Anti-inflammatory effects of siponimod on astrocytes

Siponimod, which is approved to treat active secondary progressive multiple sclerosis, acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P₁) and an agonist of S1P₅. S1P₁ antagonization, which inhibits lymphocyte egress from lymphoid tissues and subsequent infiltration into the central nervous system (CNS), is considered the main therapeutic mechanism of siponimod. In addition, siponimod's direct effects on CNS glial cells are another potential neuroprotective mechanism because siponimod can penetrate the blood-brain barrier and CNS glial cells express S1P receptors. However, it remains uncertain whether siponimod directly affects CNS glial cells. In this study, we investigated siponimod's effects on astrocytes using mouse primary cultures. Siponimod suppressed nuclear factor kappa B activation and pro-inflammatory cytokine production. Using antagonists for S1P₁ and S1P₅, we found that siponimod partially exerts its anti-inflammatory effects via S1P₁, but not via S1P₅. Moreover, siponimod also inhibited histone deacetylase, suggesting that siponimod exerts broad anti-inflammatory effects via S1P₁ antagonization and histone deacetylase inhibition. Siponimod might suppress disease progression in multiple sclerosis in part via direct inhibition of astroglial CNS neuroinflammation.