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Tanaka, M.;  Vécsei, L. Monitoring the Redox Status in Multiple Sclerosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/30968 (accessed on 21 July 2024).
Tanaka M,  Vécsei L. Monitoring the Redox Status in Multiple Sclerosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/30968. Accessed July 21, 2024.
Tanaka, Masaru, László Vécsei. "Monitoring the Redox Status in Multiple Sclerosis" Encyclopedia, https://encyclopedia.pub/entry/30968 (accessed July 21, 2024).
Tanaka, M., & Vécsei, L. (2022, October 24). Monitoring the Redox Status in Multiple Sclerosis. In Encyclopedia. https://encyclopedia.pub/entry/30968
Tanaka, Masaru and László Vécsei. "Monitoring the Redox Status in Multiple Sclerosis." Encyclopedia. Web. 24 October, 2022.
Monitoring the Redox Status in Multiple Sclerosis
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines8100406

Worldwide, over 2.2 million people suffer from multiple sclerosis (MS), a multifactorial demyelinating disease of the central nervous system. MS is characterized by a wide range of motor, autonomic, and psychobehavioral symptoms, including depression, anxiety, and dementia. The blood, cerebrospinal fluid, and postmortem brain samples of MS patients provide evidence on the disturbance of reduction-oxidation (redox) homeostasis, such as the alterations of oxidative and antioxidative enzyme activities and the presence of degradation products. 

oxidative stress redox antioxidant multiple sclerosis (MS) biomarker neurodegenerative disease clinically isolated syndrome PPMS RRMS SPMS

