Attenuation of Activated eIF2α Signaling by ISRIB Treatment After Spinal Cord Injury Improves Locomotor Function

Abstract

AbstractFollowing spinal cord injury (SCI), multiple signaling cascades are activated instantaneously in the injured segments of the spinal cord to create a complex and pathogenic microenvironment, making it difficult to treat SCI. Nevertheless, the significance of the integrated stress response (ISR) to the series of physiological and pathological changes that occur after SCI remains unclear. Through western blotting (WB), we determined that the autophosphorylation of stress receptors (GCN2, PERK, PKR, and HRI) was enhanced after SCI, leading to increased phosphorylation of eIF2α at Ser51. Strikingly, we found that eIF2α was highly phosphorylated at 1 day post injury (dpi) and that this hypophosphorylation was maintained thereafter in the spinal cord, especially in neurons, which suggests that intervening with eIF2α phosphorylation may be a treatment strategy for SCI. Therefore, we employed the small molecule ISRIB, which inhibits eIF2α phosphorylation when the ISR is activated at moderate or low levels but not when the ISR is highly activated. Daily intraperitoneal injection of ISRIB significantly inhibited ISR signaling after SCI, reduced the cytosolic localization of RNA-binding proteins, and decreased neuronal apoptosis. Histological and functional experiments further demonstrated that treatment with ISRIB after SCI effectively curbed morphological deterioration and promoted the recovery of locomotor function. In summary, the ISR plays an important role in SCI, and ISRIB is a promising drug for the treatment of SCI.