. NADHdehydrogenase type-2 suppresses irreversible visual loss and neurodegeneration in the EAE animal model of MS. Mol. Ther., 2013, 21(10), 1876-1888. Talla, V.; Koilkonda, R.; Porciatti, V.; Chiodo, V.; Boye, S.L.; Hauswirth, W.W.; Guy, J. Complex I subunit gene therapy with NDUFA6 ameliorates neurodegeneration in EAE. Invest. Ophthalmol. Vis. Sci., 2015, 56(2), 1129-1140. Grivennikova, V.G.; Vinogradov, A.D. Partitioning of superoxide and hydrogen peroxide production by mitochon-

[134]

[135]

[136] [137] [138]

[139]

[140] [141]

[142]

[143]

[144]

[145]

[146]

[147] [148]

drial respiratory complex I. Biochim. Biophys. Acta, 2013, 1827(3), 446-454. Treberg, J.R.; Quinlan, C.L.; Brand, M.D. Evidence for two sites of superoxide production by mitochondrial NADHubiquinone oxidoreductase (complex I). J. Biol. Chem., 2011, 286(31), 27103-27110. Ohnishi, S.T.; Shinzawa-Itoh, K.; Ohta, K.; Yoshikawa, S.; Ohnishi, T. New insights into the superoxide generation sites in bovine heart NADH-ubiquinone oxidoreductase (Complex I): the significance of protein-associated ubiquinone and the dynamic shifting of generation sites between semiflavin and semiquinone radicals. Biochim. Biophys. Acta, 2010, 1797(12), 1901-1909. Vinogradov, A.D.; Grivennikova, V.G. Oxidation of NADH and ROS production by respiratory complex I. Biochim. Biophys. Acta, 2016, 1857(7), 863-871. Hwang, M.S.; Rohlena, J.; Dong, L.F.; Neuzil, J.; Grimm, S. Powerhouse down: complex II dissociation in the respiratory chain. Mitochondrion, 2014, 19(Pt A), 20-28. Bourgeron, T.; Rustin, P.; Chretien, D.; Birch-Machin, M.; Bourgeois, M.; Viegas-Péquignot, E.; Munnich, A.; Rötig, A. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat. Genet., 1995, 11(2), 144-149. Jackson, C.B.; Nuoffer, J.M.; Hahn, D.; Prokisch, H.; Haberberger, B.; Gautschi, M.; Häberli, A.; Gallati, S.; Schaller, A. Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency. J. Med. Genet., 2014, 51(3), 170-175. Grimm, S. Respiratory chain complex II as general sensor for apoptosis. Biochim. Biophys. Acta, 2013, 1827(5), 565572. Hwang, M.S.; Schwall, C.T.; Pazarentzos, E.; Datler, C.; Alder, N.N.; Grimm, S. Mitochondrial Ca2+ influx targets cardiolipin to disintegrate respiratory chain complex II for cell death induction. Cell Death Differ., 2014, 21(11), 17331745. Quinlan, C.L.; Orr, A.L.; Perevoshchikova, I.V.; Treberg, J.R.; Ackrell, B.A.; Brand, M.D. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J. Biol. Chem., 2012, 287(32), 27255-27264. Szeto, S.S.; Reinke, S.N.; Sykes, B.D.; Lemire, B.D. Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate. J. Biol. Chem., 2007, 282(37), 27518-27526. Tran, Q.M.; Rothery, R.A.; Maklashina, E.; Cecchini, G.; Weiner, J.H. The quinone binding site in Escherichia coli succinate dehydrogenase is required for electron transfer to the heme b. J. Biol. Chem., 2006, 281(43), 32310-32317. Guzy, R.D.; Sharma, B.; Bell, E.; Chandel, N.S.; Schumacker, P.T. Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol. Cell. Biol., 2008, 28(2), 718-731. Lemarie, A.; Huc, L.; Pazarentzos, E.; Mahul-Mellier, A.L.; Grimm, S. Specific disintegration of complex II succinate:ubiquinone oxidoreductase links pH changes to oxidative stress for apoptosis induction. Cell Death Differ., 2011, 18(2), 338-349. Turrens, J.F. Superoxide production by the mitochondrial respiratory chain. Biosci. Rep., 1997, 17(1), 3-8. Ilieva, E.V.; Ayala, V.; Jové, M.; Dalfó, E.; Cacabelos, D.; Povedano, M.; Bellmunt, M.J.; Ferrer, I.; Pamplona, R.; Portero-Otín, M. Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain, 2007, 130(Pt 12), 3111-3123.