1. Introduction

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the brain and spinal cord, which over 2.2 million people worldwide suffer from; it affects primarily young adults from 20 to 40 years of age. After one to two decades, many MS patients enter a progressive phase of the disease. As survival rates have improved, MS patients suffer throughout the adult life. Years lived with disability begin to increase steeply early in the second decade of life and disability-adjusted life years peak in the sixth decade of life [1]. MS encompasses a wide range of symptoms from motor and autonomic dysfunctions to psychobehavioral disturbances, including gait difficulties, paresthesia, spasticity, vision problems, dizziness and vertigo, incontinence, constipation, sexual disturbances, pain, cognitive and emotional changes, anxiety, and depression [2][3][4][5]. Increased risk of depression and painful conditions in chronic illnesses are likely to be mediated by the kynurenine pathway of tryptophan metabolism [6][7].
Several genetic susceptibilities, environmental factors, and the aging process have been proposed to alter the risk of developing MS, but the underlying cause of the disease remains unknown [8][9]. The most typical pathomechanisms involved in MS are simultaneous inflammatory and neurodegenerative processes [10][11]. Main pathological findings of MS include the blood-brain barrier disruption, multifocal inflammation, demyelination, oligodendrocyte loss, reactive gliosis, and axonal degeneration [12]. Multifocal immune-mediated destruction of myelin and oligodendrocytes leading to progressive axonal loss is a main cause of neurological deficits in MS [13][14][15].
The diagnosis of MS is confirmed by the presence of two or more multifocal inflammatory or demyelinating attacks in the central nervous system (CNS) with objective clinical evidence, a single attack with magnetic resonance imaging (MRI)-detected lesions, and positive cerebrospinal fluid (CSF) analysis, or insidious neurological progression with positive brain MRI or CSF analysis [16]. The symptomatic course classifies MS into four subtypes. Approximately 85% of MS patients have alternating episodes of neurological disability and recovery that last for many years, termed relapsing-remitting MS (RRMS). Almost 90% of RRMS patients progress to steady neurological decline within 25 years, termed secondary progressive MS (SPMS). Nearly 10% of MS patients suffer from steady deterioration of neurological functions without recovery, termed primary progressive MS (PPMS). As few as 5% of MS patients present progressive neurological deficits with acute attacks with or without recovery, termed progressive-relapsing MS (PRMS) [17]. However, PRMS is no longer considered a subtype of MS and is now grouped into PPMS with active disease of new symptoms or changes in the MRI scan [18]. In addition, clinically isolated syndrome (CIS) is a single episode of monofocal or multifocal neurological deficits that lasts at least 24 h. CIS is one of the courses of MS disease [12].
As in other neurodegenerative diseases, MS is a clinically classified disease of CNS in which multifactorial factors, including genetic, environmental, socioeconomic, cultural, personal lifestyle, and aging play an initial role to form a causative complex, eventually converging into similar pathognomonic clinical pictures [4]. Inflammatory and demyelinating attacks are unique manifestations in MS, but different pathomechanisms govern the distinguished clinical courses in each subtype of MS.
Currently there is no cure for MS. Disease-modifying therapy is the mainstay of MS treatment. Immunomodulators, immunosuppressors, and cytotoxic agents are main groups of medicine. Immunomodulators, such as interferon (IFN)-beta (β), glatiramer acetate (GA), and siponimod are used for CIS. Short courses of high-dose corticosteroid methylprednisolone alleviate acute flare-ups of RRMS, indicating that an inflammatory process predominates in RRMS and relapse prevention of RRMS [19][20]. Siponimod is indicated for RRMS [20]. For active RRMS monoclonal antibodies alemtuzumab and ocrelizumab, and immunomodulator dimethyl fumarate, fingolimod, and teriflunomide are prescribed besides IFN-β and GA. For highly active RRMS, cytotoxic agents cladribine and mitoxantrone are indicated, besides immunomodulatory fingolimod, and monoclonal antibodies, natalizumab and ocrelizumab. PPMS and SPMS are characterized by a neurodegenerative process leading to neural death [18]. An immunosuppressive monoclonal antibody ocrelizumab is indicated for treatment of PPMS [21] and diroximel fumarate, siponimod, and ofatumumab were recently licensed for treatment of SPMS [20][22][23] (Table 1).
Table 1. Licensed disease-modifying drugs in multiple sclerosis [19][20][21][22][23][24][25][26].
Class Drugs Indications
Immunomodulators Interferon beta (IFN-β) CIS
Active RRMS
Methylprednisolone Acute flare-ups RRMS
Relapse prevention
Glatiramer acetate (GA) CIS
Active RRMS
Dimethyl fumarate Active RRMS
Diroximel fumarate CIS
RRMS
Active SPMS
Fingolimod Active RRMS
High-active RRMS
Teriflunomide Active RRMS
Siponimod CIS
RRMS
SPMS
Immunosuppressors Alemtuzumab Active RRMS
Natalizumab High-active RRMS
Ocrelizumab Active RRMS
High-active RRMS
PPMS
Ofatumumab CIS
RRMS
Active SPMS
Cytotoxic Agents Cladribine High-active RRMS
Mitoxantrone High-active RRMS
Either causative, accompanying, or resultant events of inflammation and neurodegeneration, disturbance of reduction-oxidation (redox) metabolism have been observed and play a crucial role in pathogenesis of MS [27][28][29]. The serum proteomics revealed that ceruloplasmin, clusterin, apolipoprotein E, and complement C3 were up-regulated in RRMS patients, compared to healthy controls. Vitamin D-binding protein showed a progressive trend of oxidation and the increased oxidation of apolipoprotein A-IV in progression from remission to relapse of MS [30]. CSF samples of patients in the remission stage of RRMS showed higher purine oxidation product uric acid, reduced antioxidant, and increased intrathecal synthesis of IgG [31]. The observations suggest the presence of redox metabolism disturbance and involvement of inflammatory process in RRMS. Furthermore, higher serum alpha (α)-tocopherol levels were associated with reduced T1 gadolinium (Gd+)-enhancing lesions and subsequent T2 lesions in MRI of RRMS patients on IFN-β. Antioxidant glutathione (GSH) mapping showed lower GSH concentrations in the frontoparietal region of patients suffering from PPMS and SPMS than RRMS and no significant difference between those of RRMS and controls. Thus, the oxidative stress in CNS was linked to neurodegeneration in progressive types of MS [32].

