The Role of the Endoplasmic Reticulum Stress Response in Neural Apoptosis of the Injured Spinal Cord

Abstract

Following spinal cord injury (SCI), oligodendrocyte progenitor cells (OPCs) that are abundantly present within the adult mammalian central nervous system proliferate around the lesion epicenter. However, most of these cells fail to differentiate into mature oligodendrocytes, hindering their potential for remyelination and functional recovery. One of the major inhibitory factors of OPC differentiation is apoptosis, which also leads to expansion of secondary injury and deterioration of neurological symptoms. There is a growing body of evidence linking the endoplasmic reticulum (ER) stress response to numerous neurodegenerative diseases. To investigate the role of ER stress response in apoptosis following SCI, we examined the in vitro and in vivo changes of ER stress effector proteins under stress conditions. Furthermore, the ER stress response was enhanced by gene transfection in vitro and the administration of amiloride in vivo, and their effect on apoptosis was studied. Amiloride is a Food and Drug Administration (FDA)-approved potassium-sparing diuretic used to treat hypertension, which has been reported to control ER stress and improve several neurological disorders in vivo. The 78 kDa glucose-regulated protein (GRP78), which is an ER chaperon that regulates protein folding in the ER and contributes to cell survival, was upregulated under stress conditions both in vitro and in vivo. However, when the stress became excessive, expression of GRP78 decreased and the expression of the pro-apoptotic factor C/EBP homologous transcription factor protein (CHOP) increased, leading to increased cell apoptosis. Overexpression of GRP78 by gene transfection protected cultured glial cells from ER stress-induced apoptosis. In the injured spinal cord of rats, amiloride treatment significantly reduced cellular apoptosis at the lesion epicenter and reduced the expansion of apoptosis caused by secondary injury. Furthermore, the decrease in ER stress-induced apoptosis increased the number of OPCs in the injured spinal cord and brought about a significant improvement in hind limb function. These studies suggest that amiloride may be an effective treatment to reduce ER stress-induced apoptosis in the acute phase of SCI.