2110 Current Medicinal Chemistry, 2017, Vol. 24, No. 19 [149] Ksenzenko, M.; Konstantinov, A.A.; Khomutov, G.B.; Tikhonov, A.N.; Ruuge, E.K. Effect of electron transfer inhibitors on superoxide generation in the cytochrome bc1 site of the mitochondrial respiratory chain. FEBS Lett., 1983, 155(1), 19-24. [150] Chen, Q.; Vazquez, E.J.; Moghaddas, S.; Hoppel, C.L.; Lesnefsky, E.J. Production of reactive oxygen species by mitochondria: central role of complex III. J. Biol. Chem., 2003, 278(38), 36027-36031. [151] Starkov, A.A.; Fiskum, G.; Chinopoulos, C.; Lorenzo, B.J.; Browne, S.E.; Patel, M.S.; Beal, M.F. Mitochondrial alphaketoglutarate dehydrogenase complex generates reactive oxygen species. J. Neurosci., 2004, 24(36), 7779-7788. [152] Kareyeva, A.V.; Grivennikova, V.G.; Cecchini, G.; Vinogradov, A.D. Molecular identification of the enzyme responsible for the mitochondrial NADH-supported ammonium-dependent hydrogen peroxide production. FEBS Lett., 2011, 585(2), 385-389. [153] Grivennikova, V.G.; Vinogradov, A.D. Mitochondrial production of reactive oxygen species. Biochemistry (Moscow), 2013, 78(13), 1490-1511. [154] Klivenyi, P.; Starkov, A.A.; Calingasan, N.Y.; Gardian, G.; Browne, S.E.; Yang, L.; Bubber, P.; Gibson, G.E.; Patel, M.S.; Beal, M.F. Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity. J. Neurochem., 2004, 88(6), 1352-1360. [155] Dumont, M.; Ho, D.J.; Calingasan, N.Y.; Xu, H.; Gibson, G.; Beal, M.F. Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid pathology and memory deficit in a transgenic mouse model of amyloid deposition. Free Radic. Biol. Med., 2009, 47(7), 1019-1027. [156] Mao, P.; Manczak, M.; Shirendeb, U.P.; Reddy, P.H. MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Biochim. Biophys. Acta, 2013, 1832(12), 23222331. [157] Schulz, E.; Wenzel, P.; Münzel, T.; Daiber, A. Mitochondrial redox signaling: Interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid. Redox Signal., 2014, 20(2), 308-324. [158] Dikalova, A.E.; Bikineyeva, A.T.; Budzyn, K.; Nazarewicz, R.R.; McCann, L.; Lewis, W.; Harrison, D.G.; Dikalov, S.I. Therapeutic targeting of mitochondrial superoxide in hypertension. Circ. Res., 2010, 107, 106-116. [159] Dikalov, S.I.; Li, W.; Doughan, A.K.; Blanco, R.R.; Zafari, A.M. Mitochondrial reactive oxygen species and calcium uptake regulate activation of phagocytic NADPH oxidase. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2012, 302(10), R1134-R1142. [160] Fischer, M.T.; Sharma, R.; Lim, J.L.; Haider, L.; Frischer, J.M.; Drexhage, J.; Mahad, D.; Bradl, M.; van Horssen, J.; Lassmann, H. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain, 2012, 135(3), 886-899. [161] Miller, R.T.; Martásek, P.; Roman, L.J.; Nishimura, J.S.; Masters, B.S. Involvement of the reductase domain of neuronal nitric oxide synthase in superoxide anion production. Biochemistry, 1997, 36(49), 15277-15284. [162] Li, H.; Poulos, T.L. Structure-function studies on nitric oxide synthases. J. Inorg. Biochem., 2005, 99(1), 293-305. [163] Li, H.; Jamal, J.; Plaza, C.; Pineda, S.H.; Chreifi, G.; Jing, Q.; Cinelli, M.A.; Silverman, R.B.; Poulos, T.L. Structures of human constitutive nitric oxide synthases. Acta Crystallogr. D Biol. Crystallogr., 2014, 70(Pt 10), 2667-2674. [164] Rosenfeld, R.J.; Bonaventura, J.; Szymczyna, B.R.; MacCoss, M.J.; Arvai, A.S.; Yates, J.R. 3rd; Tainer, J.A.; Get-

Fetisova et al.

[165]

[166] [167] [168]

[169] [170]

[171] [172]

[173]

[174]

[175]

