title: Fingolimod (FTY720-P) Does Not Stabilize the Blood-Brain Barrier under Inflammatory Conditions in an in Vitro Model.
abstract: Breakdown of the blood-brain barrier (BBB) is an early hallmark of multiple sclerosis (MS), a progressive inflammatory disease of the central nervous system. Cell adhesion in the BBB is modulated by sphingosine-1-phosphate (S1P), a signaling protein, via S1P receptors (S1P₁). Fingolimod phosphate (FTY720-P) a functional S1P₁ antagonist has been shown to improve the relapse rate in relapsing-remitting MS by preventing the egress of lymphocytes from lymph nodes. However, its role in modulating BBB permeability-in particular, on the tight junction proteins occludin, claudin 5 and ZO-1-has not been well elucidated to date. In the present study, FTY720-P did not change the transendothelial electrical resistance in a rat brain microvascular endothelial cell (RBMEC) culture exposed to inflammatory conditions and thus did not decrease endothelial barrier permeability. In contrast, occludin was reduced in RBMEC culture after adding FTY720-P. Additionally, FTY720-P did not alter the amount of endothelial matrix metalloproteinase (MMP)-9 and MMP-2 in RBMEC cultures. Taken together, our observations support the assumption that S1P₁ plays a dual role in vascular permeability, depending on its ligand. Thus, S1P₁ provides a mechanistic basis for FTY720-P-associated disruption of endothelial barriers-such as the blood-retinal barrier-which might result in macular edema.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg 97080, Germany. schuhmann_m@ukw.de.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.affiliation: Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. stefan.bittner@unimedizin-mainz.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: Department of Neurology, University of Münster, Münster 48149, Germany. sven.meuth@ukmuenster.de.|Department of Physiology I-Neuropathophysiology, University of Münster, Münster 48149, Germany. sven.meuth@ukmuenster.de.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg 97080, Germany. kleinschni_c@ukw.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg 97080, Germany. fluri_f@ukw.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Fluri
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D055806:Microvessels / Q000473:pathology; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000473:pathology; D062793:Occludin / Q000378:metabolism; D051381:Rats
chemical_list: D007166:Immunosuppressive Agents; D062793:Occludin; C568987:Ocln protein, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D000068876:Fingolimod Hydrochloride
keywords: FTY720-P; blood-brain barrier; inflammation; rat brain microvascular endothelial cell culture; tight junctions