Dimethyl fumarate as a treatment for multiple sclerosis : a role for mitochondria?

• Main Author: Schiza, Dimitra
• Other Authors: Smith, K.
• Published: University College London (University of London) 2018
• Subjects: 612.8
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.747466

Multiple sclerosis (MS) is a debilitating neurological disease, characterized by inflammatory, demyelinating lesions in the central nervous system (CNS). Dimethyl fumarate (DMF), an approved therapy for MS, is thought to act via anti-inflammatory and anti-oxidant mechanisms, specifically via the transcriptional factor Nrf2. Nrf2 upregulation may also target mitochondrial metabolism and function, and mitochondria have increasingly been identified as playing a key role in the pathophysiology of MS. This thesis explores the hypothesis that DMF acts on mitochondria, thereby protecting their function under neuroinflammatory conditions. In vivo confocal imaging of the axons of spinal cords in animals with EAE, a model of MS, revealed that prophylactic treatment with DMF protected mitochondrial membrane potential (ΔΨm), before disease onset, compared with vehicle. Importantly, this mitochondrial protection was associated with a significant decrease in EAE incidence. In accordance with previous studies, DMF administration led to significant upregulation of Nrf2. Microglial activation was present even before disease onset, and was not affected by DMF treatment, nevertheless preliminary evidence suggests the levels of some proinflammatory cytokines might be slightly decreased in the drug-treated group. Mitochondrial complex I enzymatic activity was compromised in preclinical EAE, but DMF did not restore its function. This evidence suggests that DMF treatment might not act via preventing initial mitochondrial injury, but rather by preserving ΔΨm in a complex I- independent manner. Metabolomic analysis of the tissue revealed significant changes in the metabolite composition of the inflamed spinal cords, compared with naïve animals. Interestingly, these changes were moderately prevented following DMF treatment, suggesting a potential mechanism of action of the drug. We conclude that the beneficial effects of DMF in MS may be due, at least in part, to the ability of the drug to preserve mitochondrial function. This protective effect could explain the decreased incidence of neurological deficits in the drug-treated group in EAE. The current data suggest that DMF protects mitochondria potentially by circumventing the observed complex I deficit and preserving ΔΨm through alternative pathways.