Mitochondria-targeted Antioxidants as a Prospective

Send Orders for Reprints to [email protected] 2086

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

Mitochondrial Antioxidants in Multiple Sclerosis

progressive MS (SPMS) [7], which leads to a loss of mobility and possible development of dementia. Neuronal and axonal degeneration in combination with cortical demyelination are the typical features of the SPMS stage [4]. A shorter RRMS period preceding SPMS is associated with a more quickly progressing and severe SPMS phase [7]. In 10-15% cases, MS begins abruptly with the acute stage and is called primary progressive MS (PPMS). Unfortunately, if the disease progresses, there is no effective therapy to reverse the disease [6]. Mounting observations indicate that, during the early stage of MS, oligodendrocyte demyelination is not pronounced, and patches of activated microglia are free from leukocyte infiltration [8-11]. The fact that, in some cases, the pre-active lesions spontaneously stopped without developing into demyelinating, which may indicate that therapeutic intervention in the early phases of MS could result in complete recovery of MS patients. The current available therapies of MS are primarily immunomodulatory and reduce the number of relapses but do not affect disease progression [12]. Oxidative stress and the related mitochondrial dysfunction are critically implicated in MS pathogenesis (see below). The development of new mitochondria-targeted antioxidants together with early diagnostics could be a promising way to study and develop future MS therapies. This line of investigation is possible due to (i) recent advances in studies on mitochondria-targeted antioxidants, (ii) the development of primary oligodendrocyte cultures for experimental studies of new drugs (Fig. 1) and (iii) the development of gene-screening technologies that allow persons predisposed to MS development to be diagnosed. The aim of this review is to analyze the role of mitochondrial dysfunction and oxidative damage in MS development and to discuss the protective effects of mitochondria-targeted antioxidants as promising components of the combined program of MS therapy. 2. MULTIPLE SCLEROSIS AS AN OBJECT OF THE STUDIES 2.1. Experimental Models of Multiple Sclerosis Experimental models for MS studies are generally represent oligodendrocyte cell cultures for in vitro studies and experimental autoimmune encephalomyelitis (EAE) models for animal studies. 2.1.1. Cell Culture Model Among the development of cultures of individual cells and tissues from the brain [13-15], primary oli-

Current Medicinal Chemistry, 2017, Vol. 24, No. 19 2087

godendrocyte cell cultures [16-18] provide a powerful experimental instrument to investigators of neurodegenerative diseases. Oligodendrocytes are a primary target in MS, and these cells are dramatically exhausted during the disease [19]. Such in vitro models with oligodendrocyte cells (Fig. 1) as a target of destruction during MS and various assays for studying MS have been described [20]. In contrast to animal models (Section 2.1.2.), MS in vitro models have not been widely developed. However, a few related systems have been reported for studying the mechanism of MS using oligodendrocyte or neuron co-cultures with microglial cells [21, 22]. In the following, we describe several findings among multiple significant achievements elucidating the MS mechanisms carried out using neural cell cultures. As was revealed in pure cultures, oligodendrocytes were proven to be the predominant cells for glutamate clearance in human white matter. Due to faulty glutamate receptor expression in oligodendrocytes, glutamate removal was found to be defective in MS white matter, which might underlie high extracellular glutamate levels and an increased risk for glutamate excitotoxicity [23]. Another important investigation of cultured oligodendrocytes showed that interferon-gamma (IFN gamma) was a potent inducer of apoptosis among oligodendrocytes in vitro. The authors postulated that IFN gamma played a role in MS pathogenesis by activating apoptosis in oligodendrocytes [24]. In other studies, the authors reported that ciliary neurotrophic factor was effective in preventing the natural death of oligodendrocytes in vitro [25]. Pure oligodendrocyte cultures demonstrated that lipopolysaccharide (LPS) mediated injury to oligodendrocytes and myelin as occurred in MS through the LPS-specific toll-like receptor (TLR4), which is expressed in microglia at high levels but not in astrocytes and oligodendrocytes [26]. Oligodendrocyte investigations in vitro indicated that immunoglobulin-G-demyelinating activity in patients with MS was restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes [27]. In addition to cell model in vitro studies of the factors that induce MS and participate in MS pathology (described above), other important investigations have been dedicated to uncovering ways to both prevent MS development and treat MS-affected tissues. For these purposes, oligodendrocyte cell cultures and cell tissue cultures with demyelination induced by various methods have been used. In oligodendrocytes, an MS pathology-emulating effects induced by a range of

2088 Current Medicinal Chemistry, 2017, Vol. 24, No. 19

Fetisova et al.

Fig. (1). Cultured oligodendrocytes of a rat (from our experiments; confocal microscope, Carl Zeiss LSM 510). A primary culture was prepared from the cerebellum brain tissue of a 2-day-old rat. White arrows indicate cell bodies. (a) Many processes of oligodendrocytes stained in green with antibodies for myelin basic protein are seen at the periphery of the cells. These processes wrap around axons (which are lacking in the oligodendrocyte culture shown in the image) to form myelin dielectric sheaths that support the speed of signal transmission and prevent signal dispersion. This capacity of oligodendrocytes weakens as MS progresses. (b-d) Mitochondria-targeted antioxidant SkQR1 (red-fluorescent derivative of SkQ, see below, Section 4) selectively accumulates in mitochondria. Therefore, mitochondria are seen as red-fluorescent bodies extended inside oligodendrocytes (phase contrast). The culture was preincubated with 50 nM SkQR1 for 2 h. Panel (d) is an extended view (x2) of panels (b) and (c).

Fig. (2). The general scheme of MS pathogenesis. Induced in the initial steps of MS, mitochondrial dysfunction provokes increased generation of ROS, which are involved in MS progression. MAO, mitochondria-targeted antioxidants. The direction of the progression of oligodendrocyte degeneration and MS pathogenesis is shown at the bottom of the scheme.


chemical and biological agents, such as cuprizone [28, 29], lipopolysaccharide (LPS) [30] and serum from experimental autoimmune encephalomyelitis (EAE) animals [31, 32], have been described.


EAE is a widely accepted animal model of MS. EAE is generally induced by immunizing rodents with myelin or myelin components, and the resulting symptoms depend on the animal model and method of EAE induction. The EAE models can be divided into acute and chronic EAE [33]. Acute models are characterized by severe inflammation and mild axonal injury, whereas chronic EAE leads to more prominent demyelination and axonal degeneration [34]. Therefore, acute EAE models are primarily used in studies of microglial activation and neuroinflammation accompanying MS, while chronic EAE models are more suitable for axonal demyelination and degeneration investigations.

2.2. Inflammation in Multiple Sclerosis A primary source of inflammation in the CNS is activated microglia. Further progression of inflammation occurs with damage to the blood-brain barrier (BBB) and accumulation of leukocytes in MS lesions. As inflammation starts, it is accompanied by severe ROS generation. The extent of consequent oxidative damage to inflamed tissues and the role of different cells in this process depend on the stage of MS [4, 38]. In brains of MS patients, approximately 30% of the normalappearing white matter was shown to contain activated microglia [39]. In the early phase of MS, microglia and macrophages begin to generate high levels of ROS, nitric oxide and hypochlorous acid due to activation of NADPH oxidase and NO synthase and secretion of myeloperoxidase, respectively [4]. However, some authors only consider microglia in cleaning functions, suggesting the destructive role to lie with macrophages [40].

The fact that mitochondrial dysfunctions, as observed in EAE, closely resemble those in MS suggests that similar mitochondria-driven mechanisms underlie pathogenesis. An argument in favor of this suggestion is the striking reduction in optic nerve atrophy in EAE animals, which was observed after adenoviral injection of mitochondrial superoxide dismutase, SOD2, demonstrating an important role of mtROS in axonal degeneration [35]. Further evidence of mtROS involvement in EAE pathogenesis was obtained in mice lacking cyclophilin D, a key regulator of the mitochondrial permeability transition pore (MTP). In these mice, MTPopening and the related excessive mtROS generation under stressful conditions is suppressed, leading to attenuation of EAE development and subsequent axonal protection, while inflammatory events are not affected [36]. In addition to the respiratory chain, another possible source of mtROS is the p66Shc protein, which likely contributes to EAE pathogenesis. Phosphorylation of p66Shc N-terminus targets it to the mitochondrial intermembrane space where this protein produces ROS and induces MTP-opening and apoptosis. In p66Shc-knockout mice, EAE symptoms, neuronal mitochondrial alterations and mtROS generation were less pronounced in comparison with wild-type EAE controls. p66Shc knockout and attenuation of MTPopening by cyclophilin D induced neuroprotection that was accompanied by no decrease in the inflammatory response [37]. Collectively, these findings show that EAE animals are suitable models for studying approaches to develop mitochondria-targeted therapy for MS.

