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Research Article Free access | 10.1172/JCI2169

Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury.

Y Cheng, M Deshmukh, A D'Costa, J A Demaro, J M Gidday, A Shah, Y Sun, M F Jacquin, E M Johnson, and D M Holtzman

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

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Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

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Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

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Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Demaro, J. in: PubMed | Google Scholar

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Gidday, J. in: PubMed | Google Scholar

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Shah, A. in: PubMed | Google Scholar

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Sun, Y. in: PubMed | Google Scholar

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Jacquin, M. in: PubMed | Google Scholar

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Johnson, E. in: PubMed | Google Scholar

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

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Published May 1, 1998 - More info

Published in Volume 101, Issue 9 on May 1, 1998
J Clin Invest. 1998;101(9):1992–1999. https://doi.org/10.1172/JCI2169.
© 1998 The American Society for Clinical Investigation
Published May 1, 1998 - Version history
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Abstract

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.

Version history
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