zoff, E.D. Nitric-oxide synthase forms N-NO-pterin and SNO-cys: implications for activity, allostery, and regulation. J. Biol. Chem., 2010, 285(41), 31581-31589. De Groot, C.J.; Ruuls, S.R.; Theeuwes, J.W.; Dijkstra, C.D.; Van der Valk, P. Immunocytochemical characterization of the expression of inducible and constitutive isoforms of nitric oxide synthase in demyelinating multiple sclerosis lesions. J. Neuropathol. Exp. Neurol., 1997, 56(1), 10-20. Moncada, S.; Higgs, E.A. Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur. J. Clin. Invest., 1991, 21(4), 361-374. Hobbs, A.J.; Higgs, A.; Moncada, S. Inhibition of nitric oxide synthase as a potential therapeutic target. Annu. Rev. Pharmacol. Toxicol., 1999, 39(1), 191-220. Liberman, E.A.; Topaly, V.P.; Tsofina, L.M.; Jasaitis, A.A.; Skulachev, V.P. Mechanism of coupling of oxidative phosphorylation and the membrane potential of mitochondria. Nature, 1969, 222(5198), 1076-1078. Smith, R.A.; Porteous, C.M.; Coulter, C.V.; Murphy, M.P. Selective targeting of an antioxidant to mitochondria. Eur. J. Biochem., 1999, 263(3), 709-716. Kelso, G.F.; Porteous, C.M.; Culter, C.V.; Hughes, G; Porteous, W.K.; Ledgerwood, E.S.; Smith, R.A.; Murphy, M.P. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J. Biol. Chem., 2001, 276(7), 4588-4596. Murphy, M.P.; Smith, R.A. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu. Rev. Pharmacol. Toxicol., 2007, 47, 629-656. Chernyak, B.V.; Antonenko, Y.N.; Galimov, E.R.; Domnina, L.V.; Dugina, V.B.; Zvyagilskaya, R.A.; Ivanova, O.Y.; Izyumov, D.S.; Lyamzaev, K.G.; Pustovidko, A.V.; Rokitskaya, T.I.; Rogov, A.G.; Severina, I.I.; Simonyan, R.A.; Skulachev, M.V.; Tashlitsky, V.N.; Titova, E.V.; Trendeleva, T.A.; Shagieva, G.S. Novel mitochondria-targeted compounds composed of natural constituents: conjugates of plant alkaloids berberine and palmatine with plastoquinone. Biochemistry (Moscow), 2012, 77(9), 983-995. Chernyak, B.V.; Antonenko, Y.N.; Domnina, L.V.; Ivanova, O.Y.; Lyamzaev, K.G.; Pustovidko, A.V.; Rokitskaya, T.I.; Severina, I.I.; Simonyan, R.A.; Trendeleva, T.A.; Zvyagilskaya, R.A. Novel penetrating cations for targeting mitochondria. Curr. Pharm. Des., 2013, 19(15), 2795-2806. Antonenko, Y.N.; Avetisyan, A.V.; Bakeeva, L.E.; Chernyak, B.V.; Chertkov, V.A.; Domnina, L.V.; Ivanova, O.Yu.; Izyumov, D.S.; Khailova, L.S.; Klishin, S.S.; Korshunova, G.A.; Lyamzaev, K.G.; Muntyan, M.S.; Nepryakhina, O.K.; Pashkovskaya, A.A.; Pletjushkina, O.Yu.; Pustovidko, A.V.; Roginsky, V.A.; Rokitskaya, T.I.; Ruuge, E.K.; Saprunova, V.B.; Severina, I.I.; Simonyan, R.A.; Skulachev, I.V.; Skulachev, M.V.; Sumbatyan, N.V.; Sviryaeva, I.V.; Tashlitsky, V.N.; Vassiliev, J.M.; Vyssokikh, M.Yu.; Yaguzhinsky, L.S.; Zamyatnin, A.A. (Jr.); Skulachev, V.P. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies. Biochemistry (Moscow), 2008, 73(12), 1273-1287. Skulachev, V.P.; Antonenko, Y.N.; Cherepanov, D.A.; Chernyak, B.V.; Izyumov, D.S.; Khailova, L.S.; Klishin, S.S.; Korshunova, G.A.; Lyamzaev, K.G.; Pletjushkina, O.Y.; Roginsky, V.A.; Rokitskaya, T.I.; Severin, F.F.; Severina, I.I.; Simonyan, R.A.; Skulachev, M.V.; Sumbatyan, N.V.; Sukhanova, E.I.; Tashlitsky, V.N.; Trendeleva, T.A.; Vyssokikh, M.Y.; Zvyagilskaya, R.A. Prevention of cardiolipin oxidation and fatty acid cycling as two antioxi-


[176]

[177] [178]

[179]

[180]

[181]

[182]

[183] [184]

[185]

[186]

