1-methyl-4-phenylpyridinium ion (MPP+) induces endoplasmic reticulum stress and activates caspase-12 in PC12 cells, leading to neuronal apoptosis. However, the underlying molecular mechanism remains unknown. The present study investigated the regulatory effects of nerve growth factor (Akt activator) and lithium chloride (glycogen synthase kinase-3β inhibitor) on the endoplasmic reticulum stress signaling pathway. The results revealed that MPP+ induced expression of Bip and C/EBP homologous protein. The upregulation of Bip and C/EBP homologous protein, as well as the decreased pro-caspase-12 level induced by MPP+ were inhibited by pretreatment of the nerve growth factor or lithium chloride. These results suggest that the phosphatidylinositol 3 kinase-Akt- glycogen synthase kinase-3β pathway is involved in MPP+-induced endoplasmic reticulum stress.