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

• Published in: European journal of pharmacology Vol. 481; no. 2; pp. 169 - 173
• Main Authors: Feng, Yangzheng, Fratkin, Jonathan D., LeBlanc, Michael H.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 28.11.2003; Elsevier
• 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; Caspase; Neuroprotection; Stroke; Apoptosis; Oxygen; Nervous system diseases; Enzyme; Cysteine endopeptidases; Cardiovascular disease; Environmental factor; Cerebral disorder; Vascular disease; Peptidases; Ischemia; Cell death; Newborn animal; Central nervous system disease; Hydrolases; Hypoxia; Lesion; Cerebrovascular disease
• 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<0.05). Inhibiting caspase-8 activity after hypoxic–ischemic brain injury reduces brain injury.