Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury.
Programmed cell death (apoptosis) is a normal process in the developing nervous system. Recent data suggest that certain features seen in the process of programmed cell death may be favored in the developing versus the adult brain in response to different brain injuries. In a well characterized model of neonatal hypoxia-ischemia, we demonstrate marked but delayed cell death in which there is prominent DNA laddering, TUNEL-labeling, and nuclei with condensed chromatin. Caspase activation, which is required in many cases of apoptotic cell death, also followed a delayed time course after hypoxia-ischemia. Administration of boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, was significantly neuroprotective when given by intracerebroventricular injection 3 h after cerebral hypoxia-ischemia. In addition, systemic injections of boc-aspartyl(OMe)-fluoromethylketone also given in a delayed fashion, resulted in significant neuroprotection. These findings suggest that caspase inhibitors may be able to provide benefit over a prolonged therapeutic window after hypoxic-ischemic events in the developing brain, a major contributor to static encephalopathy and cerebral palsy.
Cheng
Y
Y
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Deshmukh
M
M
D'Costa
A
A
Demaro
J A
JA
Gidday
J M
JM
Shah
A
A
Sun
Y
Y
Jacquin
M F
MF
Johnson
E M
EM
Holtzman
D M
DM
D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy*; D002339:Carotid Arteries / Q000601:surgery; D003374:Coumarins / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004249:DNA Damage / Q000187:drug effects; D000860:Hypoxia / Q000188:drug therapy*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008026:Ligation; D009842:Oligopeptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C102580:acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin; C096022:acetyl-tyrosyl-valyl-alanyl-aspartyl-7-amino-4-methylcoumarinamide; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone