Single dose of caspase inhibitor enhances long term survival and regeneration of injured motoneurons in neonates

Abstract

We have previously shown that caspase inhibitors promoted 80% of avulsed spinal motoneurons to survive for up to three weeks in neonates. The present study examined the effect of the caspase inhibitor, Boc-D-FMK on long-term survival and regeneration of the injured motoneurons. On the day of birth, root avulsion was performed in female rats. Immediately after the surgery, a gelfoam soaked with 0.5 μg Boc-D-FMK was placed into the lesioned area. The animals were allowed to survive for eight or twelve weeks. To study the regenerative capacity of the injured motoneurons, an autologous sciatic nerve was used as the peripheral nerve (PN) graft. After root avulsion, the animals received 0.5 μg Boc-D-FMK. The PN graft was placed into the lesioned area two weeks later. The postoperative survival period was four weeks. Fluorogold (FG) was used to retrogradely label the regenerated neurons. By eight weeks post-injury, 67.3% of injured motoneurons were still retained in the Boc-D-FMK treated group while no motoneuron survive in the sham group. Twelve weeks following the treatment, however, most motoneurons died while the remaining motoneurons showed shrunken and condensed nucleus and they were decreased in size. Treatment with Boc-D-FMK promoted axonal regeneration of motoneurons into the PN graft and 52.3% of the motoneurons were FG-labeled. Our results suggest that inhibition of caspases is crucial for the survival and regeneration of developing CNS neurons after axotomy. Supported by a grant from Hong Kong Research Grants Council