2. Degradation Products under Oxidative Stress

2.1. Proteins

Protein carbonyls are degradation products of reactions between reactive species and proteins, resulting in a loss of function or aggregation. Quantification with 2,4-Dinitrophenylhydrazine products showed increased carbonylation in plasma and serum of RRMS patients [33][34][35]. The plasma carbonyl levels were elevated in SPMS and correlated with the EDSS and the Beck Depression Inventory [36]. The levels of carbonyl groups were elevated in serum of patients with RRMS and lowered in the group of RRMS patients treated with INF-β [37]. The levels of CSF carbonyl proteins measured were elevated in RRMS and progressive MS [38][39] (Table 2 and Table 3).
Table 2. Oxidative stress biomarkers of multiple sclerosis. The redox status can be monitored by the activities of oxidative and antioxidative enzymes and the presence of degradation products derived from cellular components. ↑: increase, ↓: decrease, -: unknown.
Classes Types Human Samples Reference
Blood CSF
Reactive Species Reactive Nitrogen Species ↑ ↑ [40]
Oxidative Enzymes Xanthine Dehydrogenase (XDH) ↓ - [41]
Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase mixed - [42]
Superoxide Dismutase (SOD) ↑ ↓ [43][44][45][46]
Inducible Nitric Oxide Synthase (iNOS) ↑ ↑ [18][47][48][49]
Myeloperoxidase (MPO) mixed - [42]
Antioxidative Enzymes and Transcriptional Factors Glutathione Peroxidase (GPx) ↑(relapse) ↓(remission) ↓ [50][51][52][53][54][55]
Glutathione Reductase (GSR) - ↑ [55][56]
Catalase ↓ - [55][56]
Xanthine oxidase (XO)-Uric Acid ↓ - [41]
Nuclear Factor Erythroid 2-Related Factor (Nrf2) ↑ - [46]
Peroxisome proliferator-activated receptors (PPARs) - ↑ [57]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) ↓ - [58]
Degradation Products and End Products Protein Protein carbonyls ↑ - [33][34][35][59][60][61][62]
3-nitrotyrosin (3-NO-Tyr) ↑ - [59][60][61][63]
Protein glutathionylation - ↑ [64]
Dityrosine ↑ - [37]
Advanced oxidation protein products (AOPPs) ↑ - [37][43][65]
Advanced glycation end products (AGEs) ↑ ↑ [37][65]
Amino acids Asymmetric dimethylarginine (ADMA) ↓ - [66]
Lipid F2-isoprostane (F2-isoP) ↑ ↑ [67][68][69][70][71]
Malondialdehyde (MDA) mixed ↑ [55][72][73][74][75]
4-hydroxynonenal (4-HNE) - ↑ [76]
Hydroxyoctadecadienoic acid (HODE) ↑ ↑ [77]
Oxysterol mixed ↑ [78]
DNA 8-dihydro-2′deoxyguanosine (8-oxodG) ↑ - [50]
Table 3. Possible redox biomarkers in multiple sclerosis. Reactive chemical species, oxidative enzymes, antioxidants, antioxidative enzymes, degradation products, and end products are potential biomarkers for multiple sclerosis (MS). Diagnostic biomarkers allow early detection and secondary prevention; prognostic biomarkers suggest the likely clinical course; predictive biomarkers predict the response of MS patients to a specific therapy; and therapeutic biomarkers indicate a target for therapy. CIS: clinically isolated syndrome, PPMS: primary progressive MS; RRMS: relapsing-remitting MS, SPMS: secondary progressive MS, mixedMM: mixed population of MS.
Class Components Biomarkers
Diagnostic Prognostic Predictive Therapeutic
Reactive Chemical Species Total nitrite (NO2−)/nitrite (NO3−) value (tNOx) PPMS, RRMS, Relapse, SPMS RRMS - -
S-nitrosothiol RRMS, SPMS Spinal injury - -
Oxidative Enzymes Superoxide dismutase (SOD) CIS, RRMS CIS, RRMS RRMS RRMS
Myeloperoxidase (MPO) RRMS RRMS - -
Inducible nitric oxide synthase (iNOS) RRMS - - -
Antioxidants and Antioxidative Enzymes Xanthine oxidase (XO)-Uric acid PPMM, RRMM, SPMM - - -
Selenium RRMS - - -
Glutathione reductase (GSR) mixedMM MixedMM - -
Catalase CIS, RRMS RRMS - -
Thioredoxin-Peroxiredoxin (TRX-PRDX) MS - - -
Nuclear factor erythroid 2-related factor (Nrf2) RRMS - RRMS -
Peroxisome proliferator-activated receptors (PPARs) RRMS - - -
