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(Stroke. 2003;34:207.)
© 2003 American Heart Association, Inc.

Research Reports

Reperfusion Differentially Induces Caspase-3 Activation in Ischemic Core and Penumbra After Stroke in Immature Brain

C. Manabat, BS; B.H. Han, PhD; M. Wendland, PhD; N. Derugin, MA; C.K. Fox, BS; J. Choi, BS; D.M. Holtzman, MD; D.M. Ferriero, MD Z.S. Vexler, PhD

From the Departments of Neurology (C.M., C.K.F., D.M.F., Z.S.V.), Pediatrics (D.M.F.), Radiology (M.W.), and Neurosurgery (N.D.), University of California at San Francisco, and Center for the Study of Nervous System Injury, Departments of Neurology and Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, Mo (B.H.H., J.C., D.M.H.).

Correspondence to Zinaida S. Vexler, PhD, Department of Neurology, University of California at San Francisco, Box 0114, 521 Parnassus Ave, San Francisco, CA 94143-0114. E-mail zinaida{at}itsa.ucsf.edu

Abstract

Background and Purpose— Different strategies for neuroprotection of neonatal stroke may be required because the developing brain responds differently to hypoxia-ischemia than the mature brain. This study was designed to determine the role of caspase-dependent injury in the pathophysiology of pure focal cerebral ischemia in the immature brain.

Methods— Postnatal day 7 rats were subjected to permanent or transient middle cerebral artery (MCA) occlusion. Diffusion-weighted MRI was used during occlusion to noninvasively map the evolving ischemic core. The time course of caspase-3 activation in ischemic brain tissue was determined with the use of an Asp-Glu-Val-Asp-aminomethylcoumarin cleavage assay. The anatomy of caspase-3 activation in the ischemic core and penumbra was mapped immunohistochemically with an anti–activated caspase-3 antibody in coronal sections that matched the imaging planes on diffusion-weighted MRI.

Results— A marked increase in caspase-3 activity occurred within 24 hours of reperfusion after transient MCA occlusion. In contrast, caspase-3 activity remained significantly lower within 24 hours of permanent MCA occlusion. Cells with activated caspase-3 were prominent in the penumbra beginning at 3 hours after reperfusion, while a more delayed but marked caspase-3 activation was observed in the ischemic core by 24 hours after reperfusion.

Conclusions— In the neonate, caspase-3 activation is likely to contribute substantially to cell death not only in the penumbra but also in the core after ischemia with reperfusion. Furthermore, persistent perfusion deficits result in less caspase-3 activation and appear to favor caspase-independent injury.

Key Words: apoptosis • caspases • cerebral ischemia • magnetic resonance imaging, diffusion-weighted • neonate

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