Effects of dimethyl fumarate on neuroprotection and immunomodulation

Philipp Albrecht,Nadine Henke,Dmitrij Lisak,Corinna Zimmermann,Imane Bouchachia,Anne-Kathrin Mausberg,Norbert Goebels,Harald H Hofstetter,Jan Lewerenz,Zsuzsa Kovacs,Hans-Peter Hartung,Kim Quasthoff,Andrea Issberner,Axel Methner,Pamela Maher

doi:10.1186/1742-2094-9-163

Abstract

BackgroundNeuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects.FindingsWe determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays.ConclusionsThese results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.

Highlights

Neuronal degeneration in multiple sclerosis has been linked to oxidative stress
These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity
We show that neuroprotective concentrations of Dimethyl fumarate (DMF) suppress cytokine production by splenocytes from two different mouse strains without effecting apoptosis and do not impact neuronal network activity studied with dissociated cortical cultures grown on multielectrode arrays [14] which allows a highly sensitive and reproducible assessment of network activity

Summary

Introduction

Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We first investigated the concentration and time dependence of DMF-mediated protection in neuronal cells using a model of endogenous oxidative stress, oxidative glutamate toxicity, where extracellular glutamate blocks the glutamate-cystine antiporter system Χc-. This leads to deprivation of cystine and its reduced form cysteine, the rate-limiting substrate for the synthesis of glutathione. Our results suggest that low doses of DMF may promote cellular resistance against oxidative stress and cause immunomodulation independent of T cell apoptosis or alterations in endogenous brain activity

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