Superoxide anion‐ and nitric oxide‐dependent mitochondrial dysfunction in neuronal apoptosis after spinal cord injury

Abstract

Apoptosis is an important cellular event that contributes to secondary damage after spinal cord injury (SCI). Although mitochondria, nitric oxide (NO) and superoxide anion (O2−) have been implicated a role, their inter-relationship in the elicitation of apoptosis after SCI is current unknown. In the injured spinal cord of rats subject to complete transection at thoracic segment 8, the sequential activation of apoptosis inducing factor (AIF)-dependent, followed by caspase 9- and 3-dependent signaling cascade was prevented by a NO trapping agent, carboxy-PTIO; a O2− scavenger, tempol; or a peroxynitrite decomposition catalyst, FeTMPyP. These treatments, at the same time, significantly suppressed apoptotic cell death after SCI. Double immunofluorescence staining revealed a negative correlation between the O2− level and viable mitochondria density in the spinal cord. Infusion of tempol into the epicenter of injury, on the other hand, resulted in a decrease in O2− content and a restoration of mitochondria vitality. Together, these results suggest that mitochondrial dysfunction after SCT triggers sequential activation of AIF-dependent and caspase-dependent signaling cascades, leading to neuronal apoptosis in the injured spinal cord. Furthermore, NO and O2− initiate this signaling cascade by suppressing mitochondrial respiratory enzyme activity.