Functional role and therapeutic implications of neuronal caspase-1 and-3 in a mouse model of traumatic spinal cord injury

Evidence indicates that both necrotic and apoptotic cell death contribute t o tissue injury and neurological dysfunction following spinal cord injury. Caspases have been implicated as important mediators of apoptosis following acute central nervous system insults. We investigated whether caspase-1 an d caspase-3 are involved in spinal cord injury-mediated cell death, and whe ther caspase inhibition may reduce tissue damage and improve outcome follow ing spinal cord injury. We demonstrate a 17-fold increase in caspase-1 acti vity in traumatized spinal cord samples when compared with samples from sha m-operated mice. Caspase-1 and caspase-3 activation were also detected by w estern blot following spinal cord injury, which was significantly inhibited by the broad caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethy lketone. By immunofluorescence or in situ fluorogenic substrate assay, casp ase-1 and caspase-3 expression were detected in neuronal and non-neuronal c ells following spinal cord injury. N-Benzyloxycarbonyl-Val-Ala-Asp-fluorome thylketone treated mice, and transgenic mice expressing a caspase-1 dominan t negative mutant, demonstrated a significant improvement of motor function and a reduction of lesion size compared with vehicle-treated mice. Our results demonstrate for the first time that both caspase-1 and caspase- 3 are activated in neurons following spinal cord injury, and that caspase i nhibition reduces post-traumatic lesion size and improves motor performance . Caspase inhibitors may be one of the agents to be used for the treatment of spinal cord injury. (C) 2000 IBRO. Published by Elsevier Science Ltd. Al l rights reserved.