Melatonin therapy modulates cerebral metabolism and enhances remyelination by increasing PDK4 in a mouse model of multiple sclerosis

Majid Ghareghani, Linda Scavo, Yahya Jand, Naser Farhadi, Hossein Sadeghi, Amir Ghanbari, Stefania Mondello, Damien Arnoult, Sajjad Gharaghani, Kazem Zibara

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number147
JournalFrontiers in Pharmacology
Volume10
Issue numberFEB
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Melatonin
  • Multiple sclerosis
  • Myelin
  • Pyruvate dehydrogenase complex
  • Pyruvate dehydrogenase kinase

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Melatonin therapy modulates cerebral metabolism and enhances remyelination by increasing PDK4 in a mouse model of multiple sclerosis'. Together they form a unique fingerprint.

  • Cite this

    Ghareghani, M., Scavo, L., Jand, Y., Farhadi, N., Sadeghi, H., Ghanbari, A., Mondello, S., Arnoult, D., Gharaghani, S., & Zibara, K. (2019). Melatonin therapy modulates cerebral metabolism and enhances remyelination by increasing PDK4 in a mouse model of multiple sclerosis. Frontiers in Pharmacology, 10(FEB), [147]. https://doi.org/10.3389/fphar.2019.00147