2.1.3. Reactive Sulfur Species

Reactive sulfur species (RSS) are sulfur-based redox-active compounds able to oxidize or reduce biomolecules under physiological conditions, often formed by thiols (RSHs) and disulfides (RSSHs). RSS include cysteine and methionine, GSH, trypanothione, and mycothiol [130] (Table 2).

Thiyl radicals (RS•), very reactive oxidants produced in the active site of enzymes such as the ribonucleotide reductase can react with nitric oxide radicals (NO•) [131]. Thiolate ions (RS−) are better nucleophiles than alkoxides because sulfur is more polarizable than oxygen [132]. Thiol (RSH) is a metal ligand [133]. Hydrogen sulfide (H2S) is produced from from L-cysteine by cistationine-γ-lyase. Hydrogen sulfide (H2S) increases the activity of *N*-methyl-D-aspartate receptor and β-adrenergic receptors through a cAMP-dependent protein kinase and activates NOS and the hemoxygenase favoring the formation of Nitric oxide (NO) and carbon monoxide (CO) from heme metabolism [134]. Hydrogen sulfide (H2S) is a metal ligand that reacts with other biological electrophilic sulfur species such as hydropersulfide (RSSR) and sulfenic acid (RSOH) [135]. Cysteine residues in GSH were found to be readily oxidized by superoxide anions (O2 −•) to form singlet oxygen (O2 <sup>1</sup>Δg), glutathione disulfide (GSSG), and glutathione sulfonate (GSO3 −) in a reaction involved with peroxysulphenyl radical (RSOO•). This mechanism may apply to cysteine residues in proteins [136]. Hydroxyl radicals (OH•) may also initiate the conversion of amino acids to peroxyl radicals [92]. Another reaction catalyzed by XO is the decomposition of S-nitrosothiols (RSNO), a RNS, to nitric oxide (NO), which reacts with a superoxide (O2 −•) anion to form peroxynitrite (ONOO−) under aerobic conditions [137]. Hydropersulfide (RSSH) is a nucleophile, as well as electrophilic molecule that is readily reduced to extremely potent reductant thiol (RSH). Disulfide (RSSR) is electrophilic RSS that can be reduced to thiol (RSH). Hydropolysulfide (RSSnH) and dialkyl polysulfide (RSSnR) are like hydropersulfide (RSSH) [135]. RSS can interact with ROS, generating sulfur oxides such as peroxysulphenyl radical (RSOO•), sulfenate (RSO−), sulfinate (RSO2 <sup>−</sup>), sulfonate (RSO3 <sup>−</sup>), thiosulmonate (S2O3 <sup>2</sup><sup>−</sup>), and SO4 <sup>2</sup> <sup>−</sup> [138]. Sulfenate (RSO−) reacts with other thiols to give disulfides, RSSR. RSS can also interact with RNS, leading to the formation of S-N hybrid molecules, such as thiazate (NSO−), thionitrite (SNO−) isomers, S-nitrosothiols (RSNOs), nitrosopersulfide (SSNO−), and the dinitrosylated sulfite adduct, SULFI/NO. S-nitrosothiols (RSNOs) can be reduced to thiol (RSH) and nitroxyl (HNO) [139]. XO catalyzes S-nitrosothiols (RSNOs) to nitric oxide (NO), which reacts with a superoxide (O2 −•) anion to form peroxynitrite (ONOO−) under aerobic conditions [123]. The properties of thiazate (NSO−), thionitrite (SNO−) isomers, nitrosopersulfide (SSNO−) and polysulfides dinitrososulfites (Sulfi/NO), are to be determined and they appear to be a source of nitric oxide (NO) and nitroxyl (HNO) [140–142] (Table 2).

An antioxidant *N*-acetyl cysteine administration was reported to improve cognitive functions in patients in MS and *N*-acetyl cysteine supplement is under clinical trial for the treatment of fatigue in MS patients [143,144]. The levels of methionine reported mixed results. The plasma methionine levels were significantly reduced in RRMS and dietary methionine supplement was proposed for the treatment [145]. The level of methionine sulfoxide was elevated more than two-fold in CSF of MM patients and the reduction of dietary methionine was reported to slow the onset and progression of MM [146,147]. The levels of GSH in MS have not reached a consensus [147–149]. Trypanothione and mycothiol have not been investigated in MS. The serum S-nitrosothiol levels were increased in RRMS and SPMS, and selectively correlated with spinal cord injury and, thus, a high level of S-nitrosothiol is proposed to be a potential prognostic biomarker for spinal cord injury in MS [150] (Tables 3 and 4).
