**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 [2–5]. 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 [13–15].

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 [19–26].

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 [27–29]. 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].

This review article reviewed participants of redox homeostasis, including reactive chemical species, oxidative and antioxidative enzymes, and resulting degradation products, all of which serve as evidence of biochemical assaults and tissue injuries under redox disequilibrium. Literature research was carried out using PubMed/MEDLINE and Google Scholar, using appropriate search terms, such as: "reactive oxygen species", "oxidative stress", "redox", "biomarker", "neurodegenerative disease", "inflammation", "neurodegeneration", and/or "multiple sclerosis". Meta-analyses, systematic reviews, expert reviews, case-control studies, and cohort studies were included in this review. Selection criteria and a risk of bias assessment are described in Tables A1 and A2 of Appendix A. Alterations of redox components in MS in general, phase-, and treatment-specific components were reviewed in search of a potential diagnostic, prognostic, predictive, and/or therapeutic redox biomarker. Finally, monitoring different redox components, including oxidative enzymes, antioxidative enzymes, and degradation products during the disease progression helps to evaluate the redox status of MS patients, thus expediting the building of the most appropriate personalized treatment plans for MS patients [33].
