*4.3. 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 (O2 <sup>1</sup>Δg); 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) [216]. 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 [45]. 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 [217]. Hydroxyoctadecadienoic acid (HODE) is derived from the oxidation of linoleates, the most abundant PUFAs in vivo [73,211]. Meanwhile, a cyclic sugar compound inositol is a major antioxidant component of the lipid membrane, which scavenges reactive species [54].

Studies on blood F2-isoPs levels reported increases in MS, especially in RRMS and SPMS subtypes compared to controls [77,78]. A study on CSF F2-isoPs levels presented three times higher in patients with MS than ones with other neurologic diseases [79]. The levels of F2-isoPs were moderately correlated with the degree of disability, suggesting a role as a prognostic marker [80]. MDA is highly reactive aldehyde generated by the reaction between reactive species and polyunsaturated lipids to form adducts with protein or DNA [81]. Studies on blood or serum MDA reported higher levels in MS patients [83,166]. 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 [82,149]. Studies quantifying CSF MDA consistently reported higher levels in CIS and RRMS than controls [61,82,85,177]. There are positive correlations between MDA levels of plasma and CSF, and MDA levels in plasma/CSF and EDSS [84]. The levels of 4-HNE were elevated in the CSF of PPMS, RRMS, and SPMS patients, particularly in PPMS [86]. 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 [87]. 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 [218] (Tables 3 and 4).

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 [88]. Increased levels of oxidized low-density lipoprotein (oxLDL) in the serum and higher serum levels of autoantibodies against oxLDL were reported in MS patients [219,220]. 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 [219–222]. In mixed population of MS, decreased serum 24S-hydroxycholesterol and 27-hydroxycholesterol and increased CSF lathosterol, compared to healthy controls [223] (Tables 3 and 4).
