Fumaric acid dialkyl esters deprive cultured rat oligodendroglial cells of glutathione and upregulate the expression of heme oxygenase 1

doi:10.1016/j.neulet.2010.03.048

Neuroscience Letters

Volume 475, Issue 1, 7 May 2010, Pages 56-60

https://doi.org/10.1016/j.neulet.2010.03.048 Get rights and content

Abstract

Fumaric acid esters (FAE) are currently tested in clinical studies for their potential to treat multiple sclerosis. Since cellular glutathione is involved in the detoxification of xenobiotics and has been reported to form conjugates with FAE, we have analysed the consequences of an application of various FAE to oligodendroglial cells, using the oligodendroglial cell line OLN-93 and oligodendroglia-rich secondary cultures as model systems. In a concentration of 100 μM, dimethylfumarate (DMF) and diethylfumarate (DEF), but not fumarate nor the monoalkyl esters monomethylfumarate or monoethylfumarate, almost completely deprived both OLN-93 cells and secondary oligodendroglial cultures within 60 min of their cellular glutathione. None of the FAE applied compromised cell viability, nor did a treatment with DMF or DEF cause any extracellular accumulation of glutathione. Half-maximal effects on the cellular glutathione content of OLN-93 cells after 60 min of incubation were observed in the presence of 10 μM DMF or DEF. In contrast, fumaric acid monoalkyl esters had to be applied in millimolar concentrations to decrease the cellular glutathione content significantly within 60 min. After removal of DMF, OLN-93 cells completely restored their cellular glutathione content and strongly upregulated heme oxygenase 1. Thus, alterations in glutathione and heme oxygenase metabolism have to be considered when oligodendrocytes are exposed to fumaric acid dialkyl esters.

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Acknowledgements

We thank the Tönjes-Vagt-Stiftung for their generous financial support and Prof. C. Richter-Landsberg (University of Oldenburg, Germany) for kindly providing us with OLN-93 cells.

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Oxidative stress contributes to pathology associated with inflammatory brain disorders and therapies that upregulate antioxidant pathways may be neuroprotective in diseases such as multiple sclerosis. Dimethyl fumarate, a small molecule therapeutic for multiple sclerosis, activates cellular antioxidant signaling pathways and may promote myelin preservation. However, it is still unclear what mechanisms may underlie this neuroprotection and whether dimethyl fumarate affects oligodendrocyte responses to oxidative stress. Here, we examine metabolic alterations in oligodendrocytes treated with dimethyl fumarate by using a global metabolomic platform that employs both hydrophilic interaction liquid chromatography–mass spectrometry and shotgun lipidomics. Prolonged treatment of oligodendrocytes with dimethyl fumarate induces changes in citric acid cycle intermediates, glutathione, and lipids, indicating that this compound can directly impact oligodendrocyte metabolism. These metabolic alterations are also associated with protection from oxidant challenge. This study provides insight into the mechanisms by which dimethyl fumarate could preserve myelin integrity in patients with multiple sclerosis.
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Fumaric acid dialkyl esters deprive cultured rat oligodendroglial cells of glutathione and upregulate the expression of heme oxygenase 1

Abstract

Section snippets

Acknowledgements

Lancet

Brain Res. Protoc.

J. Neurol. Sci.

Lancet

Neurosci. Lett.

Free Radic. Biol. Med.

J. Invest. Dermatol.

J. Biol. Chem.

Mol. Aspects Med.

Bioorg. Med. Chem.