Potential mechanisms of efficacy and adverse effects in the use of fingolimod (FTY720).

The interactions between sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) mediate a wide range of biological functions in the CNS and immune and cardiovascular systems. Fingolimod (FTY720), an S1PR modulator with potent immunomodulatory effects, was recently approved to treat multiple sclerosis. Some adverse effects of fingolimod reflecting vascular leak phenomena may be mediated through endothelial S1PRs, particularly macular edema. Oo et al. characterized the molecular interactions of fingolimod phosphate and S1PR type 1 (S1P(1)) leading to functional antagonism - phosphorylation of S1P(1) with subsequent receptor complex internalization, polyubiquitinylation and degradation. Differences along the pharmacological pathways that mediate vascular leak and lymphopenia were demonstrated, suggesting that distinct S1P(1) mechanisms mediate the adverse effects and efficacy of fingolimod.