dant mechanisms of cationic derivatives of plastoquinone (SkQs). Biochim. Biophys. Acta., 2010, 1797(6), 878-889. Korshunova G.A.; Shishkina A.V.; Skulachev M.V. Design, synthesis and some aspects of biological activity of mitochondria-targeted antioxidants. Biochemistry (Moscow), 2017 (accepted). Jacobsen, N.; Torssell, K. Synthesis of naturally occurring quinones. Acta Chem. Scand., 1973, 27(9), 3211-3216. Severina, I.I.; Muntyan, M.S.; Lewis, K.; Skulachev, V.P. Transfer of cationic antibacterial agents berberine, palmatine, and benzalkonium through bimolecular planar phospholipid film and Staphylococcus aureus membrane. IUBMB Life, 2001, 52(6), 321-324. Skulachev, M.V.; Antonenko, Y.N.; Anisimov, V.N.; Chernyak, B.V.; Cherepanov, D.A.; Chistyakov, V. A.; Egorov, M.V.; Kolosova, N.G.; Korshunova, G.A.; Lyamzaev, K.G.; Plotnikov, E.Y.; Roginsky, V.A.; Savchenko, A.Y.; Severina, I.I.; Severin, F.F.; Shkurat, T.P.; Tashlitsky, V.N.; Shidlovsky, K.M.; Vyssokikh, M.Y.; Zamyatnin, A.A. (Jr); Zorov, D.B.; Skulachev, V.P. Mitochondrialtargeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr. Drug Targets., 2011, 12(6), 800-826. Severina, I.I.; Severin, F.F.; Korshunova, G.A.; Sumbatyan, N.V.; Ilyasova, T.M.; Simonyan, R.A.; Rogov, A.G.; Trendeleva, T.A.; Zvyagilskaya, R.A.; Dugina, V.B.; Domnina, L.V.; Fetisova, E.K.; Lyamzaev, K.G.; Vyssokikh, M.Y.; Chernyak, B.V.; Skulachev, M.V.; Skulachev, V.P.; Sadovnichii, V.A. In search of novel highly active mitochondria-targeted antioxidants: thymoquinone and its cationic derivatives. FEBS Lett., 2013, 587(13), 2018-2024. Lukashev, A.N.; Skulachev, M.V.; Ostapenko, V.; Savchenko, A.Yu.; Pavshintsev, V.V.; Skulachev, V.P. Advances in development of rechargeable mitochondrial antioxidants. In: Progress in molecular biology and translational science; Osiewacz, Ed.; Academic Press: Burlington, 2014; Vol. 127; pp. 251-265. Brzheskiy, V.V.; Efimova, E.L.; Vorontsova, T.N.; Alekseev, V.N.; Gusarevich, O.G.; Shaidurova, K.N.; Ryabtseva, A.A.; Andryukhina, O.M.; Kamenskikh, T.G.; Sumarokova, E.S.; Miljudin, E.S.; Egorov, E.A.; Lebedev, O.I.; Surov, A.V.; Korol, A.R.; Nasinnyk, I.O.; Bezditko, P.A.; Muzhychuk, O.P.; Vygodin, V.A.; Yani, E.V.; Savchenko, A.Y.; Karger, E.M.; Fedorkin, O.N.; Mironov, A.N.; Ostapenko, V.; Popeko, N.A.; Skulachev, V.P.; Skulachev, M.V. Results of a multicenter, randomized, doublemasked, placebo-controlled clinical study of the efficacy and safety of Visomitin eye drops in patients with dry eye syndrome. Adv. Ther., 2015, 32(12), 1263-1279. Jaber, S.; Polster, B.M. Idebenone and neuroprotection: antioxidant, pro-oxidant, or electron carrier? J. Bioenerg. Biomembr., 2015, 47(1-2), 111-118. Fiebiger, S.M.; Bros, H.; Grobosch, T.; Janssen, A.; Chanvillard, C.; Paul, F.; Dörr, J.; Millward, J.M.; InfanteDuarte, C. The antioxidant idebenone fails to prevent or attenuate chronic experimental autoimmune encephalomyelitis in the mouse. J. Neuroimmunol., 2013, 262(1), 66-71. Filipovska, A.; Kelso, G.F.; Brown, S.E.; Beer, S.M.; Smith, R.A.; Murphy, M.P. Synthesis and characterization of a triphenylphosphonium-conjugated peroxidase mimetic. Insights into the interaction of ebselen with mitochondria. J. Biol. Chem., 2005, 280(25), 24113-24126. Trnka, J.; Blaikie, F.H.; Smith, R.A.; Murphy, M.P. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radic. Biol. Med., 2008, 44(7), 1406-1419.

Current Medicinal Chemistry, 2017, Vol. 24, No. 19 2111 [187] Szeto, H.H. Mitochondria-targeted peptide antioxidants: novel neuroprotective agents. AAPS J., 2006, 8(3), E521E531. [188] Szeto, H.H. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol., 2014, 171(8), 2029-2050. [189] Fink, M.P.; Macias, C.A.; Xiao, J.; Tyurina, Y.Y.; Delude, R.L.; Greenberger, J.S.; Kagan, V.E.; Wipf, P. Hemigramicidin-TEMPO conjugates: novel mitochondriatargeted antioxidants. Crit. Care Med., 2007, 35(9 Suppl), S461-S467. [190] Macias, C.A.; Chiao, J.W.; Xiao, J.; Arora, D.S.; Tyurina, Y.Y.; Delude, R.L.; Wipf, P.; Kagan, V.E.; Fink, M.P. Treatment with a novel hemigramicidin-TEMPO conjugate prolongs survival in a rat model of lethal hemorrhagic shock. Ann. Surg., 2007, 245(2), 305-314. [191] McManus, M.J.; Murphy, M.P.; Franklin, J.L. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J. Neurosci., 2011, 31(44), 15703-15715. [192] Ghosh, A.; Chandran, K.; Kalivendi, S.V.; Joseph, J.; Antholine, W.E.; Hillard, C.J.; Kanthasamy, A.; Kalyanaraman, B. Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model. Free Radic. Biol. Med., 2010, 49(11), 1674-1684. [193] Miquel, E.; Cassina, A.; Martínez-Palma, L.; Souza, J.M.; Bolatto, C.; Rodríguez-Bottero, S.; Logan, A.; Smith, R.A.; Murphy, M.P.; Barbeito, L.; Radi, R.; Cassina, P. Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis. Free Radic. Biol. Med., 2014, 70, 204-213. [194] Ng, L.F.; Gruber, J.; Cheah, I.K.; Goo, C.K.; Cheong, W.F.; Shui, G.; Sit, K.P.; Wenk, M.R.; Halliwell, B. The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease. Free Radic. Biol. Med., 2014, 71, 390-401. [195] Snow, B.J.; Rolfe, F.L.; Lockhart, M.M.; Frampton, C.M.; O'Sullivan, J.D.; Fung, V.; Smith, R.A.; Murphy, M.P.; Taylor, K.M.; Protect Study Group. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov. Disord., 2010, 25(11), 1670-1674. [196] Pehar, M.; Vargas, M.R.; Robinson, K.M.; Cassina, P.; Diaz-Amarilla, P.J.; Hagen, T.M.; Radi, R.; Barbeito, L.; Beckman, J.S. Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J. Neurosci., 2007, 27(29), 7777-7785. [197] Cassina, P.; Cassina, A.; Pehar, M.; Castellanos, R.; Gandelman, M.; de León, A.; Robinson, K.M.; Mason, R.P.; Beckman, J.S.; Barbeito, L.; Radi, R. Mitochondrial dysfunctionin SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J. Neurosci., 2008, 28(16), 4115-4122. [198] Stefanova, N.A.; Fursova, A.Z.; Kolosova, N.G. Behavioral effects induced by mitochondria-targeted antioxidant SkQ1 in Wistar and senescence-accelerated OXYS rats. J. Alzheimers Dis., 2010, 21(2), 479-491. [199] Stefanova, N.A.; Muraleva, N.A.; Skulachev, V.P.; Kolosova, N.G. Alzheimer's disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1. J. Alzheimers Dis., 2014, 38(3), 681-694. [200] Loshchenova, P.S.; Sinitsyna, O.I.; Fedoseeva, L.A.; Stefanova, N.A.; Kolosova, N.G. Influence of antioxidant SkQ1 on accumulation of mitochondrial DNA deletions in

