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.
Highlights
Multiple sclerosis (MS) is a progressive inflammatory disease of the central nervous system (CNS) [1]
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Summary
Multiple sclerosis (MS) is a progressive inflammatory disease of the central nervous system (CNS) [1]. This disabling disease is characterized by multifocal demyelination, axonal loss, activation of glial cells, and infiltration by immune cells [1]. An early key event in the pathogenesis of MS is the loss of blood-brain barrier (BBB) integrity. Thereby, T helper lymphocytes secrete interleukin 17, which disrupts the BBB allowing efficient penetration of inflammatory cells into the brain [2]. The BBB consists of specialized brain endothelial cells which are supported in their barrier function by surrounding glial cells [4]. The function of the BBB is highly dependent on the expression and appropriate localization of tight junction (TJ) and adherens junction (AJ) complexes between
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