Inhibiting caspase-9 after injury reduces hypoxic ischemic neuronal injury in the cortex in the newborn rat.
A broad spectrum caspase inhibitor reduces hypoxic ischemic brain injury. We hypothesized that a specific caspase-9 inhibitor would provide similar protection. Seven-day-old rat pups had the right carotid artery ligated, then were subjected to 2.5 h of 8% oxygen. Caspase-9 activity in the right cortex was measured enzymatically. Caspase-9 activity was increased at 6, 12, and 24 h after injury. LEHD-CHO is a specific cell permeable caspase-9 inhibitor. LEHD-CHO given intracerebroventricularly (i.c.v.) into the brain after the hypoxic period eliminated the increase in caspase-9 activity. The greatest effect was at a dose of 50 microg/pup (1.6 micromol/kg). Fifty-two pups were randomly assigned to receive 50 microg/pup of i.c.v. LEHD-CHO or vehicle immediately after the hypoxic period. The loss of cortical neurons in the right hemisphere 22 days after injury was 52.0+/-8% in the vehicle treated animals, and 25+/-9% in the LEHD-CHO treated animals (P<0.05). Inhibiting caspase-9 activity reduces loss of neurons after brain injury.
Feng
Yangzheng
Y
Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Fratkin
Jonathan D
JD
LeBlanc
Michael H
MH
D000818:Animals; D000831:Animals, Newborn; D053453:Caspase 9; D061945:Caspase Inhibitors; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000473:pathology; D007276:Injections, Intraventricular; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C475574:Ac-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Leu-Glu-His-Asp-Cho; D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; D010455:Peptides; C506435:Casp9 protein, rat; D053453:Caspase 9