Fingolimod (FTY720-P) does not stabilize the blood-brain barrier under inflammatory conditions in an in vitro model
Please always quote using this URN: urn:nbn:de:bvb:20-opus-145047
- 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 tightBreakdown 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.…
Author: | Michael K. Schuhmann, Stefan Bittner, Sven G. Meuth, Christoph Kleinschnitz, Felix Fluri |
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URN: | urn:nbn:de:bvb:20-opus-145047 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Neurologische Klinik und Poliklinik |
Language: | English |
Parent Title (English): | International Journal of Molecular Sciences |
Year of Completion: | 2015 |
Volume: | 16 |
Pagenumber: | 29454–29466 |
Source: | International Journal of Molecular Sciences 2015, 16, 29454–29466. DOI: 10.3390/ijms161226177 |
DOI: | https://doi.org/10.3390/ijms161226177 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | FTY720-P; Sphingosine 1-Phosphate; Zonula Occludens-1; blood-brain barrier; endothelial cells; experimental autoimmune encephalomyelitis; inflammation; matrix metalloproteinases; novo renal transplantation; randomized controlled trial; rat brain microvascular endothelial cell culture; relapsing multiple sclerosis; tight junctions; vascular permeability |
Release Date: | 2018/11/05 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |