Melatonin Therapy Modulates Cerebral Metabolism and Enhances Remyelination by Increasing PDK4 in a Mouse Model of Multiple Sclerosis.

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-1ß 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.

Melatonin therapy reduces the risk of osteoporosis and normalizes bone formation in multiple sclerosis.

Multiple sclerosis (MS) is a common autoimmune and neurodegenerative disease of the central nervous system. Serum levels of melatonin decrease in MS patients who are also at risk of osteoporosis. Procalcitonin (proCT) has been reported as a biomarker of systemic inflammation and autoimmune disease; however, its changes in MS patients have not been well explored. This study investigated, using ELISA, the clinical correlation between serum melatonin and proCT in MS patients. We then assessed the effect of melatonin (10 mg/kg) therapy on bone metabolism and osteoporosis in experimental autoimmune encephalomyelitis (EAE) model of MS and in MS patients. Data showed a significant increase (*P < 0.05) in serum levels of proCT in MS patients, inversely correlated (r  = â€Š-0.945; P  = â€Š0.0001) with melatonin levels, compared to healthy participants. On the other hand, melatonin therapy ameliorated EAE severity by significantly decreasing (*P < 0.05) mean clinical scores, compared to control EAE mice. In addition, serum levels of proCT significantly (**P < 0.01) increased in EAE mice, compared to controls, which was significantly (*P < 0.05) reduced by melatonin. Moreover, EAE-induced decrease in 25-hydroxyvitamin D, calcium, and osteocalcin (OCN) in EAE mice, compared to controls, was significantly (*P < 0.05) increased by melatonin. Finally, OCN serum levels were found to be significantly decreased (*P < 0.05) in MS patients, in comparison with controls. Taken together, we suggest that proCT could be used as a diagnostic biomarker in MS patients and that melatonin normalizes bone metabolites in MS. Further clinical and experimental investigations are needed to understand bone metabolism in MS.