The role of microglia in the succession of inflammatory events has become evident with the accumulating information on NLRP3 (nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3) inflammasomes, as stated below. Activated microglia were previously found to produce large amounts of proinflammatory cytokines and other mediators of inflammation [9, 41, 42]. Over the recent decade, a number of reports have suggested that further maturation of proinflammatory cytokines, interleukin-1β (IL-1β) and IL-18 is catalyzed by NLRP3 inflammasomes that play an essential role in microglia activation and MS development [43]. Inflammasomes are the cytosolic sensors that catalyze the maturation of proinflammatory cytokines. The mechanisms by which the diverse signals of danger activate these molecular machines remain poorly understood. NLRP3 inflammasome activation requires two signals, a "priming" transcriptional step that involves NFkB signaling, followed by oligomerization and activation of pro-caspase-1, which is critical for maturation of cytokines [38]. Inflammasome activation is also caused by the experimental stimulation of mtROS generation evoked by the inhibitors of the respiratory chain, rotenone and antimycin [44]. Scavenging mitochondrial superoxide attenuates NLRP3 activation, while NLRP3 agonists increase mtROS generation [45-47]. The exact mechanisms of NLRP3 activation by mtROS remain unclear. It was suggested that thioredoxin-interacting protein (TXNIP) serves as one of these mechanisms. In resting cells, TXNIP is occupied with reduced thioredoxin (TRX), but upon stimulation, ROS oxidize TRX, and consequently, TXNIP

2.1.2. Animal Model


dissociates from TRX to bind and stimulate NLRP3. Silencing of TXNIP attenuates NLRP3 activation [48]. NLRP3 and TXNIP were shown to relocalize from the cytosol or ER to mitochondria upon stimulation [45]. Interestingly, clearance of damaged mitochondria by mitophagy could be an important “safety catch” mechanism that controls NLRP3 activation. Inhibition of autophagy/mitophagy leads to spontaneous NLRP3 inflammasome activation and enhances activation by NLRP3 agonists [45]. Experimental evidence of elevated inflammation during MS include increased levels of the inflammatory mediators caspase-1, IL-18 and IL-1β observed in MS plaques, peripheral mononuclear cells and cerebrospinal fluid of MS patients and EAE model animals of MS. The crucial role of NLRP3 inflammasomes in MS progression was proven by evidence that EAE symptoms were attenuated in NLRP3 −/− mice and that EAE resistance was observed in caspase-1-deficient mice. Consequently, studies of MS patients and EAE model animals imply direct participation of inflammasomes in MS pathogenesis [38, 43]. Moreover, activation of inflammasomes is considered a general mechanism of neurodegenerative disease development. For example, in the brains of Alzheimer’s patients, amyloid-β peptide was demonstrated to activate NLRP3, and NLRP3 was shown to induce IL-1β secretion [46]. 2.3. Blood–Brain Barrier Disruption and Neurodegeneration in Multiple Sclerosis Proinflammatory cytokines, ROS and other mediators of inflammation, produced by activated microglia, induce loss of the barrier functions of the BBB [38, 49]. The BBB is formed by two distinct physical barriers. The first is generated by endothelial cells that form tight intercellular contacts and express various vascular efflux pumps that extrude toxins from the CNS. The second is formed by a basement membrane and astrocytes, collectively termed glia limitans. Thus, infiltration of leukocytes into the CNS requires passage across the endothelium and invasion through the glia limitans [50]. Mediators of inflammation induce endothelial permeability, leading to edema and transmigration of leukocytes from the bloodstream into the perivascular space and further to the CNS parenchyma. Inflammatory activation of astrocytes also contributes to disruption of the BBB and invasion of leukocytes [51]. Loss of barrier function of the endothelium occurs mainly due to the expression of selectins, adhesion molecules, endothelial NO-synthase (eNOS) and matrix metalloproteases [52]. Expression of these proteins is regulated

Fetisova et al.

by several transcription factors including NFkB. Specific inhibition of NFkB activation in endothelial cells prevents organ damage and lethality in experimental models of systemic inflammation and sepsis [53, 54]. Endothelial cells do not depend on the mitochondrial ATP supply, as glycolysis is the primary source of ATP for these cells. However, mitochondria as a source of ROS participate in signaling pathways that are critical for endothelial physiology and pathophysiology [55]. NFkB activation may be regulated by several redoxsensitive components of the signaling pathways, and mtROS has been suggested to play a key role in this process [56]. In agreement with this hypothesis, mitochondria-targeted antioxidants inhibit NFkB-dependent expression of adhesion molecules both in vitro and in the aorta of aged mice [56]. Inhibition of NFkB activation with mitochondria-targeted antioxidants could underlie their protective action in animal models of sepsis [57, 58]. Breakdown of the BBB is thought to be a crucial moment in MS lesion formation [39]. Generation of ROS by leukocytes in the lesions provokes macrophages to phagocytose myelin, inducing oligodendrocyte, neuronal and axonal injury [40, 59, 60]. The close interplay between inflammation and neurodegeneration in all lesion and disease stages of MS was suggested [28]. In fact, acute demyelination and neurodegeneration during the progressive stage of MS were detected exclusively against a background of brain inflammation [61]. The myelin-producing cells, oligodendrocytes, were found to be extremely sensitive to mediators of inflammation and oxidative damage. Oxidative stress inhibits differentiation of immature oligodendrocytes and decreases the expression of genes involved in oligodendrocyte maturation [62]. Cultured oligodendrocytes are also susceptible to oxidative destruction [63]. The idea of the key role of oligodendrocyte injury in the development of neurodegenerative processes is becoming popular [63]. Protection of oligodendrocytes against oxidative damage may be an effective strategy for the treatment of MS lesions by promoting oligodendrocyte remyelination and differentiation of immature oligodendrocytes [4]. Axonal destruction in MS is considered to be a twostage process. The first stage is thought to be a result of an acute axonal injury inside an inflammatory site, and the second stage corresponds to a non-inflammatory chronic lesion. Cytotoxic inflammatory mediators, such as ROS, nitric oxide and glutamate, are believed to induce acute axonal injury at the first stage of the disease, whereas the second stage of axonal degeneration


is thought to be caused by intra-axonal mechanisms and chronic demyelination [4]. Neurodegeneration is observed in both the gray and white matter from the very beginning of MS. Focal demyelination in the white matter is considered to be an initial stage of MS pathology [6]. Analysis of brain tissues in SPMS patients indicated a decrease in axonal density and Nacetylaspartate levels (a marker of neuronal integrity) in both the white and gray matter [37]. 2.4. Oxidative Damage in Multiple Sclerosis Pathogenesis The idea that oxidative stress contributes to the multiple injuries during MS has become popular in recent years. The reason for this notion is that high oxygen uptake and large amounts of polyunsaturated fatty acids lead to hypersensitivity of the CNS to lipid peroxidation. In fact, ROS-induced damage was shown to occur at the earliest stages of neuroinflammation [4]. Multiple markers of oxidative damage in MS patients were detected in serum, cerebrospinal fluid and CNS tissues [39, 64] and in nucleic acids in neuronal cells and astrocytes [65, 66]. Increased protein carbonylation and nitrosylation were observed in normal-appearing white and gray matters of MS brain tissue [4]. The width of the expansion depth of oxidative damage during MS is illustrated in Table 1 and is outlined as follows. In the human brain, a high level of oxidative stress was observed in deep gray matter MS lesions where the highest iron (Fe) content was measured. Thereupon, it is important to note that some regions of the human brain have high levels of both iron and ascorbate, and the mixture of these factors is a potent membrane prooxidant. In addition, it was suggested that iron that is accumulated by ferritin in myelin sheets is liberated during demyelination and, thus, participates in oxidative stress in MS lesions [92]. The accumulation of iron and its role in pathogenesis may differ among CNS regions and various forms of MS. In addition to oxidative stress promotion, iron can also participate in the activation of microglia and macrophages and in mitochondrial dysfunction contributing to MS pathogenesis. In MS patients at a progressive stage of the disease, a substantial correlation between MS pathogenesis and hypoxia in the gray matter was demonstrated using positron emission tomography (PET) [95] and by direct measurements of oxygen concentration using a fiberoptic sensor in an EAE mouse model [96]. Hypoxia is known to be accompanied by increased mitochondrial ROS generation and, consequently, contributes to oxi-


