Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism

AbstractMajor depressive disorder is a complex and common mental disease, for which the pathology has not been elucidated. The purpose of this study is to provide knowledge about the importance of mitochondrial dysfunction, dysregulated lipid metabolism and inflammation. Mitochondrial carnitine palmitoyl transferase 1a (CPT1a) is a key molecule involved in lipid metabolism and mutations in CPT1a causing reduced function is hypothesized to have a protective role in the development of depression. Moreover, CPT1a is found to be upregulated in suicide patients with history of depression. Therefore, we hypothesized that inhibition of CPT1a activity can be developed as an innovative treatment strategy for depression. Stress exposure combined with different pharmacological treatment regimens; Etomoxir, CPT1 blocker, and Escitalopram, a favoured antidepressant drug, was applied in state-of-the-art chronic mild stress model. Etomoxir treatment induced statistical significant reduction of anhedonic behavior compared to vehicle treatment (p &lt; 0.0001) and reversed depression-like phenotype in 90% of the rats (p = 0.0007), whereas Escitalopram only proved 57% efficacy. Moreover, Etomoxir revealed downregulation of interferon-γ, interleukin-17α and tumor necrosis factor-α. This indicate that alteration in metabolism is pivotal in the pathogenesis of depression, since CPT1 blockage is highly efficient in treating anhedonia and inflammation, thereby opening up for a novel class of antidepressant medication.</jats:p

Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β

AbstractMultiple sclerosis (MS) is a neurodegenerative autoimmune disease, where chronic inflammation plays an essential role in its pathology. A feature of MS is the production of autoantibodies stimulated by an altered-peptide-ligand response and epitope spreading, resulting in loss of tolerance for self-proteins. The involvement of autoantibodies in MS pathogenesis has been suggested to initiate and drive progression of inflammation; however, the etiology of MS remains unknown. The effect of etomoxir and interferon-β (IFN-β) was examined in an experimental-autoimmune-encephalomyelitis (EAE) model of MS. Moreover, the impact of etomoxir and IFN-β on recognition of brain proteins in serum from EAE rats was examined with the purpose of identifying the autoantibody reactivities involved in MS. Animals treated with etomoxir on day 1 exhibited a statistically significantly lower disease score than animals treated with IFN-β (on day 1 or 5) or placebo. Etomoxir treatment on day 5 resulted in a significantly lower disease score than IFN-β treatment on day 1. After disease induction antibodies was induced to a broad pallet of antigens in the brain. Surprisingly, by blocking CPT1 and therewith lipid metabolism several alterations in the antibody response was observed suggesting that autoantibodies play a role in the EAE animal model.</jats:p

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

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