2112 Current Medicinal Chemistry, 2017, Vol. 24, No. 19

[201]

[202]

[203]

[204]

[205]

[206]

[207]

[208]

[209]

[210]

[211]

the hippocampus of senescence-accelerated OXYS rats. Biochemistry (Moscow), 2015, 80(5), 596-603. Chen, T.F.; Chiu, M.J.; Huang, C.T.; Tang, M.C.; Wang, S.J.; Wang, C.C.; Huang, R.F. Changes in dietary folate intake differentially affect oxidised lipid and mitochondrial DNA damage in various brain regions of rats in the absence/presence of intracerebroventricularly injected amyloid β -peptide challenge. Br. J. Nutr., 2011, 105(9), 12941302. Campbell, G.R.; Reeve, A.K.; Ziabreva, I.; Reynolds, R.; Turnbull, D.M.; Mahad, D.J. No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis. Mult. Scler., 2013, 19(14), 1858-1866. Avetisyan, A.V.; Samokhin, A.N.; Alexandrova, I.Y.; Zinovkin, R.A.; Simonyan, R.A.; Bobkova, N.V. Mitochondrial dysfunction in neocortex and hippocampus of olfactory bulbectomized mice, a model of Alzheimer’s disease. Biochemistry (Moscow), 2016, 81(6), 615-623. Kapay, N.A.; Popova, O.V.; Isaev, N.K.; Stelmashook, E.V.; Kondratenko, R.V.; Zorov, D.B.; Skrebitsky, V.G.; Skulachev, V.P. Mitochondria-targeted plastoquinone antioxidant SkQ1 prevents amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. J. Alzheimers Dis., 2013, 36(2), 377-383. Genrikhs, E.E.; Stelmashook, E.V.; Popova, O.V.; Kapay, N.A.; Korshunova, G.A.; Sumbatyan, N.V.; Skrebitsky, V.G.; Skulachev, V.P.; Isaev, N.K. Mitochondria-targeted antioxidant SkQT1 decreases trauma-induced neurological deficit in rat and prevents amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. J. Drug Target., 2015, 23(4), 347-352. Bakeeva, L.E.; Barskov, I.V.; Egorov, M.V.; Isaev, N.K.; Kapelko, V.I.; Kazachenko, A.V.; Kirpatovsky, V.I.; Kozlovsky, S.V.; Lakomkin, V.L.; Levina, S.B.; Pisarenko, O.I.; Plotnikov, E.Y.; Saprunova, V.B.; Serebryakova, L.I.; Skulachev, M.V.; Stelmashook, E.V.; Studneva, I.M.; Tskitishvili, O.V.; Vasilyeva, A.K.; Victorov, I.V.; Zorov, D.B.; Skulachev, V.P. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 2. Treatment of some ROS- and age-related diseases (heart arrhythmia, heart infarctions, kidney ischemia, and stroke). Biochemistry (Moscow), 2008, 73(12), 1288-1299. Isaev, N.K.; Novikova, S.V.; Stelmashook, E.V.; Barskov, I.V.; Silachev, D.N.; Khaspekov, L.G.; Skulachev, V.P.; Zorov, D.B. Mitochondria-targeted plastoquinone antioxidant SkQR1 decreases trauma-induced neurological deficit in rat. Biochemistry (Moscow), 2012, 77(9), 996-999. Silachev, D.N.; Plotnikov, E.Y.; Zorova, L.D.; Pevzner, I.B.; Sumbatyan, N.V.; Korshunova, G.A.; Gulyaev, M.V.; Pirogov, Y.A.; Skulachev, V.P.; Zorov, D.B. Neuroprotective effects of mitochondria-targeted plastoquinone and thymoquinone in a rat model of brain ischemia/reperfusion injury. Molecules, 2015, 20(8), 14487-14503. Silachev, D.N.; Isaev, N.K.; Pevzner, I.B.; Zorova, L.D.; Stelmashook, E.V.; Novikova, S.V.; Plotnikov, E.Y.; Skulachev, V.P.; Zorov, D.B. The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk. PLoS One, 2012, 7(12), e51553. Plotnikov, E.Y.; Morosanova, M.A.; Pevzner, I.B.; Zorova, L.D.; Manskikh, V.N.; Pulkova, N.V.; Galkina, S.I.; Skulachev, V.P.; Zorov, D.B. Protective effect of mitochondria-targeted antioxidants in an acute bacterial infection. Proc. Natl. Acad. Sci. USA, 2013, 110(33), E3100-E3108. Weidinger, A.; Müllebner, A.; Paier-Pourani, J.; Banerjee, A.; Miller, I.; Lauterböck, L.; Duvigneau, J.C.; Skulachev, V.P.; Redl, H.; Kozlov, A.V. Vicious inducible nitric oxide

