Fumaric acid diesters deprive cultured primary astrocytes rapidly of glutathione

Abstract

Fumaric acid esters (FAE) are used for the systemic therapy of psoriasis and are now considered for the treatment of autoimmune-based neurological disorders such as multiple sclerosis. Currently, the cellular metabolism of FAE as well as the mechanisms of their therapeutic action are poorly understood. Since cellular glutathione (GSH) is involved in the detoxification of xenobiotics, we analysed the consequences of an application of FAE on the content of GSH in brain cells using astroglia-rich primary cultures as model system. Micromolar concentrations of dimethyl fumarate (DMF) or diethyl fumarate (DEF) lowered the cellular GSH content in a time- and concentration-dependent manner. Halfmaximal effects after 60min of incubation were observed for 10μM DMF or DEF. In contrast to the diesters, monomethyl fumarate (MMF), monoethyl fumarate (MEF) or fumarate had to be applied in concentrations of 10mM for 60min to significantly lower the cellular GSH content. During 60min exposure, DMF or DEF did not significantly affect the cell viability, increase the cellular content of glutathione disulfide, nor altered the specific activities of glucose-6-phosphate dehydrogenase, glutathione reductase, or lactate dehydrogenase. After removal of DMF or DEF, cultured astrocytes restored their cellular GSH content completely within 4h. These data demonstrate that acute exposure to fumaric acid diesters deprives astrocytes of their GSH, most likely by the reaction of the reactive α,β-unsaturated diesters with GSH.