Unfolded protein response (UPR) signaling in cells stimulates UPR signaling in adjacent cells, facilitating disease progression by upregulating UPR target genes. However, whether this dissemination occurs between nerve cells and its molecular basis remains unclear. The supernatant of endoplasmic reticulum (ER) stress in rat astrocytes was prepared and treated with rat adrenal medulla pheochromocytoma cells to simulate the propagation of ER stress between nerve cells. The results showed that ER stress may propagate between rat nerve cells, ultimately leading to cell death. It was also found that the mediators mediating ER stress transmission have non-vesicular, oxidative-linked molecules with molecular weights > 100 kD. In conclusion, ER stress propagation might play a significant role in neuronal death following ER stress in central nervous system (CNS) diseases, suggesting novel therapeutic targets for these conditions.