To promote functional recovery after CNS
injuries, it is crucial to develop strategies that enhance both neuronal survival and regeneration. Here, we report that
caspase-6 is upregulated in injured retinal ganglion cells and that its inhibition promotes both survival and regeneration in these adult CNS neurons. Treatment of rat
retinal whole mounts with Z-VEID-FMK, a selective inhibitor of
caspase-6, enhanced
ganglion cell survival. Moreover,
retinal explants treated with this
drug extended neurites on myelin. We also show that
caspase-6 inhibition resulted in improved
ganglion cell survival and robust axonal regeneration following
optic nerve injury in adult rats. The effects of Z-VEID-FMK were similar to other
caspase inhibitory
peptides including
Z-LEHD-FMK and
Z-VAD-FMK. In searching for downstream effectors for
caspase-6, we identified
caspase-8, whose expression pattern resembled that of
caspase-6 in the injured eye. We then showed that
caspase-8 is activated downstream of
caspase-6 in the injured adult retina. Furthermore, we investigated the role of
caspase-8 in RGC apoptosis and regenerative failure both in vitro and in vivo. We observed that
caspase-8 inhibition by
Z-IETD-FMK promoted survival and regeneration to an extent similar to that obtained with
caspase-6 inhibition. Our results indicate that
caspase-6 and
caspase-8 are components of a cellular pathway that prevents neuronal survival and regeneration in the adult mammalian CNS.