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(Stroke. 2004;35:2189.)
© 2004 American Heart Association, Inc.

Original Contributions

Apoptotic and Necrotic Death Mechanisms Are Concomitantly Activated in the Same Cell After Cerebral Ischemia

Isn Ünal-Çevik, MD, PhD; Munire Klnç, MD, PhD; Alp Can, MD; Yasemin Gürsoy-Özdemir, MD, PhD Turgay Dalkara, MD, PhD

From the Department of Neurology (I.Ü.-Ç., Y.G.-Ö., T.D.), Faculty of Medicine, and the Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey; the Department of Neurology (M.K.), Faculty of Medicine, Baskent University, Ankara, Turkey; and the Department of Histology and Embryology (A.C.), Faculty of Medicine, Ankara University, Ankara, Turkey.

Correspondence to Dr Turgay Dalkara, Department of Neurology, Hacettepe University Hospitals, Ankara 06100, Turkey. E-mail tdalkara{at}hacettepe.edu.tr

Background and Purpose— Both necrotic and apoptotic cell death mechanisms are activated after cerebral ischemia. However, whether they are concomitantly active in the same cell or in discrete cell populations is not known.

Methods— We investigated activation of both pathways at the cellular level in mice brains subjected to transient or permanent focal ischemia.

Results— Four hours after ischemia, diffuse cathepsin-B spillage into cytoplasm, suggesting lysosomal leakage, was observed within neurons immunoreactive for the active form of caspase-3 (p20). Ischemic neurons with a leaky plasma membrane (positive for propidium iodide) were colabeled with caspase-cleaved actin fragment and exhibited TUNEL-positive nuclei having apoptotic morphology. At 72 hours, up to 27% of cells with caspase activity displayed morphological features suggestive of secondary necrosis.

Conclusions— These data, demonstrating an early and concurrent increase in caspase-3 and cathepsin-B activities followed by appearance of caspase-cleavage products, DNA fragmentation, and membrane disintegration, suggest that subroutines of necrotic and apoptotic cell death are concomitantly activated in ischemic neurons and that the dominant cell death phenotype is determined by the relative speed of each process.

Key Words: apoptosis • caspases • cathepsins • cerebral ischemia, focal • necrosis

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