Characterization of Soluble Fas Receptor as a Neuroprotective Agent following Acute Spinal Cord Injury

Spinal cord injury (SCI) is a devastating form of neurotrauma, affecting any population, and is a major cause of morbidity and mortality in children and young adults. The pathophysiology of SCI consists of a primary mechanical insult that triggers a secondary cascade of cellular damage. A key event in this pathology is delayed apoptotic cell death at and adjacent to the injury site, leading to progressive neurodegeneration. Several molecular pathways have been attributed to apoptosis after SCI. The Fas receptor pathway plays an integral role in the initiation of apoptosis through receptor-ligand binding of target cells and has been observed after CNS trauma and in several neurodegenerative diseases. Previous work in our lab has revealed that subarachnoid infusion of a soluble form of the Fas receptor (sFasR) is neuroprotective, as shown by long-term behavioral evaluation and neuronal tracing. We hypothesize that inhibition of the Fas receptor pathway is neuroprotective in the acutely injured spinal cord and results in reduction of neuronal and oligodendroglial cell death and enhanced axonal integrity across the lesion site. In this study, we used a 35g and 50g clip compression injury model at C7-T1 followed by intrathecal administration of sFasR using osmotic minipumps and catheterization at the site of injury. Using Western blotting and immunohistochemistry at 5 and 7 days following injury, our results reveal enhanced axonal preservation, enhanced survival of oligodendrocytes, and reduction in apoptotic cell death in sFasR-treated animals compared with controls. These results indicate that disruption of the Fas pathway in acute injury can lead to enhanced axonal and tissue preservation, which mirrors well with the improved long-term recovery observed previously in our lab. Moreover, this work shows the potential of soluble Fas receptor administration to be a therapeutic option for individuals suffering from acute SCI.