dative stress [97]. Mitochondrial ROS are involved in upregulation of the main regulator of the hypoxic response, hypoxia-inducible factor 1α (HIF-1α), which contributes to activation of inflammatory signaling [98]. The accumulation of reactive aldehydes in the serum of MS patients indicates severe lipid peroxidation and membrane damage [99]. 4-hydroxy-2-nonenal (4HNE) was detected in the foamy myelin-laden macrophages and in the large hypertrophic astrocytes in MSdemyelinated sites. The relatively long half-life (up to 2 minutes) of 4-HNE allows it to diffuse to sites distant from the initial oxidative event, making it highly toxic to CNS cells, including oligodendrocyte precursor cells and cerebral endothelial cells [100]. Another toxic aldehyde, acrolein, was shown to participate in various aspects of MS pathogenesis such as ischemia, inflammation and excitotoxicity [80, 101]. These aldehydes are the products and catalysts of lipid peroxidation and induce a vicious cycle that dramatically amplifies the damaging effects of oxidative stress. Acrolein is generated at much higher concentrations and is more reactive than 4-HNE. Consequently, scavenging acrolein could be a promising approach in MS therapy [80]. Thus, the FDA-approved anti-hypertensive drug hydralazine, which was shown to be an effective acrolein scavenger, significantly suppressed demyelination and behavioral decline in an EAE mouse model [101]. 2.5. Natural Antioxidant Defense Inherent to the CNS The CNS possesses many antioxidant enzymes that determine its redox status [102-104] and ability to neutralize a wide variety of ROS. Among these antioxidants are superoxide dismutase-1 and superoxide dismutase-2, which ensure superoxide anion conversion to hydrogen peroxide in the cytoplasm and in the mitochondrial matrix, respectively. The resultant hydrogen peroxide is subsequently removed by catalase mainly located in peroxisomes. Both antioxidants manifest themselves during MS-demyelination injury [67]. Many of the anti-inflammatory proteins and antioxidant enzymes were shown to be synthesized by myelinladen macrophages, hypertrophic astrocytes and activated microglia [4, 105]. One such protein is peroxiredoxin-1, which is increased during EAE and MS. It causes a decrease in ROS-induced demyelination and diminishes leukocyte penetration in the CNS. Peroxiredoxin-1 was shown to be produced in neurons, astrocytes and brain endothelial cells [106]. Proteomic analysis demonstrated a considerable rise of peroxire-


Fetisova et al.

Table 1. Multiple oxidative damage and its consequences in MS development. N

ROS-induced primary oxidative effect

Affected structures, subcellular organelles and сells

Effect on organelles, tissues and organism

8-hydroxyguanosine elevated levels mainly observed in the cytoplasm of neuronal cells

RNA

RNA oxidation in normal-appearing MS brain cortex (more pronounced in neuronal cells than in oligodendrocytes) [66]

2

8-oxo-2'-deoxyguanosine (8OHdG) elevated levels in cytoplasm

mtDNA

Oxidative damage to mtDNA in plague and MS cortical regions of cerebella [4, 6, 65, 67-70] − the process, which leads to multiple mtDNA deletions affecting complexes I, III, IV and V [70], to decrease in activities of complex I+III and citrate synthase [65, 70], to mitochondrial dysfunction and respiratory deficiency in neurons [70]

3

Protein carbonylation [71, 72], protein S-nitrosylation [73, 74]

Proteins in brain parenchyma [71], astrocytes, oligodendrocytes and neurons [72], brain white matter [73]

Protein modification/damage to white and gray matters of MS brain tissue [69, 71]; protein aggregation and apoptosis in spinal cord of EAE mice [72]

Protein nitration

Complexes I and IV; glyceraldehyde 3phosphate dehydrogenase; mtHsp70 chaperone mediating protein import to mitochondria in EAE mice [75]; proteins in axonal mitochondria [76], macrophages, astrocytes [4]

Deactivation of complex I and mtHsp70; decrease in ATP synthesis; cristae dissolution and EAE axonalmitochondria depolarization; cell apoptosis in spinal cord [75, 76]; axonal mitochondria dynamics deterioration [76]; oxidative damage to proteins in foamy macrophages and hypertrophic astrocytes [67]; BBB destruction and cerebral hemorrhage [77]

Lipid peroxidation that yields reactive aldehydes (in cerebrospinal fluid and plasma of MS patients) [69, 78-81]: acrolein [80], 4hydroxy-2-nonenal [67, 80-83], 7ketocholesterol [84], MDA [85, 86]; oxidation of polyunsaturated fatty acids (arachidonic acid [87], some other fatty acids)

Damaging effect on lipids, proteins, DNA [80, 83, 86] and membranes in large hypertrophic astrocytes, foamy myelin-laden macrophages, tight junctions in cerebral endothelial cells [4, 67, 88], oligodendrocyte precursors [82], oligodendrocytes [67, 82]

Alterations in endothelial cell permeability and monocyte penetration [4, 67]; protein carbonylation; deactivation of PDH, KGDH and complexes I, II, V; inhibition of complex I- and complex II-linked respiration; mitochondrial depolarization [86] and dysfunction [80]

4

5

Oxidative stress biomarkers

1

6

Hydroxyl radical (OH •) generation in ironaccumulating oligodendrocytes [6, 89, 90]

Oligodendrocytes, myelin and axons, mtDNA, mitochondria

Damage to oligodendrocytes, myelin sheaths and axons; iron release into extracellular space; iron accumulation by microglia and reinforcement of oxidative stress [67, 82, 91]

7

Hydroxyl radical generation in iron-laden microglia and macrophages, which accumulate iron released by damaged oligodendrocytes [92]

Activated macrophages and microglia; mtDNA; mitochondria

Damage to macrophages and microglia; second-wave-iron release into extracellular space and amplification of oxidative stress [91]

8

Oxidation of cysteine residues in Keap1 of Keap1-Nrf2 associates

Transcription factor Nrf2 escaping proteasomal degradation in neurons, foamy macrophages and astrocytes in MS active lesions

Nrf2 translocation into nucleus and activation of expression of antioxidant enzymes and other cytoprotective proteins [4, 67, 93]

9

Activation of hypoxia-inducible factor HIF-1 alfa

White matter in brain and spinal cord, cerebral endothelial cells

Expression of cytoprotective proteins, enzymes of glucose metabolism (hexokinases 1 and 2), proteins involved in angiogenesis (VEGF) and in iron metabolism (transferrin) etc. [6, 94]


doxins and superoxide dismutase at sites of MS damage. Glutathione peroxidase gene expression increases in inflammatory lesions, suggesting it plays a protective role in neuroinflammation. Increased catalase activity was found in the blood of MS patients [69, 78]. The enhanced antioxidant expression was suggested to operate as an endogenous compensatory mechanism to counteract ROS-induced damage [67]. Stimulating antioxidant production improves the health status of rats with EAE [4]. The expression of antioxidant enzymes is controlled by the transcription factor Nrf2 (nuclear E2-related factor), which is translocated into the nucleus upon oxidative stress and stimulates the expression of genes containing an antioxidant-response element (ARE) [64, 103]. More than 200 Nrf2-ARE genes participate in the organization of antioxidant protection. The expression of antioxidant enzymes in astrocytes indicates the involvement of these neuroglial cells in redox regulation of MS neuroinflammation [108]. The fact that activation of Nrf2 increases the survival of nerve cells in oxidative environments [64] suggests that substances stimulating antioxidant expression may be potential agents for MS therapy [109]. Interesting results of Nrf2 neuroprotection were obtained for dimethyl fumarate (DMF), which increases Nrf2 expression [93]. The ability of DMF to defend oligodendrocytes against the product of lipid peroxidation (7-ketocholesterol) was as effective as Trolox and α -tocopherol [84]. Increased antioxidant production was also observed in Alzheimer's disease and Parkinson's disease [110-112]. However, some authors observed reduced antioxidant activity in MS patients [69, 107, 113, 114], presumably caused by excess ROS leading to antioxidant inactivation [69]. In contrast to macrophages and astrocytes characterized by intensive antioxidant production in MS, the production of antioxidants in oligodendrocytes and endothelial cells in MS injury is rather low and does not markedly differ from that in normal brain tissue [67]. Due to poor compensatory mechanisms, high contents of polyunsaturated fatty acids and intracellular iron (in addition to the accumulation of this element in axons, which increases with aging) and low levels of radical scavengers, oligodendrocytes do not efficiently produce antioxidants for self-protection against MS oxidative damage. Of note, iron ions, similar to several transition metal ions, can be oxidized by superoxide into a strong oxidizing agent capable of hydrogen peroxide generation. Free reduced iron ions are dangerous after contact with hydrogen peroxide (Fenton reaction), resulting in generation of harmful hydroxyl radi-