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) PPMS, SPMS - - -
Degradation Products and End Products Protein carbonyls RRMS, SPMS RRMS, SPMS RRMS -
3-nitrotyrosine
(3-NO-Tyr)		 RRMS, SPMS - RRMS -
Glutathionylation Acute attack - - -
Dityrosine RRSM - - -
Advanced oxidation protein products (AOPPs) CIS, RRMS RRMS RRMS -
Advanced glycation end products (AGEs) RRMS - - -
Asymmetric dimethylarginine
(ADMA)		 RRMS, SPMS - - -
F2-isoprostane
(F2-isoP)		 RRMS, SPMS SPMS - -
Malondialdehyde (MDA) RRMS RRMS RRMS -
4-hydroxynonenal
(4-HNE)		 PPMS, RRMS, SPMS - - -
Hydroxyoctadecadienoic acid (HODE) CIS, RRMS - - -
Oxocholesterols MixedMS SPMS - -
Oxidized low-density lipoprotein (oxLDL) RRMS, SPMS - - -
8-OH2dG RRMS - - -
A highly active RNS reacts with tyrosine residues of proteins to form nitrotyrosines, leading to the alternation of protein conformation function. The main product of tyrosine oxidation is 3-nitrotyrosine (3-NO-Tyr), formed by the substitution of a hydrogen by a nitro group in the phenolic ring of the tyrosine residues. The content of 3-NO-Tyr is assessed by western blotting, high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC/MS), and enzyme-linked immunosorbent assay (ELISA) [63]. Mean 3-NO-Tyr was observed significantly higher in plasma and serum of RRMS and SPMS patients and significantly higher 3-NO-Tyr was found in SPMS than RRMS [34][59][60]. Decreased mean 3-NO-Tyr was reported following a relapse and corticosteroid treatment [61]. In the serum of MS patients, 3-NO-Tyr was found significantly lower following INF-β1b treatment [62]. Following GA treatment, 3-NO-Tyr was found significantly reduced in peripheral leukocytes [60] (Table 2 and Table 3).
Protein glutathionylation is a redox-dependent posttranslational modification that results in the formation of a mixed disulfide between GSH and the thiol group of a protein cysteine residue [79]. Protein glutathionylation is observed in response to oxidative or nitrosative stress and is redox-dependent, being readily reversible under reducing conditions. Extracellular SOD, α1-antitrypsin and phospholipid transfer protein were found glutathionylated at cysteine residues in CSF of MS Patients, witnessing the footprints of oxidative assault of MS [39].
Oxidative environments generate oxidized tyrosine orthologues such as o-tyrosine, m-tyrosine, nitrotyrosine, and dityrosine. Dityrosine was elevated in serum of RRMS patients [37][64]. Advanced oxidation protein products (AOPPs) are uremic toxins produced in reaction of plasma proteins with chlorinated oxidants such as chloramines and hypochlorous acid (HClO) [80]. The levels of AOPPs were significantly higher in plasma of MM patients [81]. The levels of AOPPs were significantly higher in plasma and CSF of CIS and RRMS patients than healthy controls, and the AOPPs levels were significantly higher CIS than RRMS. Furthermore, the levels of AOPPs were significantly higher in patients with higher EDSS scores than lower ones [44]. The AOPPs levels were decreased in serum of RRMS patients treated with IFN-β [37] (Table 2 and Table 3).
AGEs are a group of glycotoxins produced in reaction of free amino groups of proteins, lipids, or nucleic acids and carbonyl groups of reducing sugars. The AGEs can accumulate in tissues and body fluids, resulting in protein malfunctions, reactive chemical production, and inflammation [82]. The levels of AGEs were significantly elevated in serum of RRMS patients, but no significant change was observed after IFN-β treatment [37]. The concentrations of AGEs were significantly higher in brain samples of MS patients, compared to nondemented counterparts. The levels of free AGEs were correlated in CSF and plasma samples of MS patients, but not protein-bound AGEs [65] (Table 2 and Table 3).

