| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 4343926 | Neuroscience Letters | 2013 | 6 Pages |
•Fumaric acid esters (FAE) induce the Nrf2 pathway in a human endothelial cell line.•Tumor necrosis factor-alpha (TNFα) reduces the expression of tight junction proteins in endothelial cells in vitro which is partially reversed by FAE.•FAE do not affect the downregulation of the tight junction protein claudin-5 in an animal model, experimental autoimmune encephalomyelitis.•The modulation of the blood–brain barrier is not an important mechanism of FAE in inflammatory CNS diseases.
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.
