Caspase inhibition after neonatal ischemia in the rat brain.
Caspase-3 has been identified as a key protease in the execution of apoptosis and appears to be an important downstream event after hypoxia-ischemia in the immature brain. The efficacy of a pan-caspase inhibitor, boc-aspartyl-(Ome)-fluoromethyl-ketone (BAF), was tested in a model of unilateral focal ischemia with reperfusion in 7-day-old rats. The BAF inhibitor was given intraperitoneally 5 minutes before reperfusion via the carotid artery. This procedure reduced the activity of caspase-3 by 79% but did not induce a significant reduction in infarct volume (23.8 +/- 7.5% versus 30.1 +/- 6.4%). Animals were distributed in two populations. One population exhibited an infarct, whereas the other appeared to be fully protected. BAF-treated animals exhibiting an infarct mostly displayed necrotic cell death, whereas apoptotic nuclei were observed in untreated or vehicle-treated animals. Repeated dose of BAF (5 minutes before and 9 hours after reperfusion) did not also provide benefit after neonatal ischemia, although a general trend to reduce lesion was observed (20.5 +/- 3.7% versus 34.4 +/- 5.9%). These findings raise critical questions about the use of peptide ketone apoptotic inhibitors in improving histopathologic outcomes after neonatal stroke.
Joly
Luc-Marie
LM
UMR-CNRS 7102, Laboratoire Developpement et Vieillissement du Système Nerveux, Paris, France.
Mucignat
Valérie
V
Mariani
Jean
J
Plotkine
Michel
M
Charriaut-Marlangue
Christiane
C
D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002544:Cerebral Infarction / Q000473:pathology; D003374:Coumarins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D008297:Male; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009842:Oligopeptides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D003374:Coumarins; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009842:Oligopeptides; C115495:aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; C417985:butyloxycarbonyl-aspartyl-fluoromethyl ketone