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Int. J. Mol. Sci. 2015, 16(12), 29454-29466; doi:10.3390/ijms161226177

Fingolimod (FTY720-P) Does Not Stabilize the Blood–Brain Barrier under Inflammatory Conditions in an in Vitro Model

1
Department of Neurology, University of Würzburg, Würzburg 97080, Germany
2
Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany
3
Department of Neurology, University of Münster, Münster 48149, Germany
4
Department of Physiology I-Neuropathophysiology, University of Münster, Münster 48149, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Katalin Prokai-Tatrai
Received: 11 June 2015 / Revised: 16 November 2015 / Accepted: 1 December 2015 / Published: 10 December 2015
(This article belongs to the Special Issue Advances in Multiple Sclerosis)
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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. View Full-Text
Keywords: FTY720-P; blood-brain barrier; rat brain microvascular endothelial cell culture; inflammation; tight junctions FTY720-P; blood-brain barrier; rat brain microvascular endothelial cell culture; inflammation; tight junctions
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Schuhmann, M.K.; Bittner, S.; Meuth, S.G.; Kleinschnitz, C.; Fluri, F. Fingolimod (FTY720-P) Does Not Stabilize the Blood–Brain Barrier under Inflammatory Conditions in an in Vitro Model. Int. J. Mol. Sci. 2015, 16, 29454-29466.

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