Inhibiting caspase-8 after injury reduces hypoxic-ischemic brain injury in the newborn rat.

A broad spectrum caspase inhibitor reduces brain injury. Will a caspase-8 inhibitor provide protection? Seven-day-old rat pups had the right carotid artery ligated, then were subjected to 2.5 h of 8% oxygen. Caspase-8 activity in the right cortex was measured enzymatically. Caspase-8 activity was increased at 12 and 24 h after injury and IETD-CHO, (Ac-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Pro-Ile-Glu-Thr-Asp-CHO, CHO is aldehyde) a cell permeable caspase-8 inhibitor, given by i.c.v. injection after the hypoxic period eliminated this increase with significant effect at 15 and 50 microg/pup (1.7 micromol/kg). Thirty pups were randomly assigned to receive 50 microg/pup of IETD-CHO or vehicle i.c.v. immediately after the hypoxic period. The loss of brain weight in the right hemisphere 22 days after injury was 29+/-5% in the vehicle-treated animals and 12+/-5% in the IETD-CHO-treated animals (P<0.05). Inhibiting caspase-8 activity after hypoxic-ischemic brain injury reduces brain injury.