Fetisova et al.

[212]

[213]

[214]

[215]

[216]

[217]

[218]

[219]

[220]

[221]

[222]

[223]

synthase-mitochondrial reactive oxygen species cycle accelerates inflammatory response and causes liver injury in rats. Antioxid. Redox Signal., 2015, 22(7), 572-586. Demyanenko, I.A.; Popova, E.N.; Zakharova, V.V.; Ilyinskaya, O.P.; Vasilieva, T.V.; Romashchenko, V.P.; Fedorov, A.V.;, Manskikh, V.N.; Skulachev, M.V.; Zinovkin, R.A.; Pletjushkina, O.Y.; Skulachev, V.P.; Chernyak, B.V. Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice. Aging (Albany NY), 2015, 7(7), 475-485. Andreev-Andrievskiy, A.A.; Kolosova, N.G.; Stefanova, N.A.; Lovat, M.V.; Egorov, M.V.; Manskikh, V.N.; Zinovkin, R.A.; Galkin, I.I.; Prikhodko, A.S.; Skulachev, M.V.; Lukashev, A.N. Efficacy of mitochondrial antioxidant plastoquinonyl-decyl-triphenylphosphonium bromide (SkQ1) in the rat model of autoimmune arthritis. Oxid. Med. Cell Longev., 2016, 2016, 8703645. Galkin, I.I.; Pletjushkina, O.Y.; Zinovkin, R.A.; Zakharova, V.V.; Birjukov, I.S.; Chernyak, B.V.; Popova, E.N. Mitochondria-targeted antioxidants prevent TNFα-induced endothelial cell damage. Biochemistry (Moscow), 2014, 79(2), 124-130. Sovari, A.A.; Rutledge, C.A.; Jeong, E.M.; Dolmatova, E.; Arasu, D.; Liu, H.; Vahdani N.; Gu L.; Zandieh, S.; Xiao, L.; Bonini, M.G.; Duffy, H.S.; Dudley, S.C. Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death. Circ. Arrhythm. Electrophysiol., 2013, 6(3), 623-631. Xun, Z.; Rivera-Sánchez, S.; Ayala-Peña, S.; Lim, J.; Budworth, H.; Skoda, E. M.; Skoda, E.M.; Robbins, P.D.; Niedernhofer, L.J.; Wipf, P.; McMurray, C.T. Targeting of XJB-5-131 to mitochondria suppresses oxidative DNA damage and motor decline in a mouse model of Huntington’s disease. Cell Rep., 2012, 2(5), 1137-1142. Carvalho, C. The interplay between vascular and mitochondrial abnormalities in type 2 diabetes and Alzheimer’s disease. PhD Thesis, The University of Coimbra (Portugal): Coimbra, June 2013. Available: https://eg.sib.uc.pt/ handle/10316/23526. Lu, L.; Guo, L.; Gauba, E.; Tian, J.; Wang, L.; Tandon, N.; Shankar, M.; Beck, S.J.; Du, Y.; Du, H. Transient cerebral ischemia promotes brain mitochondrial dysfunction and exacerbates cognitive impairments in young 5xFAD mice. PloS One, 2015, 10(12), e0144068. Park, J.; Min, J.S.; Kim, B.; Chae, U.B.; Yun, J.W.; Choi, M.S.; Kong, I.K.; Chang, K.T.; Lee, D.S. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neurosci. Lett., 2015, 584, 191-196. Yang, L.; Zhao, K.; Calingasan, N.Y.; Luo, G.; Szeto, H.H.; Beal, M.F. Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Antioxid. Redox Signal., 2009, 11(9), 2095-2104. Calkins, M.J.; Manczak, M.; Mao, P.; Shirendeb, U.; Reddy, P.H. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum. Mol. Genet., 2011, 20(23), 45154529. Wu, J.; Zhang, M.; Hao, S.; Jia, M.; Ji, M.; Qiu, L.; Sun, X.; Yang, J.; Li, K. Mitochondria-targeted peptide reverses mitochondrial dysfunction and cognitive deficits in sepsisassociated encephalopathy. Mol. Neurobiol., 2015, 52(1), 783-791. Li, G.; Wu, J.; Li, R.; Yuan, D.; Fan, Y.; Yang, J.; Ji, M.; Zhu, S. Protective effects of antioxidant peptide SS-31 against multiple organ dysfunctions during endotoxemia. Inflammation, 2016, 39(1), 54-64.



