Sphingosine-1-phosphate and its effect on glucose deprivation/glucose reload stress: from gene expression to neuronal survival.

Sphingosine kinase-1 (Sphk1-1, EC 2.7.1.91) is a regulator of pro-survival signalling, and its alterations have been observed in Alzheimer's disease, brain ischemia and other neurological disorders. In this study we addressed the question whether Sphk1 and its product, sphingosine-1-phosphate (S1P), play a significant role in glucose deprivation (GD)/glucose reload (GR) stress in hippocampal neuronal cells (HT22). It was found that GD (6 h) followed by 24 h of GR evoked enhancement of the free radical level and neuronal HT22 cell death. Moreover, the significantly stronger gene expression for the pro-apoptotic Bax protein and down-regulation of the anti-apoptotic Bcl-2 and Bcl-XL proteins were observed. Concomitantly, this stress up-regulated: gene expression, protein level and activity of Sphk1. Exogenous S1P at 1 μM concentration and the other agonists of the S1P1 receptor (SEW 2871 and P-FTY720) enhanced HT22 cell viability affected by GD/GR stress. This mechanism is mediated by S1P receptor(s) signalling and by the activation of gene expression for Bcl-2 and Bcl-XL. Summarising, our data suggest that sphingolipid metabolism may play an important role in the early events that take place in neuronal cell survival/death under GD/GR stress. Our data demonstrate that exogenous S1P, through the activation of specific receptors S1P1 and S1P3 signalling pathways, regulates the gene expression for anti-apoptotic proteins and enhances neuronal cell survival affected by GD/GR stress.