cals (for review see [115]). In summary, it is plausible to assume that oligodendrocytes play a leading role in neurodegeneration induced by oxidative stress. 2.6. Participation of Mitochondria in Multiple Sclerosis Pathogenesis Accumulating evidence has shown that mitochondrial dysfunction plays an important role in MS pathogenesis [116]. Myelin degradation leads to relocalization of voltage-gated sodium (VGNa) and potassium (VGK) channels that distribute along the length of the axon instead of concentrating in Ranvier nodes and the juxtaparanodal region, respectively. This induces calcium and potassium ion outflow, leading to conduction failure [67, 80]. To restore the axonal conduction, Na+/K+-ATP-ase activity is enhanced by means of the rise in ATP production. The increased number of mitochondria in chronically demyelinated axons is likely an adaptive response to the increased energy demand but can also lead to the rise in mitochondrial ROS generation [4]. Specific markers of mitochondrial oxidative stress such as mitochondrial heat shock protein 70 (mtHSP70) were detected in axons and astrocytes in MS lesions [6]. Mitochondrial dysfunction in the cortex in MS was confirmed by the reduced levels of the neuronal mitochondrial marker, N-acetylaspartate (NAA) [37, 116], which is consistent with the increase in the degree of inflammation. In newly formed acute inflammatory lesions, NAA levels are low as a result of decreased mitochondrial function at this stage but increase in chronically demyelinated lesions in accordance with the rise in mitochondrial activity. As was revealed in neurons in non-demyelinated MS gray matter, activities of the respiratory complexes I and III were diminished, which might lead to dangerous changes in mitochondrial function in chronically demyelinated axons [117]. This reduction in activity of complexes I and III correlated with decreased expression of 26 subunits of the oxidative phosphorylation complexes in cortical neurons of MS patients [117]. In addition to the induction of Leber’s hereditary optic neuropathy, complex I dysfunction, which is the result of mitochondrial DNA mutations, enhanced the risk of MS promotion by 50 times [118, 119]. Respiratory chain alterations were observed not only in neurons but also in oligodendrocytes and astrocytes of MS patients [120]. Dysfunction of the respiratory chain and excessive mtROS generation can activate hypoxia-inducible factor 1α (HIF1α), thus resembling a chronic hypoxic effect. As reported, HIF1α translocation into the nucleus as a result of HIF1α activation was observed in the brain tissue of MS patients [6].


In EAE models, axonal oxidative injury and mitochondrial dysfunction precede the infiltration of leukocytes [4]. However, microglial activation occurring early in EAE pathogenesis likely contributes to early mitochondrial dysfunction. Ultrastructural changes of mitochondria at the sites of demyelination in EAE were demonstrated by electron microscopy [37]. Prior to axonal damage, normally tubular mitochondria become swollen and fragmented, indicating an early drop in the mitochondrial membrane potential and possible opening of the MTP. This and other evidence of mitochondrial involvement in EAE pathogenesis were discussed above (see Section 2.1). Although the full mechanisms of demyelination and neurodegeneration in MS are not clear, oxidative stress and mitochondrial dysfunction have been proven to play an important role in MS pathogenesis, as in many other neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease [121]. Considering the findings discussed above, it can be concluded that the early phase and relapsing-remitting episodic phase of MS depend on microglia activation, neuroinflammation and demyelination in the white matter. In the secondary progressive phase and chronic phase, demyelination and neurodegeneration in both the gray and white matter become the more prominent features of the disease. In the early phase of MS lesion formation, local inflammation induces ROS-dependent BBB disruption and infiltration of leukocytes. In the inflammatory lesions, axonal damage may be a bystander effect of myelin destruction and phagocytosis by activated microglia caused by inflammatory mediators, such as ROS, glutamate and NO. ROS, generated in leukocytes and activated microglia, promote oligodendrocyte cell death and mitochondrial dysfunction. In chronic MS lesions, internal neuronal mechanisms are responsible for axonal degeneration, and these mechanisms are generally similar to those in various neurodegenerative disorders. Mitochondrial dysfunction and primarily excessive mtROS generation could be important in all phases of MS. Activation of microglia depends on NLRP3 inflammasomes, which are controlled by mtROS. Neurodegeneration, in turn, depends on mtROS-dependent damage to the signaling pathways, and their deregulation crucial for cell survival. Of considerable importance are recent observations of the correlation of mitochondrial dynamics deterioration (that is, increased fragmentation of mitochondria and their reduced movement along axons) and the development of neurological deficits in EAE mouse

Fetisova et al.

model of MS [76]. In vivo imaging in the mentioned study showed that mitochondrial dynamics deterioration was accompanied by depolarization of axonal mitochondria and preceded the onset of neurological deficits. Further mitochondrial depolarization accompanied the development of the disease while mitochondrial potential in axons recovered in EAE mice during remission with clinical recovery of neurological functions. During relapse episodes, mitochondrial depolarization returned. These findings are in good agreement with the earlier observations on the violation of mitochondrial mobility in axons in mouse cerebellar slice cultures exposed to lipopolysaccharide or hydrogen peroxide [122]. Of note, in this ex vivo model, neuroinflammation was accompanied by an increase in the size of axonal mitochondria possibly resulting from a compensatory response. Furthermore, neurological deficits in MS have been widely attributed to worsening axonal conductance resulting from axon demyelination [123], but in the described EAE model, demyelination was not observed for the first day of neurological deficits [76]. Thereafter, the authors suggested that mitochondrial dysfunction, fragmentation and movement cessation contributed to the development of neurological deficits at the onset of disease and probably also during relapse episodes. The reason for mitochondrial dysfunction in MS remains unclear, but one may suggest that mitochondrial ROS overproduction plays an important role in this phenomenon in that (i) decreased activity of complex I (which is one of the major sources of ROS in mitochondria) was observed for the first day of loss of neurological functions [76], and (ii) mitochondrial ROS are powerful stimuli for mitochondrial fragmentation as was shown using mitochondria-targeted antioxidants [124]. The general scheme that illustrates the important role of mitochondrial ROS generation in MS pathogenesis is shown in Fig. (2). In the following sections of this review, we discuss the mechanisms of mitochondrial ROS generation and the properties of mitochondria-targeted antioxidants as potential components of MS therapy. 3. MITOCHONDRIAL ROS GENERATORS Reactive oxygen and nitrogen species (ROS, RNS) are terms for the following compounds: hydrogen peroxide (H2 O2), superoxide radical (O2•-), hydroxyl radical (OH•), nitric oxide radical (•NO) and peroxynitrite (ONOO-). ROS are generated in reactions of incomplete dioxygen reduction by single-electron carriers


(ions of transition metals and organic molecules such as semiquinone species of quinone and flavin, comprising enzyme cofactors) [115]. It is widely accepted that mitochondria are one of the major sources of ROS in various pathophysiological states [91]. The enzymes participating in ROS generation in the mitochondrial respiratory chain are complexes I, II and III, which are localized in the inner mitochondrial membrane. RNS as ONOO- can also be generated as the by-product in mitochondria, while specific RNS-producing reactions ensured by nitric oxide synthases proceed in nerve tissue, immune cells (for example, macrophages) and other tissues and require flavin species, tetrahydrobiopterin and heme b as cofactors [125, 126]. In this section, we briefly describe ROS-mediated and, to some extent, RNS-mediated mechanisms that have been shown to induce several neurodegenerative diseases with MS among them. These mechanisms include the mitochondrial respiratory complexes mentioned above as well as other mitochondrial and non-mitochondrial producers of ROS and RNS. 3.1. Complex I Complex I (EC number 1.6.5.3) is considered as a major source of ROS in various neurodegenerative diseases, particularly in Parkinson's disease [127]. Complex I, poisoned by neurotoxins (the most studied is MPP+, metabolized in organisms from external MPTP), was shown to induce ROS-mediated dopaminergic cell death and a parkinsonian state. Mutations in complex I were identified among the genetic causes of familial Parkinson's disease. It was shown that complex I derived ROS are sufficient to trigger Aβ production in vitro and in vivo [128]. Complex I deficiency was detected in an animal model of ALS [129] and in ALS patients [130]. A loss of complex I activity was observed in autopsied MS brains [117] and in the optic nerves of EAE mice [131]. Moreover, the same authors recently reported that gene therapy using an adenoassociated viral vector with the NDUFA6 gene of the complex I subunit completely rescued retinal complex I activity and significantly prevented axonal loss, retinal ganglion cell apoptosis and the ultimate loss of vision in EAE mice [132]. These findings indicated that complex I dysfunction could be involved in mitochondrial oxidative stress accompanied by neurodegeneration associated with permanent visual loss in animal models of MS. Complex I generates ROS both via the forward NADH oxidase reaction and the reverse reaction of NAD+ reduction. In these reactions, complex I was


