Pharmacological inhibition of carnitine palmitoyl transferase 1 inhibits and reverses experimental autoimmune encephalitis in rodents

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  • Anne Skøttrup Mørkholt, Aalborg University
  • ,
  • Michal Krystian Oklinski, Aalborg University
  • ,
  • Agnete Larsen
  • Robert Bockermann, University of Copenhagen
  • ,
  • Shohreh Issazadeh-Navikas, University of Copenhagen
  • ,
  • Jette Goller Kloth Nieland, Aarhus C
  • ,
  • Tae Hwan Kwon, Department of Biochemistry and Cell Biology, Kyungpook National University
  • ,
  • Angelique Corthals, City University of New York
  • ,
  • Søren Nielsen, Department of Health Science and Technology, Aalborg University, Aarhus C
  • ,
  • John Dirk Vestergaard Nieland, Department of Health Science and Technology, Aalborg University

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination and inflammation. Dysregulated lipid metabolism and mitochondrial dysfunction are hypothesized to play a key role in MS. Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting enzyme for beta-oxidation of fatty acids in mitochondria. The therapeutic effect of pharmacological CPT1 inhibition with etomoxir was investigated in rodent models of myelin oligodendrocyte glycoprotein- and myelin basic protein-induced experimental autoimmune encephalitis (EAE). Mice receiving etomoxir showed lower clinical score compared to placebo, however this was not significant. Rats receiving etomoxir revealed significantly lower clinical score and lower body weight compared to placebo group. When comparing etomoxir with interferon-β (IFN-β), IFN-β had no significant therapeutic effects, whereas etomoxir treatment starting at day 1 and 5 significantly improved the clinical scores compared to the IFN-β and the placebo group. Immunohistochemistry and image assessments of brain sections from rats with EAE showed higher myelination intensity and decreased expression of CPT1A in etomoxir-treated rats compared to placebo group. Moreover, etomoxir mediated increased interleukin-4 production and decreased interleukin-17α production in activated T cells. In conclusion, CPT1 is a key protein in the pathogenesis of EAE and MS and a crucial therapeutic target for the treatment.

Original languageEnglish
Article numbere0234493
JournalPLOS ONE
Volume15
Issue6
ISSN1932-6203
DOIs
Publication statusPublished - 2020

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