CASPASE INHIBITOR AFFORDS NEUROPROTECTION WITH DELAYED ADMINISTRATIONIN A RAT MODEL OF NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY

Programmed cell death (apoptosis) is a normal process in the developin g nervous system. Recent data suggest that certain features seen in th e process of programmed cell death may be favored in the developing ve rsus the adult brain in response to different brain injuries. In a wel l characterized model of neonatal hypoxia-ischemia, we demonstrate mar ked but delayed cell death in which there is prominent DNA laddering, TUNEL-labeling, and nuclei with condensed chromatin. Caspase activatio n, which is required in many cases of apoptotic cell death, also follo wed a delayed time course after hypoxia-ischemia. Administration of bo c-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, was signi ficantly neuroprotective when given by intracerebroventricular injecti on 3 h after cerebral hypoxia-ischemia. In addition, systemic injectio ns of boc-aspartyl(OMe)-fluoromethylketone also given in a delayed fas hion, resulted in significant neuroprotection. These findings suggest that caspase inhibitors may be able to provide benefit over a prolonge d therapeutic window after hypoxic-ischemic events in the developing b rain, a major contributor to static encephalopathy and cerebral palsy.