*3.3. Exogenous and Endogenous Antioxidants*

A daily diet rich in naturally occurring polyphenolic antioxidants, such as flavonoids and phenolic acids are regularly recommended for disease prevention and antioxidant supplements, such as vitamin C, vitamin E, *N*-acetyl cysteine, L-carnitine and folic acid are frequently employed as a complementary therapy for various diseases [190,191]. Those preventive and therapeutic measures are based on the pathogenesis of diseases which are induced and developed under oxidative cellular environment. Furthermore, plant polyphenols were reported to alleviate oxidative stress and enhance neuroprotection [192]. Olive leaf-derived polyphenols are strong antioxidants and their therapeutic use are of particular interest against oxidant-induced diseases including cancer and neurodegenerative diseases [193–195]. The Mediterranean diet can present a biphasic dose-response curve toward hormetic stimuli, preventing low-grade inflammation and inflammageing [196,197]. There is a growing interest in supplementation of nonessential compounds that trigger the redox feedback loop activating the nucleophilic response, parahormesis (Figure 1c) [198].

N-Methyl-D-aspartic acid receptor antagonist memantine and memantine-ferulic acid conjugate improved oxidative stress in patients with AD [199]. A meta-analysis of randomized controlled trials showed that an exogenous antioxidant *N*-acetylcysteine supplement improved cognitive function in patients with schizophrenia [200]. Traditional Chinese medicine curcumin is an antioxidant and anti-inflammatory molecule that relieves pain and stress at least partly through the kynurenine metabolic pathway of tryptophan metabolism [201]. The kynurenine pathway produces endogenous oxidative and antioxidative metabolites. Single nucleotide polymorphism of the first rate-limiting enzyme indoleamine 2,3-dioxygenase 1 was associated with inflammation and depressive symptoms and influenced the age onset of neurodegenerative diseases [202]. The elevated levels of an oxidative metabolite 3-hydroxykynurenine and an antioxidative kynurenic acid were linked to depressive symptom of patients with stroke [203]. Meanwhile, administration of kynurenic acid induced antidepressant-like effects in animal model of depression [204].

However, unmonitored chronic antioxidant supplementation imposes reductive stress, the counterpart of oxidative stress. The reductive stress-induced inflammation is observed in hypertrophic cardiomyopathy, muscular dystrophy, pulmonary hypertension, rheumatoid arthritis, AD, and metabolic syndrome [168]. In adipose tissue a long-term antioxidant supplementation caused a paradoxical increase in oxidative stress which was associated with mitochondrial dysfunction [205]. Leptin secreted from adipose tissue serves as an inflammatory mediator and subsequent development of leptin resistance make obese individuals more susceptible to autoimmune disease including MS [206] (Figure 1c).

Vitamin supplements are recommended for the treatment of MS, as nutritional deficits are frequently observed in patients with MS [207]. MS induced by reductive stress has not been reported, but it deserves to monitor redox status in MS patients.
