Abstract
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.
Highlights
Multiple sclerosis (MS) is a neuroinflammatory disorder, characterized by the attack of immune cells to the central nervous system (CNS) resulting in myelin and axonal damage [1]
We showed that melatonin inhibits pyruvate dehydrogenase complex (PDC) and subsequently leads to a reduction in the substrate required for fatty acid (FA) synthesis, which we suggested is a side effect of melatonin therapy
Combination therapy was not better than melatonin alone in increasing NAA levels (p=0.9950). These results demonstrate that combination therapy of melatonin and diisopropylamine dichloroacetate (DADA) has an effect on cerebral energy metabolism
Summary
Multiple sclerosis (MS) is a neuroinflammatory disorder, characterized by the attack of immune cells to the central nervous system (CNS) resulting in myelin and axonal damage [1]. MS is revealed by demyelinated axons (plaques) whose lipid structure is produced by oligodendrocyte cells in the CNS. FA synthesis within oligodendrocytes plays a key role in myelination and remyelination [7]. The current immunomodulatory treatments in MS managed only to slow down the progression of the disease and to reduce the number of relapses [8]. Our group showed that FA synthesis in the remyelination process could be impaired following MS therapy, which seems to be one of the side effects of the current medications. Our previous animal study showed that while melatonin ameliorates the severity of the disease; its efficiency is reduced owing to its effect on FA synthesis, which is required for proper remyelination
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call