ISRIB facilitates post-spinal cord injury recovery through attenuation of neuronal apoptosis and modulation of neuroinflammation

Background: Neuronal apoptosis and inflammation are two critical factors that impede functional recovery post spinal cord injury (SCI). Previous studies have demonstrated the inhibitory effects of integrated stress response inhibitor (ISRIB) on neuroinflammation in brain injury. However, whether ISRIB can regulate neuron death and neuroinflammation in the context of SCI remains elusive. Methods: We employed an oxygen-glucose deprivation/reperfusion (OGD/R) model to simulate spinal cord ischemia-reperfusion injury and utilized lipopolysaccharide (LPS) to activate microglia. We assessed cell viability and death to demonstrate the neuroprotective effect of ISRIB against neuron death, while evaluating cytokine levels and the expression of Arg1 and iNOS to elucidate the regulatory role of ISRIB in neuroinflammation. Bulk RNA-seq analysis was employed to investigate the global transcriptional changes in neurons and microglia induced by ISRIB treatment. Additionally, we validated the promoting effects of ISRIB on motor and sensory recovery in a mouse model of SCI. Results: We observed that ISRIB exerted a suppressive effect on neuron death and neuroinflammation. RNA-seq data revealed that the ISRIB exhibited regulation of neuron apoptosis through the P53 signaling pathway, as well as modulation of neuroinflammation by the JAK2/STAT3 signaling pathway. Western blotting and immunofluorescence analyses demonstrated that ISRIB reduced P53 expression in neuronal nuclei and inhibited the phosphorylation of JAK2 and STAT3 in microglia. In addition, we validated the capacity of ISRIB to promote locomotor function recovery in a mouse model of SCI. Conclusion: Our study confirmed the ability of ISRIB to regulate neuron apoptosis and neuroinflammation in SCI via the P53 signaling pathway and the JAK2/STAT3 signaling pathway, respectively. Treatment with ISRIB in mice with SCI promoted the recovery of neural function. This research provides new evidence and options for therapeutic strategies of SCI. The translational potential of this article: Our study provides experimental evidence to support the application of ISRIB in the repair of spinal cord injury.