Effect of amiloride on endoplasmic reticulum stress response in the injured spinal cord of rats

Abstract

After traumatic spinal cord injury (SCI), endoplasmic reticulum (ER) stress exacerbates secondary injury, leading to expansion of demyelination and reduced remyelination due to oligodendrocyte precursor cell (OPC) apoptosis. Although recent studies have revealed that amiloride controls ER stress and leads to improvement in several neurological disorders including SCI, its mechanism is not completely understood. Here, we used a rat SCI model to assess the effects of amiloride on functional recovery, secondary damage expansion, ER stress-induced cell death and OPC survival. Hindlimb function in rats with spinal cord contusion significantly improved after amiloride administration. Amiloride significantly decreased the expression of the pro-apoptotic transcription factor CHOP in the injured spinal cord and significantly increased the expression of the ER chaperone GRP78, which protects cells against ER stress. In addition, amiloride treatment led to a significant decrease in ER stress-induced apoptosis and a significant increase of NG2-positive OPCs in the injured spinal cord. Furthermore, in vitro experiments performed to investigate the direct effect of amiloride on OPCs revealed that amiloride reduced CHOP expression in OPCs cultured under ER stress. These results suggest that amiloride controls ER stress in SCI and inhibits cellular apoptosis, contributing to OPC survival. The present study suggests that amiloride may be an effective treatment to reduce ER stress-induced cell death in the acute phase of SCI.

Amiloride Promotes Oligodendrocyte Survival and Remyelination after Spinal Cord Injury in Rats

“…Studies have also demonstrated that the administration of amiloride, which enhances the ER stress response, decreased OPC apoptosis [ 11 , 12 ]. In our previous study by Kuroiwa, et al [ 9 ], we demonstrated that amiloride administration increased GRP78 expression and decreased CHOP expression within the spinal cord, which decreased neural cell apoptosis and led to an increase of OPCs in the injured spinal cord. The group treated with amiloride had improved motor function compared to the control group up to 28 days after injury.…”

“…Compared to control animals, the rats that received amiloride administration had enhanced ER stress responses, with significantly increased expression of GRP78 and decreased expression of CHOP. The enhanced ER stress response led to a significant reduction in apoptosis and secondary injury expansion, and induced a significant increase in OPCs [ 9 ].…”

“…One of the factors implicated in OPC apoptosis is endoplasmic reticulum (ER) stress, which occurs due to the accumulation of misfolded proteins in the ER [ 9 , 10 ]. Unfolded or misfolded proteins are a common occurrence in cellular maintenance, and are usually handled by an intricately choreographed process, called the ‘ER stress response’ or ‘unfolded protein response (UPR)’.…”

Thioredoxin-1 Protects Spinal Cord from Demyelination Induced by Methamphetamine through Suppressing Endoplasmic Reticulum Stress and Inflammation

“…However, spinal cord injury (SCI) induced by addictive drugs attracts less attention. It has been reported that opioid addiction affects myelination ( 4 ). It is still unknown whether METH induces demyelination in spinal cord.…”

“…Oxidative stress ( 5 ), inflammation ( 6 ), endoplasmic reticulum (ER) stress ( 7 ), ecotoxicity, and dysregulation of metabolic processes are involved in SCI. After traumatic SCI, ER stress exacerbates secondary injury, leads to expansion of demyelination and reduction of remyelination resulting from oligodendrocyte precursor cell apoptosis ( 4 ).…”