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

Kinga Czubowicz,Joanna B Strosznajder,Magdalena Cieślik,Joanna Pyszko,Robert P Strosznajder

doi:10.1007/s12035-014-8807-5

Kinga Czubowicz, Joanna B Strosznajder + Show 3 more

Open Access

https://doi.org/10.1007/s12035-014-8807-5

Copy DOI

Abstract

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.

Highlights

Homeostasis of blood and cellular glucose is very important for the functioning of the central nervous system (CNS)
Our study presented that glucose deprivation (GD)/glucose reload (GR) leads to: significant cell death, enhancement of the free radical level and changes in the gene expressions of proand anti-apoptotic Bcl-2 proteins (Fig. 1a,b,c)
We observed that exogenously added S1P significantly suppressed oxidative stress and increased HT22 cell survival affected by GD/GR (Fig. 3a,b)

Summary

Introduction

Homeostasis of blood and cellular glucose is very important for the functioning of the central nervous system (CNS). Moderate hypoglycemia impairs neuronal functions, but severe hypoglycemia causes the death of vulnerable cells [1,2,3]. Despite intense efforts in research, the mechanism of neuronal cell death evoked by glucose deprivation (GD) followed by glucose reload (GR) is not yet fully understood. It was observed that hypoglycemia induces a several-fold increase in glutamate and aspartate concentrations in the brain extracellular space [4]. Adenosine, which may reduce neuronal activity, can increase during hypoglycemia [5, 6]. A Ca2+ and Zn2+ influx, production of reactive oxygen (ROS) and nitrogen (RNS) species and mitochondrial failure have been described to be associated with hypoglycemic neuronal damage [7, 8]

Objectives

Results

Conclusion