A Computational Investigation of FTY720P-Mediated Neuroprotection in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by autoimmune-mediated inflammation, demyelination, and lesion formation in the central nervous system (CNS). FTY720, a structural analogue of the endogenous sphingolipid, sphingosine, has been discovered as an orally-available immunomodulator effective at treating MS. FTY720-phosphate (FTY720P), the phosphorylated form of FTY720, resembles sphingosine-1-phosphate (S1P), and is a potent ligand on four out of the five S1P receptors. This investigation used a qualitative systems biology approach, aided by the computer modeling tool, CellDesigner, to create computational signaling models of the S1P receptors and of cell types that are involved in the observed FTY720P-mediated neuroprotection in MS. These models were used to explore the actions of S1P and FTY720P on the S1P receptors in different cell types and to test the ability of the models to qualitatively reproduce results in the literature. While the S1P receptor and cell type models were not perfect in a quantitative sense, they succeeded in qualitatively reproducing events described in the literature