Antioxidant Upregulation Contributes to Improvements in Diaphragm Function Following Cervical Spinal Cord Injury and...

Cervical spinal cord injury directly impacts the phrenic motor neuron pool, resulting in impaired ventilation and diaphragm muscle dysfunction. Previously, we demonstrated that hyperbaric oxygen (HBO) therapy, delivered during the acute phase following SCI, can attenuate diaphragm dysfunction. However, despite the demonstrated efficacy of HBO to improve muscle function, the molecular signaling pathways regulating this effect remain unclear. These experiments test the hypothesis that the protective effects of HBO therapy are associated with upregulation of the endogenous antioxidants SOD1, SOD2 and GPX1. Adult male Sprague-Dawley rats underwent a lateral spinal contusion injury at C4 followed by 10 consecutive days of HBO (3 ATA, 100% O₂, 1 h/day). Room air-treated spinal intact and injured rats were placed in a non-pressurized chamber for equal durations. To prevent the HBO-induced increase in antioxidant expression, antisense oligonucleotides directed towards each gene of interest were administered by intraperitoneal injection daily immediately following completion of HBO exposure (10 mg/kg/day). Saline was used as both the vehicle and placebo. Our results reveal that prevention of the HBO-induced upregulation of SOD1, SOD2 and GPX1 reduces diaphragm-specific force production compared to the control, injured HBO-treated rats. This effect occurred concomitantly with increased gene expression of the inflammatory cytokines IL-6, IL-1β and TNF-α and altered redox balance in the diaphragm. Thus, these data provide evidence that the HBO-induced increase in SOD1, SOD2 and GPX1 antioxidant expression contributes, at least in part, to the therapeutic effect of HBO to preserve diaphragm function following cervical spinal cord injury.