Sphingosine kinases (Sphk1/2) are crucial enzymes in regulation of the biostat between sphingosine-1-phosphate (S1P) and ceramide and play an important role in the pathogenesis/pathomechanism of Alzheimer's disease (AD). These enzymes synthesise S1P, which regulates neurotransmission, synaptic function and neuron cell proliferation, by activating five G protein-coupled receptors (S1P1-5). However, S1P synthesised by Sphk2 could be involved in amyloid β (Aβ) release by stimulation of Aβ precursor protein degradation. The significance of this bioactive sphingolipid in the pathogenesis of Parkinson's disease (PD) is unknown. The aim of our study was to investigate the expression level of Sphk1 and its role in human dopaminergic neuronal cell (SH-SY5Y) viability under oxidative stress, evoked by 1-methyl-4-phenylpyridinium (MPP+). Moreover, the mechanism of S1P action on the death signalling pathway in these experimental conditions was evaluated. Our study indicated marked downregulation of Sphk1 expression in this cellular PD model. Inhibition of Sphk1 decreased SH-SY5Y cell viability and concomitantly enhanced the reactive oxygen species (ROS) level. It was found that exogenous S1P (1 μM) exerted the neuroprotective effect by activation of Sphk1 and S1P1 receptor gene expression. Moreover, S1P downregulated Bax and harakiri, death protein 5 (Hrk/DP5) expression and enhanced cell viability in MPP+-treated cells. The neuroprotective mechanism of S1P is mainly dependent on S1P1 receptor signalling, which was indicated by using specific agonists and antagonists of S1P1 receptor. The results show that S1P and S1P1 receptor agonists protected a significant population of neuronal cells against death.
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.
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