Sodium rutin attenuates blood-spinal cord barrier disruption and mitochondrial oxidative stress via SIRT1/β-catenin pathway in distractive spinal cord injury.

BACKGROUND: Distractive spinal cord injury (DSCI) is a severe complication of spinal deformity correction surgery, causing early disruption of the blood-spinal cord barrier (BSCB). However, the molecular mechanisms that translate mechanical distraction stress into vascular endothelial dysfunction remain unclear, and effective pharmacological strategies targeting this process are lacking. PURPOSE: This study aimed to investigate the therapeutic effects of sodium rutin (NaR), a water-soluble derivative of rutin, on BSCB disruption following DSCI, and to elucidate the underlying molecular mechanisms. METHODS: In vivo rat DSCI models and in vitro mechanical distraction models of spinal cord microvascular endothelial cells were employed. The therapeutic effects of oral NaR administration on locomotor function and BSCB permeability in rats following DSCI were systematically evaluated. Mechanistic investigations targeting the SIRT1/β-catenin axis and oxidative stress were conducted utilizing RNA sequencing, interventions with small interfering RNA and SIRT1 inhibitors, alongside standard molecular biology techniques. RESULTS: NaR treatment dose-dependently improved locomotor recovery in DSCI rats and significantly reduced BSCB permeability by restoring the expression of tight junction proteins. Mechanical distraction caused a significant downregulation of SIRT1 in endothelial cells. NaR treatment upregulated SIRT1 expression and promoted its nuclear-to-cytoplasmic translocation. This upregulation of SIRT1 was associated with significant inhibition of mitochondrial oxidative stress. Furthermore, oxidative stress was found to promote β-catenin phosphorylation and subsequent degradation via the ubiquitin-proteasome pathway. NaR stabilized β-catenin through SIRT1-mediated antioxidant effects, promoting its nuclear translocation and the downstream expression of tight junction genes. Consequently, by repairing the BSCB, NaR restricted the infiltration of immune cells (CD68+ macrophages/microglia and MPO+ neutrophils) into the spinal parenchyma, thereby attenuating secondary neuroinflammation. CONCLUSION: The SIRT1/β-catenin axis may serve as a critical mechanotransduction pathway for regulating BSCB integrity. NaR protects the BSCB after DSCI by restoring SIRT1 activity, suppressing oxidative stress, and stabilizing β-catenin signaling. NaR may be a promising pharmacological strategy for the treatment of DSCI.