shown to generate both superoxide radicals and hydrogen peroxide [133]. Among all the cofactors that carry out a single-electron transfer in complex I (FMN, 8-9 FeS clusters and tightly bound ubiquinol), the roles of ROS generators are supposed to be fulfilled by FMN [134] and ubisemiquinone [135] in the forward and reverse reactions, respectively, and possibly by the FeS center, N2 [136]. 3.2. Complex II ROS produced by complex II (EC 1.3.99.1) could be implicated in the pathogenesis of neurological disorders (for review, see [137]). This interplay was determined by investigations of mutations in complex II, which resulted in Leigh syndrome, a neurodegenerative disease that is associated with neuronal cell death and impaired motor functions [138, 139]. ROS produced by complex II have been suggested to play a possible role in apoptosis of neuronal cells, as specific inhibitors of the quinone reduction site in complex II stimulate apoptosis, while inhibitors of the succinate-binding site are antiapoptotic [140]. More recent studies indicated that specific disintegration of complex II induced by intracellular acidification and Ca2+ influx into mitochondria could stimulate massive ROS generation and neuronal cell death [141]. In rat skeletal muscles, where the mitochondrial complex II was shown to generate both superoxide and hydrogen peroxide at a high rate [142], FAD was suggested to generate ROS. In other studies, the CoQbinding site [143, 144] and an additional unresolved cite were also suggested as possible locations of ROS generation in complex II [145, 146]. However, the precise mechanism of ROS generation by complex II remains unclear. 3.3. Complex III Complex III (EC 1.10.2.2) could be an important site of ROS generation comparable to complex I [147], but its possible role in neurodegenerative diseases remains virtually unstudied. Loss of complex III (concurrently with complex I) was detected in the spinal cords of patients with sporadic ALS [148] and in a transgenic mouse model of ALS [129]. Gene therapy with mitochondrial heat shock protein 70 nearly completely restored the activity of complex III and complex I in the retina and attenuated visual loss in EAE mice, suggesting that invalid assembly of these complexes could underlie the pathogenesis of MS. It was suggested that superoxide production by complex III was catalyzed by ubisemiquinone as a sin-


gle-electron donor [149]. Based on its X-ray crystallographic structure, the detailed mechanism of ROS generation by complex III [150] confirmed the early hypothesis of ubisemiquinone-mediated ROS generation mentioned above [149]. 3.4. Mitochondrial Non-Respiratory Chain Producers of ROS Careful studies on ROS generation in isolated mitochondria and submitochondrial vesicles derived from the inner mitochondrial membrane demonstrated that the rate of ROS generation by complexes of the respiratory chain is very low. By contrast, significant mitochondrial ROS generation was derived from α ketoglutarate dehydrogenase (EC 1.2.4.2) and pyruvate dehydrogenase (1.2.4.1) located in the mitochondrial matrix and from the key component of these two enzyme complexes, dihydrolipoamide dehydrogenase (EC 1.8.1.4) in particular [151-153]. In brain tissues, the latter enzyme was shown to catalyze the reduction of NAD+ to NADH at the expense of the disulfidebridge- and FAD-mediated electron transfer from dihydrolipoamide and to generate superoxide and hydrogen peroxide. Mice deficient in dihydrolipoamide dehydrogenase were shown to have an increased vulnerability to various neurotoxins [154]. Partial gene deletion of dihydrolipoyl succinyltransferase, which is one of the components of the α -ketoglutarate dehydrogenase complex, accelerates the onset of Alzheimer's disease pathogenesis, which was demonstrated using a transgenic mouse model of amyloid deposition [155]. This effect was attributed to increased mitochondrial oxidative stress, although the details of ROS generation in this model remain obscure. According to calculations of Grivennikova and Vinogradov [153], the contribution of dihydrolipoamide dehydrogenase to total ROS generation is similar to that of complex I, and the total rate of ROS generation by these enzymes in mitochondria is very low. However, multiple experimental proofs using mitochondriatargeted antioxidants (see below) suggest that ROS generation in mitochondria is meaningful and plays a key role in the pathogenesis of various neurological disorders including MS [125, 156]. Therefore, it is reasonable to suggest two non-mutually exclusive explanations of this controversy: (i) mitochondrial ROS generation strongly increases during pathological states due to the disturbance of enzyme complexes, and (ii) mitochondrial ROS ignite the generation of ROS by the other more powerful sources. The second suggestion received strong support from studies of the cross-talk

Fetisova et al.

between mitochondrial ROS and NAD(P)H oxidases of the NOX family (EC 1.6.3) located in the plasma membrane and intracellular vesicles (for review see [157]) and is described in the following subsection. 3.5. Non-Mitochondrial Producers of ROS NAD(P)H oxidases of the NOX family are the enzyme complexes that produce hydrogen peroxide as the main function and hence are among the main ROS producers. Activation of NOX in endothelial cells by mitochondrial ROS was convincingly demonstrated by Dikalov and co-workers [158]. It was shown that NOX activation induced with hormone angiotensin II was inhibited by the mitochondria-targeted antioxidant Mito-TEMPO or by the overexpressed mitochondrial MnSOD (SOD2). Later, the same phenomenon was observed in neutrophils indicating a possible role of mitochondrial ROS in the oxidative burst catalyzed by NOX2 [159]. One of the members of the NOX family, NOX4, is located in the outer mitochondrial membrane, but its particular role in mitochondrial oxidative stress has not been studied. Although functions of NAD(P)H oxidase in neurological disorders have been poorly studied, it was clearly demonstrated that changes in the expression of NOX1 and NOX2 subunits accompany the progression of multiple sclerosis at early stages [160]. NOX subunits were detected in activated microglia and infiltrated macrophages, suggesting that inflammation-associated oxidative burst plays an important role in demyelination and MS pathogenesis. Xanthine dehydrogenase, whose conversion to oxidase can be induced by mitochondrial ROS, is one of the other possible sources of oxidative stress [157]. A possible cross-talk between mitochondrial ROS and NO synthases (EC 1.14.13.39) could also contribute to neurodegeneration. Notably, ROS can induce “uncoupling” of NO synthases (NOS) when electrons leak from the reductase domain to molecular oxygen to yield superoxide instead of NO. It is known that not only endothelial NOS but also neuronal NOS may be uncoupled and produce superoxide [161]. As used here, NOS merits further consideration. NOS induces synthesis of NO in mammals via catalyzing a special reaction of L-arginine and dioxygen that proceeds at the expense of NADPH oxidation. To ensure single-electron transfer, the enzyme disposes of four cofactors [162], FMN, FAD, tetrahydrobiopterin, and b-type heme, whose spatial locations are now known due to the availability of the crystallographic structures of human nNOS, human eNOS [163] and



iNOS from Mus musculus [164]. The three NOS isoforms, each located in cells lining blood vessels (endothelial, eNOS), muscle and neuronal cells (neuronal, nNOS) and macrophages (inducible, iNOS) [126], have similar, although distinct, principle architectures, while each isoform in different mammalian species is nearly equivalent with some minor singularities that are crucial in the different modes of NOS interplay with potential chemical substances. Among the three known isoforms of the enzyme, nNOS and iNOS, which highly produce NO, may be relevant in the study of plausible causes of the rise and development of MS. The following factors suggest this possibility: (i) the highest NO release occurs in areas of inflammation [115] where the expression of iNOS in macrophages was shown to be induced by certain cytokines, (ii) the most iNOS in the brain and spinal cord of humans with MS that were found in macrophages infiltrating these tissues in demyelination lesions and astrocytes [165], and (iii) the elevated as well as depressed levels of NO as a result of abnormal nNOS activity in nerve tissue lead to a number of neurodegenerative disorders [166]. Actually, in a rodent EAE model of MS, a number of iNOS inhibition studies and observations of iNOS expression resulting in progression of the disease argue in favor of iNOS being implicated in MS (for review, see [167]). The autopsy findings on iNOS overexpression in active demyelinating regions of human brain tissue from MS patients are particularly valuable and persuading. 4. MITOCHONDRIA-TARGETED DANTS

ANTIOXI-

The development of a new type of therapy based on mitochondria-targeted antioxidants (MAO) has opened a new chapter in treatment of many pathologies, including neurological diseases associated with oxidative stress. The lipophilic cations that can penetrate membranes and selectively accumulate in mitochondria, which are unique subcellular organelles in that they have a negative internal charge, were first described by Liberman and Skulachev in the sixties [168]. Later, in the pioneering works of Murphy's group, these lipophilic cations were linked to antioxidants that led to the first mitochondria-targeted drugs [169, 170]. In these works, the decyltriphenylphosphonium cation was used for the targeted delivery of antioxidants such as vitamin E and ubiquinol to mitochondria. One such compound characterized by ubiquinone conjugated with the triphenylphosphonium cation by means of a normal hydrocarbon linker with ten methylene groups, namely, [10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-

