Caspase inhibitors promote the survival of avulsed spinal motoneurons in neonatal rats.

Following ventral root avulsion in neonatal animals, the degeneration of spinal motoneurons occurs by an apoptotic-like morphological pathway. In adult animals, however, the mechanism of degeneration of injured motoneurons is still controversial. Because caspases are important mediators of apoptosis, we have investigated the effects of the caspase inhibitors, benzyloxycarbonyl-Asp(OMe)fluoromethylketone (Boc-D-FMK), and N-acetyl-Asp-Glu-Val-Asp aldehyde (Ac-DEVD-CHO) on the survival of neonatal and adult spinal motoneurons after root avulsion of the C7 spinal cord. In the control neonatal animals, virtually all motoneurons had degenerated by 7 days following root avulsion. Treatment with either 0.5 microg Boc-D-FMK or 1 microg Ac-DEVD-CHO enhanced the survival of motoneurons to 80% and 85% for up to 2 weeks post-injury. By 21 days post-injury, 70% of avulsed motoneurons were still present after Boc-D-FMK treatment, whereas all avulsed motoneurons died after treatment with Ac-DEVD-CHO. In adult animals, neither inhibitor was neuroprotective for motoneurons following root avulsion. In summary, the inhibition of caspases effectively rescued avulsed neonatal motoneurons which are died by apoptotic pathway. By contrast, because caspase inhibitors failed to rescue injured motoneurons in adult animals, their death may occur by a non-apoptotic pathway.