[224] Davies, A.L.; Desai, R.A.; Bloomfield, P.S.; McIntosh, P.R.; Chapple, K.J.; Linington, C.; Fairless, R.; Diem, R.; Kasti, M.; Murphy, M.P.; Smith, K.J. Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann. Neurol., 2013, 74(6), 815-825. [225] Stucki, D.M.; Ruegsegger, C.; Steiner, S.; Radecke, J.; Murphy, M.P.; Zuber, B.; Saxena, S. Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondriatargeted antioxidant MitoQ. Free Radic. Biol. Med., 2016, 97, 427-440. [226] Yin, X.; Manczak, M.; Reddy, P.H. Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtininduced mitochondrial toxicity and synaptic damage in Huntington's disease. Hum. Mol. Genet., 2016, 25(9), 17391753. [227] Santini, E.; Turner, K.L.; Ramaraj, A.B.; Murphy, M.P.; Klann, E.; Kaphzan, H. Mitochondrial superoxide contributes to hippocampal synaptic dysfunction and memory deficits in angelman syndrome model mice. J. Neurosci., 2015, 35(49), 16213-16220. [228] McManus, M.J.; Murphy, M.P.; Franklin, J.L. Mitochondria-derived reactive oxygen species mediate caspasedependent and-independent neuronal deaths. Mol. Cell. Neurosci., 2014, 63, 13-23. [229] Manczak, M.; Mao, P.; Calkins, M.J.; Cornea, A.; Reddy, A.P.; Murphy, M.P.; Szeto, H.H.; Park, B.; Reddy, P.H. Mitochondria-targeted antioxidants protect against amyloid-β toxicity in Alzheimer's disease neurons. J. Alzheimer's Dis., 2010, 20(S2), 609-631. [230] Bai, J.Z.; Lipski, J. Differential expression of TRPM2 and TRPV4 channels and their potential role in oxidative stressinduced cell death in organotypic hippocampal culture. Neurotoxicology, 2010, 31(2), 204-214. [231] Liu, C.; Li, X.; Lu, B. The Immp2l mutation causes agedependent degeneration of cerebellar granule neurons prevented by antioxidant treatment. Aging Cell, 2016, 15(1), 167-176. [232] Stefanova, N.A.; Muraleva, N.A.; Maksimova, K.Y.; Rudnitskaya, E.A.; Kiseleva, E.; Telegina, D.V.; Kolosova, N. An antioxidant specifically targeting mitochondria delays progression of Alzheimer's disease-like pathology. Aging (Albany NY), 2016, 8(11), 2713-2733. [233] Kapay, N.A.; Isaev, N.K.; Stelmashook, E.V.; Popova, O.V.; Zorov, D.B.; Skrebitsky, V.G.; Skulachev, V.P. In vivo injected mitochondria-targeted plastoquinone antioxidant SkQR1 prevents β -amyloid-induced decay of longterm potentiation in rat hippocampal slices. Biochemistry (Moscow), 2011, 76(12), 1367-1370. [234] Ye, J.; Jiang, Z.; Chen, X.; Liu, M.; Li, J.; Liu, N. Electron transport chain inhibitors induce microglia activation through enhancing mitochondrial reactive oxygen species production. Exp. Cell Res., 2016, 340(2), 315-326. [235] Alfonso-Loeches, S.; Ureña-Peralta, J.R.; Morillo-Bargues, M.J.; Guerri, C. Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front. Cell. Neurosci., 2014, 8, 216. [236] Ma, Q.; Chen, S.; Hu, Q.; Feng, H.; Zhang, J.H.; Tang, J. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann. Neurol., 2014, 75(2), 209219. [237] Kim, H.; Kim, S.H.; Cha, H.; Kim, S.R.; Lee, J.H.; Park, J.W. IDH2 deficiency promotes mitochondrial dysfunction and dopaminergic neurotoxicity: implications for Parkinson’s disease. Free Radic. Res., 2016, 50(8), 853-860. [238] Liu, C.; Ye, Y.; Zhou, Q.; Zhang, R.; Zhang, H.; Liu, W.; Xu, C.; Liu, L.; Huang, S.; Chen, L. Crosstalk between Ca2+

