Sphingosine 1-phosphate signaling at the blood–brain barrier

• S1P is a pleiotropic signaling molecule that regulates BBB permeability.
• Fingolimod targets S1P receptors and may have therapeutic potential in BBB dysregulation.
• S1P1 primarily increases BBB integrity while S1P2 enhances permeability.
• Complex S1P pharmacokinetics modulate endothelial cell and astrocyte function.

The characterization of molecular pathways that modulate blood–brain barrier (BBB) function and integrity has been fueled by a growing body of literature implicating BBB dysfunction in a wide range of neurologic diseases. Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that has been effectively targeted by the immunomodulatory S1P1 functional antagonist fingolimod in the treatment of multiple sclerosis (MS). Investigation into the pathways modulated by S1P has revealed its important role in regulating BBB integrity via signaling through receptor isoforms on astrocytes and endothelial cells (ECs). Current evidence supports a significant role for S1P signaling as a key determinant of BBB permeability and hence as a potential pathogenic player or therapeutic target in diseases characterized by BBB dysfunction.