Protective effects of monomethyl fumarate at the inflamed blood–brain barrier

• Published in: Microvascular research Vol. 105; pp. 61 - 69
• Main Authors: Lim, Jamie L., van der Pol, Susanne M.A., Di Dio, Flaminia, van het Hof, Bert, Kooij, Gijs, de Vries, Helga E., van Horssen, Jack
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2016
• Subjects: Anti-Inflammatory Agents - pharmacology; Antioxidants - pharmacology; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Blood–brain barrier; Cell Adhesion - drug effects; Cell adhesion molecules; Cell Adhesion Molecules - metabolism; Cells, Cultured; Coculture Techniques; Cytoprotection; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Fumarates - pharmacology; Heme Oxygenase-1 - metabolism; Humans; Leukocyte transendothelial migration; Leukocytes - drug effects; Leukocytes - metabolism; Leukocytes - pathology; Maleates - pharmacology; Monomethyl fumarate; Multiple Sclerosis - drug therapy; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; NAD(P)H Dehydrogenase (Quinone) - metabolism; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-ĸB; Nrf2; Transendothelial and Transepithelial Migration - drug effects; Monomethyl fumarate; Leukocyte transendothelial migration; NF-ĸB; Nrf2; Blood–brain barrier; Cell adhesion molecules
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1016/j.mvr.2015.12.003

Reactive oxygen species play a key role in the pathogenesis of multiple sclerosis as they induce blood–brain barrier disruption and enhance transendothelial leukocyte migration. Thus, therapeutic compounds with antioxidant and anti-inflammatory potential could have clinical value in multiple sclerosis. The aim of the current study was to elucidate the therapeutic effects of monomethyl fumarate on inflammatory-mediated changes in blood–brain barrier function and gain insight into the underlying mechanism. The effects of monomethyl fumarate on monocyte transendothelial migration across and adhesion to inflamed human brain endothelial cells (hCMEC/D3) were quantified using standardized in vitro migration and adhesion assays. Flow cytometry analysis and qPCR were used to measure the concomitant effects of monomethyl fumarate treatment on protein expression of cell adhesion molecules. Furthermore, the effects of monomethyl fumarate on the expression and nuclear localization of proteins involved in the activation of antioxidant and inflammatory pathways in human brain endothelial cells were elucidated using nuclear fractionation and Western blotting. Statistical analysis was performed using one-way ANOVA followed by the Bonferroni post-hoc test. Our results show that monomethyl fumarate induced nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and concomitant production of the antioxidant enzymes heme oxygenase-1 and NADPH:quinone oxidoreductase-1 in brain endothelial cells. Importantly, monomethyl fumarate treatment markedly decreased monocyte transendothelial migration across and adhesion to inflamed human brain endothelial cells. Treatment of brain endothelial cells with monomethyl fumarate resulted in a striking reduction of vascular cell adhesion molecule expression. Surprisingly, monomethyl fumarate did not affect nuclear translocation of nuclear factor-кB suggesting that monomethyl fumarate potentially affects activity of nuclear factor-ĸB downstream of nuclear translocation. Taken together, we show that monomethyl fumarate, the primary metabolite of dimethyl fumarate, which is currently used in the clinics for the treatment of relapsing–remitting multiple sclerosis, demonstrates beneficial therapeutic effects at the inflamed blood–brain barrier. •Monomethyl fumarate (MMF) has beneficial effects on the inflamed blood–brain barrier.•MMF increases levels of endogenous antioxidant proteins in brain endothelial cells.•MMF reduces expression of VCAM-1 in inflamed brain endothelial cells.•Transendothelial monocyte migration is limited upon MMF treatment.