signaling and mitochondrial H2O2 is required for rotenone inhibition of mTOR signaling pathway leading to neuronal apoptosis. Oncotarget, 2016, 7(7), 7534-7549. Zhou, Q.; Liu, C.; Liu, W.; Zhang, H.; Zhang, R.; Liu, J.; Zhang J.; Xu C.; Liu L.; Huang S.; Chen, L. Rotenone induction of hydrogen peroxide inhibits mTOR-mediated S6K1 and 4E-BP1/eIF4E pathways, leading to neuronal apoptosis. Toxicol. Sci., 2015, 143(1), 81-96 Hu, H.; Li, M. Mitochondria-targeted antioxidant mitotempo protects mitochondrial function against amyloid beta toxicity in primary cultured mouse neurons. Biochem. Biophys. Res. Commun., 2016, 478(1), 174-180. Shirani, A.; Okuda, D.T.; Stüve, O. Therapeutic advances and future prospects in progressive forms of multiple sclerosis. Neurotherapeutics, 2016, 13(1), 58-69. National MS Society. The MS disease-modifying medications. Brochure, 2016, pp. 1-30. Available: http://www.nationalmssociety.org/NationalMSSociety/medi a/MSNationalFiles/Brochures/Brochure-The-MS-DiseaseModifying-Medications.pdf. Scott, L.J.; Figgitt, D.P. Mitoxantrone: a review of its use in multiple sclerosis. CNS Drugs, 2004, 18(6), 379-396. Open label extension trial of idebenone for primary progressive multiple sclerosis, 2017 (Principal Investigator: Bielekova, B.). Available: https://clinicaltrials.gov/ct2/ show/NCT01854359. Fiebiger, S.M., Bros, H.; Grobosch, T.; Janssen, A.; Chanvillard, C.; Paul, F.; Dörr, J.; Millward, J.M.; InfanteDuarte, C. The antioxidant idebenone fails to prevent or attenuate chronic experimental autoimmune encephalomyelitis in the mouse. J. Neuroimmunol., 2013, 262(1-2), 66-71. Lipoic acid for secondary progressive multiple sclerosis (MS), 2016 (Principal Investigator: Spain, R.). Available: https://clinicaltrials.gov/ct2/show/NCT01188811. Spain, R.I.; Powers, K.; Murchison, C.; Heriza, E.; Horak, F.B.; Simon, J.; Bourdette, D.N. Lipoic acid for neuroprotection in secondary progressive multiple sclerosis: results of a randomised placebo-controlled pilot trial. ECTRIMS Online Library, 2016, 147064. Available: http://onlinelibrary.ectrims-congress.eu/ectrims/2016/32nd/147064/rebecca.spain.lipoic.acid.for.neuroprotection.in.secondary.progressive.html?f=m3. Lipoic acid and omega-3 fatty acids for cognitive impairment in multiple sclerosis, 2014 (Principal Investigator: Shinto, L.). Available: https://clinicaltrials.gov/ct2/show/ NCT02133664. Monocentric, prospective, doubleblind, randomised/stratified, placebocontrolled two-arm study to evaluate the effect of sunphenon EGCg (main component epigallocatechin-gallat) on the increase of brain atrophy in the cerebral magnetic resonance tomography in a 36-months treatment time in patients with primary or secondary chronicprogressive multiple sclerosis, 2016 (Principal Investigator: Friedemann, P.). Available: https://clinicaltrials.gov/ct2/ show/NCT00799890. Aktas, O.; Prozorovski, T.; Smorodchenko, A.; Savaskan, N.E.; Lauster, R.; Kloetzel, P.M.; Infante-Duarte, C.; Brocke, S.; Zipp, F. Green tea epigallocatechin-3-gallate mediates T cellular NF-κB inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J. Immunol., 2004, 173(9), 5794-5800. Sun, Q.; Zheng, Y.; Zhang, X.; Hu, X.; Wang, Y.; Zhang, S.; Zhang, D.; Nie, H. Novel immunoregulatory properties of EGCG on reducing inflammation in EAE. Front. Biosci. (Landmark Ed.), 2012, 18, 332-342. Mirshafiey, A.; Mohsenzadegan, M. Antioxidant therapy in multiple sclerosis. Immunopharmacol. Immunotoxicol., 2009, 31(1), 13-29.

[239]

[240]

[241] [242]

[243] [244]

[245]

[246] [247]

[248]

[249]

[250]

[251]

[252]

2114 Current Medicinal Chemistry, 2017, Vol. 24, No. 19

Fetisova et al.

[253] Petersen, R.C.; Thomas, R.G.; Grundman, M.; Bennett, D.; Doody, R.; Ferris, S.; Galasko, D.; Jin, S.; Kaye, J.; Levey, A.; Pfeiffer, E.; Sano, M.; van Dyck, C.H.; Thal, L.J. Vitamin E and donepezil for the treatment of mild cognitive impairment. New Engl. J. Med., 2005, 352(23), 2379-2388. [254] Kamat, C.D.; Gadal, S.; Mhatre, M.; Williamson, K.S.; Pye, Q.N.; Hensley, K. Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J. Alzheimers Dis., 2008, 15(3), 473-493.

[255] Bjelakovic, G.; Nikolova, D.; Gluud, L.L.; Simonetti, R.G.; Gluud, C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst. Rev., 2012, 3, CD007176. Available: http://dx.doi.org/10.1002/14651858.CD007176.pub2.

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PMID: 28302008