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Abstract
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.
Highlights
As Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting step in mitochondrial lipid metabolism of fatty acid beta-oxidation, we tested if blocking of CPT1 with etomoxir is effective in the treatment of experimental autoimmune encephalitis (EAE) progression by reversing functional deficits
EAE was induced by immunization of C57BL/6 mice (n = 42) and Lewis rats (n = 42 and n = 55) with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide and myelin basic protein (MBP) respectively, as described in methods
The classical EAE parameters showed that mice treated with etomoxir revealed lower mean maximum EAE score, later mean day of disease onset and lower disease incidence compared to the placebo group (Fig 2c)
Summary
One of the key functions of lipids in the CNS is to build and maintain the myelin sheath on the axons of neurons, as well as to facilitate protein transfer from oligodendrocytes to the myelin. After transport of acyl-carnitine, CPT2 localized at the inner mitochondrial membrane removes the carnitine group from the lipid molecule which enables its degradation via betaoxidation Biological systems switch their metabolism from glucose to lipid, i.e. enhanced catabolism of lipids, under locally occurring hypoxic stress. Under hypoxic conditions lipid metabolism is associated with increased prostaglandin production [12,18], and enhanced chemotaxis of immune cells to the exposed myelin sheath proteins. Based on these mechanisms, we hypothesize that blockage of CPT1A function may result in both therapeutic and preventative effects in the progression of MS. The effect of etomoxir on inflammation and production of cytokines were examined
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