Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 16, Issue 12, Pages 29454-29466Publisher
MDPI
DOI: 10.3390/ijms161226177
Keywords
FTY720-P; blood-brain barrier; rat brain microvascular endothelial cell culture; inflammation; tight junctions
Funding
- Sonderforschungsbereich [688]
- Interdisziplinares Zentrum fur klinische Forschung Wurzburg
- Novartis Pharma GmbH, Nurnberg
- Novartis
- Bayer Schering
- Biogen Idec
- Genzyme
- Merck Serono
- MSD
- Novo Nordisk
- Sanofi-Aventis
- Teva
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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 (S1P(1)). Fingolimod phosphate (FTY720-P) a functional S1P(1) 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 permeabilityin particular, on the tight junction proteins occludin, claudin 5 and ZO-1has 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 S1P(1) plays a dual role in vascular permeability, depending on its ligand. Thus, S1P(1) provides a mechanistic basis for FTY720-P-associated disruption of endothelial barrierssuch as the blood-retinal barrierwhich might result in macular edema.
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