Neuroprotective effects of chronic exposure of SH-SY5Y to low lithium concentration involve glycolysis stimulation, extracellular pyruvate accumulation and resistance to oxidative stress

Abstract

Recent studies suggest that lithium protects neurons from death induced by a wide array of neurotoxic insults, stimulates neurogenesis and could be used to prevent age-related neurodegenerative diseases. In this study, SH-SY5Y human neuronal cells were cultured in the absence (Con) or in the presence (Li+) of a low lithium concentration (0.5 mm Li2CO3, i.e. 1 mm lithium ion) for 25-50 wk. In the course of treatment, growth rate of Con and Li+ cells was regularly analysed using Alamar Blue dye. Resistance to oxidative stress was investigated by evaluating: (1) the adverse effects of high concentrations of lithium (4-8 mm) or glutamate (20-90 mm) on cell growth rate; (2) the levels of lipid peroxidation (TBARS) and total glutathione; (3) the expression levels of the anti-apoptotic Bcl-2 protein. In addition, glucose metabolism was investigated by analysing selected metabolites in culture media and cell extracts by 1H-NMR spectroscopy. As compared to Con, Li+ cells multiplied faster and were more resistant to stress, as evidenced by a lower dose-dependent decrease of Alamar Blue reduction and dose-dependent increase of TBARS levels induced by toxic doses of lithium and glutamate. Total glutathione content and Bcl-2 level were increased in Li+ cells. Glucose consumption and glycolytic activity were enhanced in Li+ cells and an important release of pyruvate was observed. We conclude that chronic exposure to lithium induces adaptive changes in metabolism of SH-SY5Y cells involving a higher cell growth rate and a better resistance to oxidative stress.