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Within the TCA cycle, succinate is oxidized to fumarate and subsequently hydrated to malate via the action of two enzymes, succinate dehydrogenase and fumarase. We found that after 24 and 72?h of DMF treatment these intermediates were significantly upregulated compared to controls (Fig.?2A�CC). The succinate to fumarate reaction is coupled to the production of reducing equivalents and functions in both the TCA cycle and the electron transport chain. The dysregulation of these metabolites could influence electron transport chain function and subsequent antioxidant responses. A recent study has shown that increased fumarate levels can drive production of succinate through a reversal of Complex II function leading to the generation of reactive oxidative species [33]. Therefore, perturbations in succinate and fumarate induced by DMF have the potential to influence mitochondrial function and may facilitate the activation of antioxidant signaling. Fig.?2 DMF treatment find more perturbs TCA cycle metabolism in oligodendrocytes. Box and whisker plots for succinate (A), fumarate (B), and malate (C) all showing upregulation after DMF treatment for 24 and 72?h compared to vehicle-treated controls (succinate ... We then analyzed levels of reduced glutathione (GSH), a key molecule involved in the detoxification of antioxidant species [34,35]. We found that DMF treatment increased GSH levels in MO3.13 cells at both 24 and 72?h (Fig.?3A). This effect Histone demethylase is consistent with experimental evidence showing that GSH levels in neurons were increased by DMF treatment [36]. Similarly, DMF treatment of human astrocytes induced early depletion of cellular GSH followed by recovery and a subsequent increase of this antioxidant above basal levels by 24?h [37]. We also found DMF-induced increases in other antioxidant molecules such as carnitine and ascorbic acid (Supplementary Fig. S4). Carnitine can scavenge free radicals and is protective against oxidative damage in an animal model of Huntington's disease [38,39]. Ascorbic acid is an essential micronutrient and one of the major low molecular weight antioxidants present in the brain [40]. Ascorbic acid has also been shown to promote the myelination of peripheral nerves [41]. In addition, it is involved in the maintenance this website of membrane integrity during oxidative stress by reducing the tocopheroxyl radical of vitamin E and preventing lipid peroxidation [42]. The ability of DMF to increase levels of these low molecular weight antioxidants suggests that this compound may function by increasing the levels of antioxidant proteins through the Nrf2 pathway and promoting the uptake or synthesis of protective small molecules. Fig.?3 DMF induces glutathione and protects oligodendroglial cells from oxidative stress. (A) Box and whisker plot of GSH levels after 24 and 72?h of treatment with 10??M DMF. GSH is significantly increased at both time points (**q