Comparison of Etomoxir, a Lipid Metabolism Blocker, and Interferon-Beta Treatment on Antibody Recognition of Brain Proteins in Multiple Sclerosis
The pathogenesis of Multiple Sclerosis (MS) involves a new hypothesis concerning mitochondrial dysfunction, dysregulated lipid metabolism and inflammation. Carnitine palmitoyl transferase 1a (CPT1a) is a key molecule involved in lipid metabolism, which is necessary for transport of lipids into mitochondria. Lipids are important for the central nervous system as it constitute myelin sheaths and thereby shield proteins, e.g. myelin basic protein (MBP), for the immune system. Dysregulated lipid metabolism results in changes in concentration and composition of lipids and down regulates glucose metabolism, which is the main energy source of the brain. Furthermore, an upregulated lipid metabolism results in prostaglandin E2 (PGE2) production, thereby inducing an inflammatory B and T cell response. It has been found that B cells start generating antibodies to brain proteins after immunization with MBP suggesting a correlation between MS induction and brain antigens. Blocking CPT1a by Etomoxir favours glucose metabolism rather than lipid metabolism, thus normalizing lipid levels in the brain, as well as downregulating PGE2 production and B cell response. This suggests Etomoxir as an innovative treatment strategy for MS.
Experimental autoimmune encephalomyelitis (EAE) models of MS were established to test the efficacy of the CPT1 blocker, Etomoxir. Western Blotting was executed in order to test antibody response against brain proteins in EAE animal sera. Antigens recognized by autoantibodies were immunoprecipitated and analyzed by mass spectrometry with the purpose to identify these antigens, and thereby identifying a correlation between MS and brain antigens.
EAE models of both mice and rats showed 50 % and 25 % healthy animals after treatment with Etomoxir. We identified autoantibodies in sera from the EAE animals by an altered antibody response between different treatment groups and also isotype of the antibody response. After Etomoxir treatment, antibodies to antigens such as apolipoprotein-E, clusterin and serum amyloid P component are i.e. recognized and involved in downregulation of the immune system.
Alteration in metabolic pathways is pivotal regarding the pathogenesis of MS, as Etomoxir treatment is efficient in treating MS by downregulating lipid metabolism and inflammation. Moreover, autoantibodies against brain antigens were identified suggesting a role of these antigens in the progression of MS with the potential of using these as biomarkers for MS.