dien-1-yl)decyl]triphenylphosphonium bromide, was designated MitoQ (Fig. 3) and remains the most studied MAO. Later, a number of other lipophilic cations (including some natural compounds) were linked to various antioxidants and other active residues [171-173]. Among mitochondria-targeted antioxidants, MitoQ (Fig. 3) was shown to be the first rechargeable compound, as after it was oxidized by MtROS to the nonactive ubiquinone-containing form, it was re-reduced by the respiratory chain to the active ubiquinolcontaining form. Such resettability and selective accumulation in mitochondria contribute to the high efficacy of MitoQ to prevent oxidative stress both in vitro and in vivo [171]. However, at high doses, quinols and many other antioxidants, are known to acquire prooxidant properties. In this regard, MitoQ has a comparatively narrow therapeutic window between the antioxidant and prooxidant doses, which could complicate its administration in therapy. In the search for the best antioxidant, Skulachev and co-workers designed the so-called SkQ1 compound ([10-(4,5-dimethyl-3,6dioxocyclohexa-1,4-dien-1-yl)decyl]triphenyl phosphonium bromide) (Fig. 3) in which the quinone moiety compared to the ubiquinone moiety in MitoQ was replaced by plastoquinone, which is known to operate in the photosynthetic electron transport chains of chloroplasts and cyanobacteria [174]. Similar to MitoQ, SkQ1 is actively accumulated by mitochondria. In these organelles, after its oxidation by MtROS, the plastoquinol moiety of the compound is rapidly reduced by the respiratory chain to produce the reduced form of SkQ1 (containing an active plastoquinol moiety) and, thereby, regaining the antioxidant capacity of SkQ1. In SkQ1, the substitution of methyls at positions 2 and 3 for methoxy groups and the absence of the methyl group at position 5 of the quinone ring resulted in widening of the window between the anti- and prooxidant concentrations by more than 30 times compared to MitoQ [174]. Consequently, the reduced SkQ1 form possesses some of the best antioxidant properties among the mitochondria-targeted quinol compounds [175]. Due to this property, SkQ1 protects cardiolipin molecules, which are the primary targets of ROSmediated oxidation and the key initiators of lipid peroxidation and dysfunction of the enzymes in mitochondria [175]. Skulachev’s group later synthesized a set of antioxidants of the SkQ family with various modifications in the quinone-containing moiety and cationic region [176]. All of them contained lipophilic triphenylphosphonium cations linked by means of an nalkylhydrocarbonic fragment (mainly, n-decyl) to vari-


Fetisova et al.

Fig. (3). Chemical structures оf the active forms of MitoQ and SkQ1 with the reduced ubiquinol and plastoquinol antioxidant moieties that are indicated in gray on the left and right of each compound, respectively. The lipophilic decyltriphenylphosphonium cations play a role in transmembrane “vehicles” that drive the accumulation of MitoQ and SkQ1 inside mitochondria.

ous p-quinones, in particular 1,4-benzoquinone, 1,4tоluquinone, trimethyl-1,4-benzoquinone, thymoquinone and others. One way to synthesize these pquinone moieties is shown in Fig. (4). The corresponding p-quinone (Fig. 4, 1a-1d) is subjected to radical alkylation by ω-bromdecanoic acids with simultaneous decarboxylation in the presence of ammonium persulfate and silver nitrate [177]. Then, the obtained bromdecylquinones (Fig. 4, 2a-2d) are involved in the quaternization reaction of triphenylphosphine at high temperatures, which results in formation of the target products, SkQ1, SkQ3, SkQB and SkQT (Fig. 4, 3a3d). Furthermore, in some SkQ molecules, the triphenylphosphonium residue is replaced by lipophilic cations such as tributylammonium, methylcarnitine, and rodamines and natural cations such as berberine and palmatine, all of which bear an ionized nitrogen atom (Fig. 5) [172, 173]. Among these cations, tributylammonium, methylcarnitine and rodamines are wellknown as membrane penetrants. The property of berberine and palmatine allowing them to cross both model and natural membranes was demonstrated before designing SkQ molecules [178]. The abovementioned SkQ analogues all demonstrated a very high protection efficiency in various models of ROS-related pathologies both in vitro and in vivo [179-181]. SkQR1 was shown to be a neuroprotectant and nefroprotectant, while in a model of local ischemia, it can prevent or correct pathological changes in different tissues (e.g., heart, kidney, brain, etc.). In a multicenter, randomized, double-masked, placebocontrolled clinical study, SkQ1-containing eye drops (Visomitin®) were shown to improve the functional state of the cornea and reduce the symptoms of dry eye syndrome [182]. Visomitin® is the first registered drug (in Russia) containing a mitochondria-targeted antioxidant, SkQ1, as an active ingredient.

Among mitochondria-targeted antioxidants, the drug idebenone should be mentioned, a synthetic analog of coenzyme Q10 that bears no cationic residue but presumably operates in the inner mitochondrial membrane [183]. Idebenone was shown to be beneficial in Friedreich's ataxia and Leber's hereditary optic neuropathy, diseases which are caused by mitochondrial disorders. However, in a recent study, idebenone did not exhibit any clinical effect in EAE mice [184]. Histopathological examination of the CNS in idebenone-treated mice revealed no decrease in inflammation, demyelination or axonal damage. Nevertheless, a phase II trial of idebenone in patients with progressive MS is currently underway (NCT01854359). The mimetic of superoxide dismutase (SOD), TEMPO, conjugated with triphenylphosphonium-based lipophilic cations (Mito-TEMPO), is also an important member of the mitochondria-targeted antioxidant family [158, 185, 186]. This compound could also be classified as a “rechargeable antioxidant”. In addition to penetrating cations, positively charged short peptides (SS-peptides) are also selectively addressed to mitochondria, although they do not penetrate the inner mitochondrial membrane [187]. These peptides bind to cardiolipin, a specific component of the inner mitochondrial membrane, and modify its interaction with cytochrome c, thus preventing cardiolipin peroxidation [188]. Gramicidin S, a peptide antibiotic, also binds to cardiolipin and, therefore, was used as a vehicle for targeting TEMPO to mitochondria (hemigramicidin-TEMPO) [189]. Interestingly, MitoTEMPO, accumulated in mitochondria due to transmembrane electric potential, was approximately 1000 times more active than hemigramicidin-TEMPO when tested in the same in vivo model [190]. To date, the most widely used mitochondriatargeted antioxidant is MitoQ. MitoQ has been shown to inhibit oxidative stress and to improve normal



Fig. (4). The synthesis of mitochondria-targeted antioxidants of the SkQ family.

Fig. (5). Conjugates of antioxidant plastoquinol (marked on the left in gray) with lipophilic cations (marked on the right in gray) such as rhodamine-19 (SkQR1, reduced), berberine (SkQBerb, reduced) and palmatine (SkQPalm, reduced).

physiological readouts in various animal models of neurological diseases, including Alzheimer's disease (AD) [191], Parkinson's disease (PD) [192], ALS [193]

and MS [156]. It was reported that treatment with MitoQ for 5 months prevented cognitive decline, synaptic loss and amyloid (Aβ) accumulation in the brains of


mice of a triple-transgenic AD model. MitoQ also attenuated Aβ-induced oxidative stress, neurotoxicity and loss of mitochondrial membrane potential in cortical neurons [191]. In a recent study, MitoQ delayed Aβinduced paralysis and extended the lifespan of Caenorhabditis elegans worms overexpressing human Aβ, whereas it did not affect any markers of oxidative stress, including mitochondrial DNA oxidation [194]. In experimental models of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), MitoQ inhibited loss of neurons in the substantia nigra and a decline in locomotor activity in mice. MitoQ also prevented loss of tyrosine hydroxylase, depolarization of mitochondria and activation of apoptotic caspase-3 in cultured dopaminergic cells treated with 1-methyl-4phenylpyridinium (MPP+), an active metabolite of MPTP [192]. A clinical study (double blinded) administering two MitoQ doses during 12 months to 128 newly diagnosed untreated PD patients revealed no significant improvement according to the United Parkinson Disease Rating Scale when treated patients were compared with a placebo control. It was concluded that MitoQ did not slow the progression of PD [195]. The most likely explanation for this trail failure is that approximately 50% of neuronal loss is already observed in the patients diagnosed with PD, rendering ineffective any treatment administered at this stage in an attempt to reverse or even prevent further progression of the disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration, and its pathogenesis has many features in common with MS. The most widely used animal model of ALS is transgenic mice expressing a familial ALSlinked SOD1 mutation. These mice were treated with MitoQ-containing drinking water beginning from the moment of early symptoms of neurodegeneration at the age of 90 days until death. Interestingly, in this case, MitoQ retarded the decline of mitochondrial function in both the spinal cord and quadricep muscles, as evaluated by high-resolution respirometry [193]. MitoQ administration reduced motor neuron loss and astrogliosis in the lumbar spinal cord and preserved neuromuscular junctions in the extensor digitorum longus muscle. These effects were accompanied by a significant increase in hindlimb strength and prolonged life spans of mutant mice [193]. Studies in SOD1 mutant mice have demonstrated the importance of glia in motor neuron support and have uncovered the capacity of MitoQ to prevent the toxicity of mutant SOD1 in cul-

Fetisova et al.

