Abstract
Metabolic disturbances have been implicated in demyelinating diseases including multiple sclerosis (MS). Melatonin, a naturally occurring hormone, has emerged as a potent neuroprotective candidate to reduce myelin loss and improve MS outcomes. In this study, we evaluated the effect of melatonin, at both physiological and pharmacological doses, on oligodendrocytes metabolism in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Results showed that melatonin decreased neurological disability scores and enhanced remyelination, significantly increasing myelin protein levels including MBP, MOG, and MOBP. In addition, melatonin attenuated inflammation by reducing pro-inflammatory cytokines (IL-1β and TNF-α) and increasing anti-inflammatory cytokines (IL-4 and IL-10). Moreover, melatonin significantly increased brain concentrations of lactate, N-acetylaspartate (NAA), and 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR). Pyruvate dehydrogenase kinase-4 (PDK-4) mRNA and protein expression levels were also increased in melatonin-treated, compared to untreated EAE mice. However, melatonin significantly inhibited active and total pyruvate dehydrogenase complex (PDC), an enzyme under the control of PDK4. In summary, although PDC activity was reduced by melatonin, it caused a reduction in inflammatory mediators while stimulating oligodendrogenesis, suggesting that oligodendrocytes are forced to use an alternative pathway to synthesize fatty acids for remyelination. We propose that combining melatonin and PDK inhibitors may provide greater benefits for MS patients than the use of melatonin therapy alone.
Highlights
Multiple sclerosis (MS) is a complex disease characterized by inflammation and demyelination in the central nervous system (CNS), affecting approximately 2.5 million people worldwide (Hagemeier et al, 2012)
EAE mice treated with pharmacological doses of melatonin showed a significant gain in their body weight at days 25 and 30 (∗∗p < 0.01, ∗∗∗p < 0.001, respectively), in comparison to vehicle (EAE+phosphate buffered saline (PBS)) (Figure 1D)
This study demonstrated that myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), which are myelin-associated proteins localized on the surface of oligodendrocytes, showed marked reduction in EAE mice compared to controls
Summary
Multiple sclerosis (MS) is a complex disease characterized by inflammation and demyelination in the central nervous system (CNS), affecting approximately 2.5 million people worldwide (Hagemeier et al, 2012). MS has been shown to cause neurodegeneration through different mechanisms including oxidative stress, activation of microglia and astrocytes, impairment in energy state and metabolism, and other processes (Mahad et al, 2015; Heidker et al, 2017; Kawachi and Lassmann, 2017). Current therapies are using medications to suppress immunological attacks on myelin, without suppressing the entire immune system (Steinman, 1996). Metabolic alterations in MS have been investigated in relation to the multiple pathophysiological processes linking mitochondrial function, myelin, and inflammation (Kalman et al, 2007). Lipid synthesis is a critical process for remyelination since lipids and cholesterol are key components of myelin and their increased synthesis has been related to the therapeutic mechanism of MS medications (Sedel et al, 2016). In order to be clinically effective, therapeutic agents of MS need to have broad neuroprotective effects targeting these multiple mechanisms
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