S1P receptors are expressed by oligodendrocytes, astrocytes, microglia, and neurons. EAE is attenuated and fingolimod efficacy is lost in conditional null-mutant mice lacking S1P1 by astrocytes, which suggests that S1P receptor agonists may mitigate EAE through functional antagonism of S1P1 expressed by astrocytes. Further, other studies indicate the function of S1P receptors expressed by cells of the oligodendrocyte kinase inhibitors lineage. Oligodendrocytes are myelinating cells of the CNS, which are the principal target of immune attack in MS. Loss of myelin and the failure of remyelination by oligodendrocytes contribute to the functional impairment of patients with MS. Fingolimod-P treatment rescues oligodendrocyte progenitor cells from undergoing apoptosis in a death-inducing environment through S1P1 signaling. S1P or fingolimod-P promotes the survival of mature oligodendrocytes through S1P5. Fingolimod-P enhances remyelination in lysolecithin-induced demyelination in cerebellar slice culture, and an agonist specific for S1P5 shows a trend toward an increase in remyelination. ASP4058 acts agonistically on S1P1 and S1P5 and penetrates the CNS. Thus, the beneficial effects of ASP4058 for treating EAE may involve its direct effect on cells of the CNS. In clinical trials, fingolimod induced adverse events such as reduction of heart rate or mean FEV1. Preclinical findings that bradycardia induced by a nonselective S1P receptor agonist administered to wild-type mice is abolished in S1P3 knockout mice and that an S1P1-selective agonist does not induce bradycardia suggest that S1P3 signaling induces bradycardia. Consistent with these reports, ASP4058, which has weak agonistic activity for S1P3, required a higher dose than fingolimod-P to induce bradycardia in conscious rats. The safety margin between the lymphocyte-reducing effect and the bradycardia-inducing effect was evaluated by determining the plasma or blood concentrations of compounds. The concentrations of fingolimod-P required to change heart rate and to exert the maximal effect on lymphocyte counts in rats were similar. In contrast, the concentration of ASP4058 required to induce bradycardia was more than 30-times higher than that required to induce lymphopenia. These results suggest that ASP4058 presents less risk for adverse cardiovascular events than fingolimod-P because of its low activity for S1P3. Transient bradycardia was observed in healthy humans treated with the S1P1, S1P5 agonist BAF312, which suggest species-specific differences in S1P receptor specificity for first-dose cardiac effects. Therefore, whether or not ASP4058 exerts cardiovascular effects in human remains to be determined. S1P affects airway constriction in a Rho-dependent manner. For example, S1P stimulates contraction of human airway smooth muscle cells and guinea pig tracheal strips and enhances methacholine-induced contraction of guinea pig trachea.