tured motor neurons [196] and astrocytes [197]. These data indicate that both motor neurons and glial cells were protected by MitoQ in the animal model of ALS. A possible application of MitoQ in MS therapy was studied in an EAE mouse model [156]. Mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide in complete Freund's adjuvant. In the preventive protocol, MitoQ (100 nmol/mouse) was injected i.p. 10 days before immunization and then continuously (twice a week) for another 30 days. In the therapeutic protocol, MitoQ (100 nmol/mouse) was injected i.p. 14 days after immunization and then twice a week for 30 days. It was shown that preventive treatment with MitoQ resulted in a modest but statistically significant delay of the onset of behavioral deficits, and moreover, a therapeutic effect of MitoQ was observed. MitoQ treatment decreased inflammation in the spinal cords of EAE mice, as revealed by the reduced expression of genes that are associated with central nervous system inflammation. This effect resembled the decrease in the level of inflammatory cytokines and oxidative stress under the influence of MitoQ in the model of sepsis [58] and the anti-inflammatory action of other mitochondria-targeted antioxidants in various models [52-54]. MitoQ treatment increased myelin basic protein (MBP) expression and attenuated neurodegeneration in EAE mice. Interestingly, MitoQ protected also against the axonal damage induced by lipopolysaccharide-activated microglia in vitro [156]. These data suggest that MitoQ therapy prevented neuronal damage induced by mediators of inflammation produced by microglia in animal models of MS. SkQ1 and its analogs were intensively studied in long-term experiments that revealed the strong antiaging effect of these antioxidants [179]. It was found that SkQ1 significantly improved the exploratory activity of aging rats in the open field test [198]. This effect was even more pronounced in senescence-accelerated OXYS rats. Magnetic resonance tomography and analysis of amyloid-β together with behavioral tests indicated a striking similarity between neurological deficits in OXYS rats and AD patients [199]. The longterm treatment of OXYS rats with SkQ1 (250 nmol/kg body weight daily from the age of 1.5 to 23 months) slowed the pathological accumulation of Aβ and the hyperphosphorylation of tau-protein (another marker of AD pathogenesis) in the cortex and hippocampus in these animals. Age-related alterations in behavior and spatial memory deficits tested using the Morris water maze were also attenuated.


Recently, it was found that the development of neurodegenerative changes in the brains of OXYS rats were accompanied by accelerated accumulation of the large mitochondrial DNA deletion (ΔmtDNA4834) in the hippocampus [200]. The level of ΔmtDNA4834 strongly increased during the period crucial for manifestation of neurological deficit in OXYS rats at the age of 1.5-3 months, but at the age of 24 months, there were no detectable differences between OXYS and Wistar (control) rats. An earlier increase in the amount of ΔmtDNA4834 was observed in the hippocampus of rats in an AD model induced by Aβ administration [201]. Daily SkQ1 (250 nmol/kg) administration between 1.5 and 3 months of age reduced the level of ΔmtDNA4834 in the hippocampus of OXYS and Wistar rats [200]. mtDNA deletions are the predominant type of mtDNA mutations in neurodegeneration including MS pathogenesis (see Table 1, Section 2.4). Post-mortem studies of progressive MS demonstrated multiple deletions of mtDNA throughout the gray matter [70], while no excess mtDNA deletions were found within muscle [202]. Importantly, OXYS rats showed signs of demyelination of foci in 75% of 3-month-old and 100% of 13- and 23month-old animals [199], indicating that the described AD-like pathology was likely accompanied by some signs of MS. Recently, the protective effect of SkQ1 was observed in intracerebroventricular streptozotocin rat models of AD (N.K. Isaev, personal communication). Olfactory bulbectomized mice were also used as an AD model in studies of the protective action of SkQ1 [203]. Aβ in vitro application to rat hippocampal slices impaired long-term potentiation of the spike population in the pyramidal layer of the CA1 field of the hippocampus, suggesting that this phenomenon was a result of some pathological changes in AD brains. Indeed, SkQ1 (250 nmol/kg) given 24 h before slice preparation or 1 h-treatment of hippocampal slices with 250 nM SkQ1 prevented the deleterious effect of Aβ [204]. The SkQ1 analog, SkQT1, in which the plastoquinone residue is replaced by thymoquinone, was found to be even more potent in preventing the Aβ effect [205]. These findings argue for a possible use of SkQ1 for the treatment and prophylaxis of various neurodegenerative diseases including MS. The pronounced protective effects of SkQ1 and its analogs were observed in models of acute brain injury and stroke. Furthermore, the analogs SkQR1 and SkQTR1, in which the triphenylphosphonium cation is replaced by rhodamine-19, were usually more active. These antioxidants were administered either intraperitoneally or intranasally, with the latter demonstrating a high level of penetration into the brain tissues. Their


neuroprotective properties were demonstrated in an open focal trauma of sensorimotor cortex [206, 207] and in a model of brain ischemia/reperfusion injury induced by middle cerebral artery occlusion [208]. The long-term administration of antioxidants or treatment immediately after reperfusion reduced neurological deficits but affected the volume of brain damage to different extents. Interestingly, the protective effects of SkQR1 were not observed in rats with bilateral nephrectomy or in those treated with the nephrotoxic antibiotic gentamicin, indicating the crucial role of humoral factors (presumably erythropoietin), which are released from the kidneys [209]. The leading role of neuroinflammation in neurodegenerative diseases, acute brain injury and stroke is well recognized. The pronounced anti-inflammatory effects of SkQ1 and its analogs have been clearly demonstrated [210-213] and likely at least partially underlie their neuroprotective effects. The anti-inflammatory effects of SkQ1 and SkQR1 were primarily related to protection of the endothelium against both activation and loss of isolation functions induced by the mediators of inflammation [56, 214]. The mitochondria-targeted SOD-mimetic MitoTEMPO was intensively studied in models of cardiovascular disease. Mito-TEMPO administration attenuated angiotensin-induced hypertension [158]. In a mouse model of cardiac renin-angiotensin system activation, accompanied by a high rate of spontaneous ventricular tachycardia and sudden cardiac death, MitoTEMPO also reduced cardio-vascular pathology [215]. Only one attempt to apply mitochondria-targeted TEMPO to treat neurodegenerative diseases has been published [216]. The authors designed a conjugate of a TEMPO residue with a mitochondria-targeted cationic peptide and applied this compound, termed XJB-5-131, to a transgenic mouse model of Huntington’s disease. It was shown that XJB-5-131 reduced oxidative damage to mitochondrial DNA, suppressed motor decline and weight loss, and enhanced neuronal survival. The in vitro studies demonstrated the capacity of MitoTEMPO to prevent Aβ-induced toxicity in microvascular endothelial cells under hyperglycemic conditions [217] and the protective action of Mito-TEMPO against glucose and oxygen deprivation-induced apoptotic death in Aβ-treated neurons [218]. Mito-TEMPO treatment also significantly prevented the production of proinflammatory cytokines induced by lipopolysaccharide in primary microglia cells [219]. These data suggest a high neuroprotective potential of Mito-TEMPO based on its anti-inflammatory effects.


The first studies of the therapeutic effects of mitochondria-targeted SS peptides were carried out in a mouse model of Parkinson's disease. These peptides, SS-20 and SS-31, were shown to protect against the loss of dopamine and its metabolites in the striatum and tyrosine hydroxylase immunoreactive (dopaminergic) neurons in the mouse substantia nigra caused by MPTP [220]. SS-20 and SS-31 also reduced MPP+-induced inhibition of respiration and cell death in dopaminergic neurons in vitro. Later, it was shown that SS-31 restored mitochondrial transport and synaptic viability in neurons isolated from Aβ-precursor-protein transgenic mice [221]. More recently, a strong neuroprotective effect of SS-31 was observed in a model of sepsisassociated encephalopathy induced by cecal ligation and puncture [222]. In this study, the intraperitoneal injection of SS-31 (5 mg/kg) immediately after operation and once daily thereafter for six days was shown to reduce mortality rate and ameliorate cognitive deficits. SS-31 significantly attenuated neuronal apoptosis and inflammation in the hippocampus. In the same model, treatment with SS-31 inhibited the increase in proinflammatory cytokines and significantly improved sepsis-induced organ dysfunction, as evidenced by decreased histological scores and biochemical markers in blood and urea [223]. Experimental data on the most widely studied mitochondria-targeted antioxidants and their effects in different neurodegenerative diseases are summarized in Table 2. Over the last 30 years, nearly 50 phase II or phase III clinical trials recruiting patients with progressive forms of MS have been completed [241]. There are currently 12 approved drugs by the US Food and Drug Administration (FDA) for treatment of MS in the early relapsing-remitting phase [242]. This list includes several formulations of interferon beta and immunosuppressive drugs including Alemtuzumab, a type of monoclonal antibody that binds to glycoprotein on the surface of mature lymphocytes. Another type of monoclonal antibody, Natalizumab (Tysabri), is directed against cell adhesion molecule α4-integrin and inhibits attachment and invasion of leukocytes across the endothelium and the BBB. These drugs primarily reduce the number of relapses but do not affect disease progression [13]. The only drug specifically approved by the FDA for progressive MS is mitoxantrone, a cytostatic immunomodulatory agent. However, the use of this drug is limited because of its high toxicity [243]. The National MS Society of the USA currently supports

Fetisova et al.

