Sphingosine-1-phosphate: a crucial mediator in glial proliferation, migration and neuroprotection.

ABRAHAN C; NAVALLAS S; GERMAN O. L.; POLITI L.; ROTSTEIN N.

Rio de Janeiro

Congreso; 1st Meeting of the Institute of Glia: a South American Alliance; 2011

Institute of Glia: a South American Alliance. iGlia

Purpose: The apoptosis of photoreceptors is a hallmark of retina degenerative diseases and oxidative stress participates in triggering this death. We have demonstrated that oxidative stress induces the apoptosis of retina neurons in culture, and promotes the proliferation of  Müller glial cells. In addition, glial cells in coculture protect neurons from oxidative damage. We now investigated whether sphingolipids, a group of lipids with key functions on cell proliferation, migration and survival, are emerging as possible tools for controlling these processes. We have identified the sphingolipid sphingosine-1-phosphate (S1P) as a crucial mediator in the proliferation and survival of photoreceptors. In this study we investigated the roles of S1P in proliferation and migration of Müller glial and microglial cells, and neuroprotection in coculture.Methods: Glial cultures, retinal explants and neuroglial co-cultures were prepared from rat retinas. The effect of S1P on glial cultures was evaluated by Br-deoxyuridine (BrdU) and [3H]thymidine uptake. Glial migration was studied by scratch-wound assays using glial cultures or on retinal explants treated with or without S1P. The requirement for S1P synthesis and activation of a S1P receptor (S1P3) for S1P effects was analyzed by adding an inhibitor of S1P synthesis or a S1P3 antagonist, BML-241, respectively. Oxidative stress was then induced with oxidant paraquat (PQ). Apoptosis was evaluated by TUNEL labeling.Results: Addition of S1P promoted [3H]thymidine and BrdU uptake and increased the number of cells in glial cultures. S1P stimulated glial migration on scratch-wound assays, and microglial migration from retinal explants. This migration was blocked by BML-241 addition. Inhibiting S1P synthesis or adding BML-241 before treating neuroglial co-cultures with PQ blocked neuroprotection from oxidative stress-induced apoptosis.Conclusions: These results suggest that S1P acts as a potent stimulator of proliferation and migration of Müller and microglial cells in vitro. S1P might also be one of the key mediators released by glial cells to promote neuronal protection.