Modulatory Effect of Norepinephrine on Cardiorespiratory Improvement, Spinal Microenvironment and Gene Expression Following Mid-Cervical Spinal Cord Contusion in Rats.

Abstract

Maintaining the arterial blood pressure within an appropriate range following acute spinal cord injury is crucial for neurological recovery. However, the therapeutic efficacy and underlying mechanism of hemodynamic management remain to be determined. The present study aimed to investigate the modulatory effect of norepinephrine on cardiorespiratory function, spinal cord microenvironment, and gene expression following cervical spinal cord injury. Adult rats underwent implantation of osmotic pump filled with norepinephrine (125 μg/kg/h, 7 days) or saline (0.9%) immediately after mid-cervical spinal cord contusion. The cardiorespiratory parameters and spinal cord microenvironment (i.e., spinal cord blood flow, oxygenation, and hemorrhage level) were measured in anesthetized rats at 1 week post-injury. Transcriptome analysis was also used to evaluate the alteration of spinal cord gene expression following cervical spinal cord injury and norepinephrine treatment. Cervical spinal cord injury caused reductions in both arterial blood pressure and minute ventilation at 1 week post-injury. These cardiorespiratory impairments were profoundly improved by norepinephrine treatment. Although spinal cord blood flow and oxygenation were not significantly enhanced by norepinephrine, the correlation analysis revealed that there is a significant and positive correlation between the systolic blood pressure and minute ventilation and spinal oxygenation in contused rats that received norepinephrine. Notably, spinal hemorrhage was alleviated more in contused + NE animals (24 ± 4 mg/dL) than in contused + saline animals (45 ± 12 mg/dL). Moreover, transcriptome analysis of spinal cord tissue revealed that cervical spinal cord contusion led to an up-regulation of inflammation-related genes and down-regulation of neural transmission-related genes, which were partially mitigated by norepinephrine. These results demonstrated that hemodynamic management using norepinephrine effectively improves cardiorespiratory function and modulates the spinal microenvironment following cervical spinal cord injury.