We recently showed that
melatonin ameliorates the severity of
experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, efficiency of
melatonin therapy was associated with side effects, manifested by slowing down of remyelination, through increasing the inhibitory effects of brain
pyruvate dehydrogenase kinase-4 (PDK-4) on
pyruvate dehydrogenase complex (PDC), a key
enzyme in
fatty acid (FA) synthesis during remyelination. In this study, we investigated the metabolic profile of FA synthesis using combination
therapy of
melatonin and
diisopropylamine dichloroacetate (DADA), a PDK4 inhibitor, in EAE mice.
Disease progression was monitored by recording the disability scores. Immunological, oligodendrogenesis and metabolic factors were also evaluated. Results showed that combination
therapy of
melatonin and DADA significantly reduced EAE disability scores, compared to
melatonin, whereas DADA alone did not have any effect. In addition, co-
therapy inhibited pro-inflammatory while increasing anti-inflammatory
cytokines, significantly better than
melatonin alone. Moreover, administration of combination drugs recovered the declined expression of oligodendrocytic markers in EAE, more potently than
melatonin. Furthermore, co-
therapy affected cerebral energy metabolism by significantly reducing
lactate levels while increasing
N-acetylaspartate (NAA) and 3-hydroxy-3-methyl-glutaryl-coenzyme-A
reductase (HMGCR) levels. Finally, while
melatonin increased
lactate and PDK4 expression levels and greatly reduced PDC activity, co-
therapy significantly restored PDC function while reducing the
lactate levels. In summary, administration of
melatonin with DADA increased the efficiency of
melatonin treatment by eliminating the inhibitory effects of PDK4 on PDC's function, a critical step for proper FA synthesis during remyelination.