Salubrinal alleviates traumatic spinal cord injury through suppression of the eIF2α/ATF4 pathway in mouse model

Abstract

Spinal cord injury (SCI) remains an intractable clinical challenge of neurosurgery, it can be divided into two stages: uncontrollable primary injury induced by mechanical damage and controllable secondary injury regulated by continuous cell death. The apoptosis was the one of most important events in secondary injury, previous studies revealed that excessive endoplasmic reticulum (ER) stress breaks down the homeostasis and triggers apoptosis in the spinal cord. To deter or alleviate the secondary jury, we screen one of fat-soluble compounds, salubrinal, which was an inhibitor of eIF2α dephosphorylation can repair SCI by inhibiting ER stress in mice after SCI. Administration of salubrinal effectively represses apoptosis, protects neuronal cell, and promotes the restoration of locomotor function in mice SCI models. Furthermore, the level of phosphorylated eIF2α was raised in the presence of salubrinal, but the protein expression of ATF4 and CHOP was downregulated. Unexpectedly, transcriptional expression of CHOP-regulated pro-apoptotic genes was decreased. These data suggest salubrinal suppress ER stress by targeting eIF2α/ATF4 pathways and reduces cell death after SCI. It is suggested that the mitigation of secondary lesion by inhibiting ER stress induced apoptosis in the early phase of SCI is promising treatment strategy.