approximately 30 studies of potential treatments or rehabilitation interventions. Clinical trials of antioxidants such as idebenone (NCT01854359), lipoic acid (NCT01188811) and epigallocatechin-3-gallate (NCT00799890) in patients with progressive MS are currently underway. A clinical trial of idebenone sponsored by the National Institute of Neurological Disorders and Stroke [244] was begun in February, 2013, and completion of this study is expected by August, 2019. Patients with primary-progressive multiple sclerosis and those who have undergone two-year traditional therapy were included in this study. An idebenone dose of 2250 mg/day was used during the 1st year of the study. Biomarker samples of both disease progression and oxidative stress and neuroimaging including quantitative measurements of CNS tissue destruction and clinical data are being collected. So far, no results of the study have been reported by the National Institutes of Health Clinical Center. It should be mentioned that, in parallel with this trial, a study on idebenone effects in an EAE mouse model was published [245]. It was reported that idebenone failed to affect disease incidence or onset when applied preventively and did not reduce disease severity when applied therapeutically. Histopathological examination of the CNS in idebenone-treated mice showed no improvement in inflammation, demyelination and axonal damage. A clinical trial of lipoic acid (LA) sponsored by the VA Office of Research and Development in collaboration with the Oregon Health and Science University included patients with diagnosed secondary progressive multiple sclerosis. It was completed in August 2015, but no results have been published [246]. However, at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2016), it was reported that a 96-week, doubleblind, randomized controlled trial of LA with a daily dose of 1200 mg demonstrated a significant reduction in whole brain atrophy and suggested a clinical benefit. It was concluded that “a larger trial is necessary to confirm the neuroprotective effects, explore clinical benefits, and ensure the safety of LA in progressive MS populations” [247]. The same team in the Oregon Health and Science University initiated a new clinical trial of LA and omega-3 fatty acids with the aim of correcting cognitive impairment in MS patients [248]. The results have not been published.



Table 2. Mitochondria-targeted antioxidants and their effects in different neurodegenerative diseases. Abbreviated name MitoQ, reduced

Structure and Chemical Name (IUPAC) OH CH3

H3C O

Br

Effects in Neuroinflammation Models

Effects in Neurodegeneration Models

EAE murine models [156, 224]

Spinocerebellar ataxia type 1 model [225]; inherited amyotrophic lateral sclerosis [193]; mitochondrial and synaptic damage induced by mutant huntingtin protein [226]; hippocampal synaptic dysfunction and memory deficits in Angelman syndrome mouse model [227]; neuronal death induced by neurotrophin deficiency [228]; EAE mouse model [156]; transgenic mouse model of Alzheimer's disease [191, 229]

P+

H3C O OH

[10-(4,5-Dimethoxy-2-methyl-3,6-dioxуphen-1-yl) decyl] (triphenyl) phosphonium bromide ([10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa1,4-dien-1-yl)decyl]triphenylphosphonium bromide, reduced)* MitoVitE, reduced

Neuronal and astrocytic cell death induced by oxidative stress in organotypic rat hippocampal slice cultures, the model of neuron-glia interaction [230]

OH

Br

HO

+ P

O

H3C OH

Triphenyl[2-(5,6,8-trihydroxy-2,7-dimethyl-3,4dihydro-2H-1-benzopyran-2-yl)ethyl]phosphonium bromide (α-Tocopheroldecyltriphenylphosphonium bromide, reduced)* SkQ1, reduced

Age-dependent degeneration of cerebellar granule neurons [231]; Alzheimer's disease-like pathology in OXYS rats [192, 199, 232]

OH H3C

Br P+

H3C OH

[10-(4,5-Dimethyl-3,6-dioxyphen-1-yl) decyl] (triphenyl) phosphonium bromide ([10-(4,5-dimethyl-3,6-dioxocyclohexa-1,4-dien-1yl)decyl]triphenylphosphonium bromide, reduced)* SkQR1, reduced

H 3C

OH H3C

Cl

H N

O

H 3C

H3C

O

H N

Compression ischemia/reperfusion in brain [206, 207]; amyloidinduced decay of long-term potentiation in rat hippocampal slices [233]

CH3

CH3

O OH

10-(4,5-Dimethyl-3,6-dioxyphen-1-yl) decyl 2-[(3Z)6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3Hxanthen-9-yl]benzoate chloride (10-(6'-plastoquinonyl)decylrhodamine-19, reduced)* Mito TEMPO

CH3 H3C O N CH3

Cl

H N

P O

CH3

H 2O

Triphenyl({[(2,2,6,6-tetramethyl-1-oxidopiperidin-4yl)carbamoyl]methyl})phosphonium chloride *

Suppressor effects towards pro-inflammatory response in microglia cells [219, 234], NLRP3 inflammasome activation in astroglial cells [235], rotenone-induced NLRP3 inflammasome activation in brain [236]

MPTP model of Parkinson’s disease [237]; rotenone neurotoxicity [238, 239]; amyloid beta toxicity in primary cultured mouse neurons [218, 240]

In parenthesis under IUPAC chemical name, a rational name of each structure is given as it is used in the cited publications.


A clinical trial of epigallocatechin-3-gallate (EGCG, Sunphenon) in patients with progressive forms of MS was initiated at Charite University (Berlin, Germany) in 2009 and completed in 2016 [249]. The results have not been published. Earlier, the neuroprotective and anti-inflammatory action of EGCG was observed in an EAE model [250, 251]. One of the possible reasons for the absence or low effect of the antioxidants being tested in the trials described above might lie in their chemical structure. Despite their membranophilic nature, these compounds— LA, IB and FGGD—cannot accumulate in mitochondria, as they have no mitochondria-addressed constituents. This implies that there is no positively charged lipophilic moieties in their structure, but in contrast, some of them (LA) bear a negative charge under physiological conditions. Due to these characteristics, these compounds not only are unable to accumulate in mitochondria, but some of them, including LA, must be expelled from mitochondria. It is well-known that the contribution of mitochondrial membranes to the total area of cell membranes ranges from 2 to 40% depending on the tissue type in the organism. Thereafter, only a portion of lipophilic compounds bearing no mitoaddress are able to reach mitochondrial membranes, as some of these lipophilic compounds are retained by other non-mitochondrial membranes. Moreover, the accumulation capacity of these compounds in mitochondrial membranes is approximately 104 times lower compared to mitochondria-addressed substances, as they cannot accumulate in mitochondrial membranes due to electrical potential. Currently, the mentioned ratio of the bioavailability of different tissues for the mentioned antioxidants is true only for cell and tissue cultures and systems. Studies on the bioavailability of various tissues for antioxidants at the level of whole organisms are only starting. Consequently, we can only assume that the several-order lower total-accumulation capacity of the antioxidants used in the described trials could be one reason for the inability of LA, IB and FGGD to effectively scavenge mitochondria-produced ROS and prevent damage to mitochondrial structures.

Fetisova et al.

models [104, 243, 252]. Clinical trials of antioxidants such as idebenone (NCT01854359), lipoic acid (NCT01188811) and epigallocatechin-3-gallate (NCT00799890) in patients with progressive MS are currently underway. However, despite the encouraging preclinical data in the completed clinical trials with dietary antioxidants, only minor improvements in clinical signs or no benefit have been reported [253]. Most clinical trials using antioxidants as therapeutic agents for treatment of other neurodegenerative diseases also resulted in disappointing outcomes [254, 255]. The lack of success is likely a consequence of several factors, including dosage, route of administration and drug treatment time schedule. In fact, very large doses of traditional antioxidants are needed to reach effective therapeutic levels in the CNS. As it was discussed above, mitochondrial dysfunction and excessive mitochondrial ROS generation could be crucial factors in MS pathogenesis. The application of the novel mitochondria-targeted antioxidants in combined programs of MS therapy could be a promising approach to treating this devastating disease, as mitochondria-targeted antioxidants are effective at extremely low doses and could concurrently exert antiinflammatory and neuroprotective activities. LIST OF ABBREVIATIONS NAA

=

N-acetylaspartate, neuronal mitochondrial marker

AD

=

Alzheimer's disease

ALS

=

Amyotrophic lateral sclerosis

ARE

=

Antioxidant-response element

BBB

=

Blood-brain barrier

CNS

=

Central nervous system

DMF

=

Dimethyl fumarate

ER

=

Endoplasm reticulum

EAE

=

Experimental autoimmune encephalomyelitis

4-HNE

=

4-hydroxy-2-nonenal, oxidative injury marker

HIF1α

=

Hypoxia-inducible factor 1α

KGDH

=

α-ketoglutarate dehydrogenase

MPTP

=

1-methyl-4-phenyl-1,2,3,6tetrahydropyridine

mtROS

=

Mitochondrial reactive oxygen species

CONCLUSIONS AND PERSPECTIVES The findings reviewed above demonstrate that oxidative damage caused by excessive ROS generation plays a central role in the onset and progression of MS. Antioxidants of various origin were suggested as possible components of complex therapy for MS and other neurological diseases. Antioxidant therapies have been found to attenuate axonal damage in some EAE animal



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]

[12]

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


[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]


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.

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.

PMID: 28302008