Proceedings of The Physiological Society

Mitochondria: Form and function (London, UK) (2017) Proc Physiol Soc 38, PC08

Poster Communications

Dimethylfumarate as a treatment for multiple sclerosis: a role for mitochondria?

D. Schiza1, F. Peters1, M. Clark1, M. Duchen2, K. Smith1

1. Neuroinflammation, UCL, London, Please select below, United Kingdom. 2. Cell and Developmental Biology, University College London, London, Please select below, United Kingdom.

Mitochondria have been recently recognized as a key player in the pathophysiology of multiple sclerosis (MS), and mitochondrial membrane potential (ΔΨm) is decreased in animals with experimental autoimmune encephalomyelitis (EAE), a model of MS. Dimethylfumarate (DMF), a treatment for multiple sclerosis, is thought to act on inflammation and oxidative stress, specifically via upregulation of the transcriptional factor Nrf2. As mitochondrial metabolism may be regulated by Nrf2, and fumarate participates in the Krebs cycle, we have explored whether DMF might protect ΔΨm in EAE. Methods: Female mice with transgenically labelled axonal mitochondria were immunized with MOG35-55 and treated prophylactically with DMF (30mg/kg; twice daily) or vehicle. At eight days post-immunisation, and on the first day of neurological deficit, the spinal cord of the mice was exposed for in vivo confocal imaging of ΔΨm, under terminal anesthesia, using the fluorescent dye TMRM. Subsequent immunohistochemical examination included assessment of inflammation and Nrf2 upregulation. Complex I and II activity was analyzed in spinal cord mitochondrial isolates from immunized mice to determine a deficit in their enzymatic activity. Results: Prophylactic DMF treatment significantly reduced EAE incidence, but did not affect disease course. The decrease in ΔΨm, normally observed in axonal mitochondria shortly before the expected onset of neurological deficit, was averted in the DMF-treated animals, whereas after disease onset ΔΨm was decreased in both treatment groups. Post mortem examination showed significantly increased levels of Nrf2 in the DMF-treated animals, within 8 days of treatment. Inflammatory cell infiltration was minimal at the preclinical stage of the disease for both treatment groups, and microglial activation was not affected by DMF treatment. Topical application of DMF had no significant effect on ΔΨm compared with vehicle-treated mice. Conclusions: In the days preceding the onset of neurological deficit, DMF treatment results in the preservation of ΔΨm of axonal mitochondria, which can be the underlying mechanisms of the observed decrease in EAE incidence compared to controls. Although acute application of DMF is not sufficient to avert the mitochondrial deficit, Nrf2 upregulation following systemic DMF upregulation may play a role in the observed mitochondrial protection. ΔΨm preservation does not seem to occur via an Nrf2-mediated decrease in inflammation, as shown by the minimal presence of infiltrating inflammatory cells, as well as the lack of an effect on the levels of activated microglia following DMF treatment.

Where applicable, experiments conform with Society ethical requirements