Activation of S1P₁ receptor regulates PI3K/Akt/FoxO3a pathway in response to oxidative stress in PC12 cells.

FTY720 (fingolimod) is a sphingosine analogue that, when phosphorylated, becomes a prototypical sphingosine-1-phosphate (S1P) receptor modulator. It can enter the CNS and act on S1PRs expressed by most neural lineages. Recently, FTY720 neuroprotective and regenerative actions in the CNS have been demonstrated. In the present study, we have investigated whether the PI3K-Akt-FoxO3a axis is downstream to the S1P1 receptor modulation and involved in the cytoprotective effect of FTY720 in PC12 cells exposed to hydrogen peroxide (H2O2). The data showed that oxidative stress induces cell death in parallel with a significant decrease in PI3K, Akt and Akt target, and FoxO3a phosphorylation. FTY720 pretreatment increased cell survival which can be attributed to enhanced levels of inactive phosphorylated FoxO3a, a transcription factor playing critical role in oxidative stress-induced cell death. FTY720-phosphate (p-FTY720), a pan agonist of S1P receptors, as well as SEW2871, a selective S1P1 receptor agonist, similarly exerted cytoprotective effects. W123, a S1P1 receptor antagonist, abolished the effects of all three drugs, and concomitant application of DMS, a sphingosine kinase inhibitor, prevented the protective effects of FTY720. The data suggests that S1P1 receptor activation in the context of oxidative stress maintains PI3K/Akt signaling to prevent activation of FoxO3a, thereby promoting PC12 cell survival.