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.
Highlights
Traumatic spinal cord injury (SCI) usually causes intense external intense stimulus, a severe type of high disability and incurable disease of the central nervous system (CNS)
The results of Basso mouse scale (BMS) shown no significant difference in recovery of motor function at 1 and 3 days after administration of salubrinal compared with the vehicle group (Fig. 1A)
The aggravation of secondary damage gives rise to poorer functional recovery after SCI, and the death of a large number of spinal nerve cells leads to the emergence of irreversible damage (Choo et al, 2008)
Summary
Traumatic spinal cord injury (SCI) usually causes intense external intense stimulus, a severe type of high disability and incurable disease of the central nervous system (CNS). Allen first proposed the two-stage damage theory, which classified acute SCI into primary and secondary injuries (Allen, 1914; Allen, 1911). Studies have recognized secondary injury as the main cause for the loss of bodily function after SCI, the specific pathological mechanism remains unclear. Recent studies have shown that secondary injury is closely correlated with endoplasmic reticulum (ER) stress (Ohri et al, 2013; Ohri et al, 2011; Valenzuela et al, 2012). Identifying the mechanism of ER stress and its role in the secondary injury of the spinal cord will further assist in the discovery of therapeutic targets, promoting the functional recovery of patients subjected to SCI
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