2.2. Amino Acids

Asymmetric dimethylarginine (ADMA) is a L-arginine analogue produced in the cytoplasm in the process of protein modification. The formation of ADMA is dependent on oxidative stress status. ADMA is elevated by native or oxidized LDL and interferes with L-arginine in the production of nitric oxide (NO) [83]. Significantly higher ADMA concentrations were observed in serum and CSF of patients with RRMS and SPMS, while levels of arginine, L-homoarginine, nitrate, nitrite, ADMA did not differ between patients with MS and healthy controls [66] (Table 2 and Table 3).

2.3. Lipid Membrane and Lipoproteins

Lipids in biological membrane are major target of OS. Peroxidation of lipid membrane is initiated by ROS, including superoxide anion (O2−•), hydroxyl radical (OH•), hydrogen peroxide (H2O2), and singlet oxygen (O21Δg); and by RNS, including nitric oxide radical (NO•), peroxynitrite (ONOO−), and nitrite (NO2−) stealing electron from PUFAs, such as arachidonic (20:4) and docosahexaenoic acid (22:6) [84]. The abstraction of bis-allylic hydrogen of PUFA leads to the formation of arachidonic acid hydroperoxyl radical (ROO•) and hydroperoxide (ROOH) in a chain reaction manner [85]. A portion of arachidonic acid peroxides and peroxy radicals generate endoperoxides rather than hydroperoxide (ROOH). The endoperoxides undergoes subsequent formation of a range of bioactive intermediates, such as F2-isoprostanes (F2-isoPs), MDA and 4-HNE. Hexanoyl-lysine (HEL) adduct is a lipid peroxidation by-product which is formed by the oxidation of omega-6 unsaturated fatty acid, such as linoleic acid [86]. Hydroxyoctadecadienoic acid (HODE) is derived from the oxidation of linoleates, the most abundant PUFAs in vivo [64][79]. Meanwhile, a cyclic sugar compound inositol is a major antioxidant component of the lipid membrane, which scavenges reactive species [48].
Studies on blood F2-isoPs levels reported increases in MS, especially in RRMS and SPMS subtypes compared to controls [67][68]. A study on CSF F2-isoPs levels presented three times higher in patients with MS than ones with other neurologic diseases [69]. The levels of F2-isoPs were moderately correlated with the degree of disability, suggesting a role as a prognostic marker [70]. MDA is highly reactive aldehyde generated by the reaction between reactive species and polyunsaturated lipids to form adducts with protein or DNA [71]. Studies on blood or serum MDA reported higher levels in MS patients [73][87]. The blood MDA levels were significantly higher in RRMS than controls or CIS, higher in RRMS than in remission, and higher in remission than controls. MDA levels were elevated at relapse, while lowered at day 5 of corticosteroid treatment [72][88]. Studies quantifying CSF MDA consistently reported higher levels in CIS and RRMS than controls [55][72][75][89]. There are positive correlations between MDA levels of plasma and CSF, and MDA levels in plasma/CSF and EDSS [74]. The levels of 4-HNE were elevated in the CSF of PPMS, RRMS, and SPMS patients, particularly in PPMS [76]. No study regarding HEL in MS was found in literature search. The serum 13-HODE was identified as a part of metabolomic signatures associated with more severe disease such as non-relapse-free MS or MS with higher EDSS [77]. The levels of 9-HODE and 13-HODE were significantly increased in CSF of CIS and RRMS patients, compared to healthy controls, but baseline levels of HODE did not differ between patients with signs of disease activity during up to four years of follow-up and patients without MS [90] (Table 2 and Table 3).
Cholesterol oxidization products oxysterols were studied. Levels of plasma oxysterols increased in progressive MS patients and oxysterol levels were positively correlated with apolipoprotein C-II and apolipoprotein E. Furthermore, oxysterol and apolipoprotein changes were associated with conversion to SPMS [78]. Increased levels of oxidized low-density lipoprotein (oxLDL) in the serum and higher serum levels of autoantibodies against oxLDL were reported in MS patients [91][92]. Although studies on HDL levels in MS patients reported mixed results, lowered HDL antioxidant function in MS patients was observed, suggesting the involvement of lipoprotein function MS pathogenesis [91][92][93][94]. In mixed population of MS, decreased serum 24S-hydroxycholesterol and 27-hydroxycholesterol and increased CSF lathosterol, compared to healthy controls [95] (Table 2 and Table 3).

2.4. Nucleic Acid

The biomarkers of oxidative damage of nucleic acids—8-Hydroxy-2′-deoxyguanosine (8-OH2dG) and 8-hydroxyguanosine (8-OHG)—can be assessed by ELISA, as well as by direct methods, such as HPLC and GC/MS [96][97]. Elevated levels of 8-OH2dG were reported in the blood of RRMS patients. DNA oxidation products were proposed as diagnostic biomarkers for MS [98] (Table 2 and Table 3).

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Masaru Tanaka
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László Vécsei
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