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.
Feng
Yangzheng
Y
Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Fratkin
Jonathan D
JD
LeBlanc
Michael H
MH
D000818:Animals; D000831:Animals, Newborn; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases