Effects of fumaric acid esters on blood-brain barrier tight junction proteins.
The blood-brain barrier (BBB) is composed of a network of tight junctions (TJ) which interconnect cerebral endothelial cells (EC). Alterations in the TJ proteins are common in inflammatory diseases of the central nervous system (CNS) like multiple sclerosis (MS). Modulation of the BBB could thus represent a therapeutic mechanism. One pathway to modulate BBB integrity could be the induction of nuclear-factor (erythroid derived 2) related factor-2 (Nrf2) mediated oxidative stress responses which are targeted by fumaric acid esters (FAE). Here we analyze effects of FAE on the expression of TJ proteins in the human cerebral endothelial cell line hCMEC/D3 and experimental autoimmune encephalomyelitis (EAE). We show that dimethylfumarate (DMF) and its primary metabolite monomethylfumarate (MMF) induce the expression of the Nrf2/NQO1 pathway in endothelial cells. Neither MMF nor DMF had a consistent modulatory effect on the expression of TJ molecules in hCMEC/D3 cells. Tumor necrosis factor (TNFα)-induced downregulation of TJ proteins was at least partially reversed by treatment with FAE. However, DMF had no effect on claudin-5 expression in EAE, despite its effect on the clinical score and infiltration of immune cells. These data suggest that the modulation of the BBB is not a major mechanism of action of FAE in inflammatory demyelinating diseases of the CNS.
Department of Neurology, Hannover Medical School, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
Karelle
K
Bénardais
Refik
R
Pul
Vikramjeet
V
Singh
Thomas
T
Skripuletz
De-Hyung
DH
Lee
Ralf A
RA
Linker
Viktoria
V
Gudi
Martin
M
Stangel
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D000069462:Dimethyl Fumarate; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D062793:Occludin / Q000378:metabolism; D062725:Tight Junction Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
D062507:Claudin-5; D005650:Fumarates; D006873:Hydroquinones; D008298:Maleates; D051267:NF-E2-Related Factor 2; D062793:Occludin; D062725:Tight Junction Proteins; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; C073341:citraconic acid; C018855:2-tert-butylhydroquinone; D000069462:Dimethyl Fumarate
Blood–brain barrier, Experimental autoimmune encephalomyelitis, Fumaric acid esters, hCMEC/D3, ter-Butylhydroquinone