The mood stabilizer agents, lithium and valproate, inhibit staurosporine-induced apoptosis and eukaryotic initiation factor-2 alpha phosphorylation in SH-SY5Y neuroblastoma cells

Abstract

Both lithium and valproate have been used for the treatment of bipolar (manic-depressive) disorders. Despite their efficacy, the molecular mechanisms underlying their action remained to be elucidated. Eukaryotic initiation factor2a (eIF2a) plays a key role in protein translation and elongation. The phosphorylation of eIF2a involves several protein kinases and negatively regulates its activity and promotes apoptosis. This study aims to examine whether reduction of eIF2a phosphorylation exerts beneficial effects to neurons against stress. In this study, human neuroblastoma SH-SY5Y cell culture was exposed to staurosporine to induce apoptosis and cell death as shown by cell shrinkage, nuclei condensation or fragmentation and lactate dehydrogenase (LDH) release. Immunoblot techniques showed that apoptosis was associated with an increase in the phosphorylation of eIF2a on the serine-51 epitope in a time- and dose-dependent manner. Furthermore, neuroblastoma cells pretreated with either lithium chloride (LiCl) or sodium valproate (VPA) per se did not elicit morphological changes of apoptosis. Both mood stabilizers provided protection for neurons by reducing staurosporine-induced apoptosis as well as the increase in eIF2a phosphorylation. Our results suggest that a novel mode of neuroprotection is mediated by lithium and valproate which may explain some of the long-term therapeutic effects of mood stabilizing agents.