Modulation of cellular metabolism as therapy for progressive multiple sclerosis

Multiple sclerosis (MS) is one of the most widespread autoimmune pathologies of the central nervous system (CNS), which is clinically characterized by relapsing-remitting phase, followed by secondary progression, although some patients manifest from the beginning a primary progressive form of MS. The chronic inflammation established in CNS, resulting in axonal damage and demyelination, furthermore determinates metabolism impairment in both neural and immune cells, especially regarding oxidative metabolism, which is the main pathway used by brain to produce energy. By performing spectrometry mass imaging on experimental autoimmune encephalitis (EAE) mice spinal cord, we identified specific metabolic impairments in the CNS of progressive-MS, which primary concern tricarboxylic acid cycle, amino acids metabolism and taurine and hypotaurine metabolism. Further, we observed the dysregulation of different types of metabolites, such as coenzyme A, L-homocysteic acid and N-6-acetyl-L-lysine. The latter results overexpressed also in human progressive-MS patients’ plasma. We, previously demonstrated that diet supplementation with essential amino acids and tricarboxylic acid cycle substrate of neurodegenerative diseases mouse models, promote oxidative metabolism recovery and nervous tissue regeneration, whit an improvement of clinical conditions. By these assumptions we decided to test the effect of cells metabolism rewiring, by supplementing EAE mice diet with metabolites mixture, as a new potential pharmacological approach for progressive-MS. The efficacy of the treatment has been evaluated through hysto-pathological and spatial mass spectrometry imaging analysis, with the aim to understand the impact of the metabolism reprogramming on neural and immune cell.