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

• Published in: European journal of pharmacology 2003-11, Vol.481 (2), p.169-173
• Main Authors: Feng, Yangzheng, Fratkin, Jonathan D., LeBlanc, Michael H.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Apoptosis; Biological and medical sciences; Caspase; Caspase 8; Caspase Inhibitors; Caspases - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - enzymology; Cerebral Cortex - pathology; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - enzymology; Hypoxia-Ischemia, Brain - pathology; Male; Medical sciences; Neurology; Neuroprotection; Rats; Rats, Sprague-Dawley; Stroke; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2003.09.016

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 μg/pup (1.7 μmol/kg). Thirty pups were randomly assigned to receive 50 μg/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