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The Journal of Neuroscience, September 15, 2001, 21(18):7127-7134
Specific Caspase Pathways Are Activated in the Two Stages of Cerebral Infarction
Alexandra Benchoua1, Christelle Guégan3, Cécile Couriaud1, Hassan Hosseini1, Nathalie Sampaïo1, Didier Morin2, and Brigitte Onténiente1 1 Institut National de la Santé et de la Recherche Médicale, Unité 421/IM3, and 2 Laboratoire de Pharmacologie, Faculté de Médecine, F-94010 Créteil Cedex, France, and 3 Department of Neurology, Columbia University, New York, New York 10032
Necrosis and apoptosis have been initially identified as two exclusive pathways for cell death. In acute brain lesions, such as focal ischemia, this binary scheme is challenged by demonstrations of mixed morphological and biochemical characteristics of both apoptosis and necrosis in single cells. The resulting difficulty in defining the nature of cell death that is triggered by severe insults has dramatically impeded the development of therapeutic strategies. We show that in the early stages of cerebral infarction, neurons of the so-called "necrotic" core display a number of morphological, physiological, and biochemical features of early apoptosis, which include cytoplasmic and nuclear condensations and specific caspase activation cascades. Early activation cascades involve the death receptor pathway linked to caspase-8 and the caspase-1 pathway. They are not associated with alterations of mitochondrial respiration or activation of caspase-9. In contrast, pathways that are activated during the secondary expansion of the lesion in the penumbral area include caspase-9. In agreement with its downstream position in both mitochondria-dependent and -independent pathways, activation of caspase-3 displays a biphasic time course. We suggest that apoptosis is the first commitment to death after acute cerebral ischemia and that the final morphological features observed results from abortion of the process because of severe energy depletion in the core. In contrast, energy-dependent caspase activation cascades are observed in the penumbra in which apoptosis can fully develop because of residual blood supply.
Key words: apoptosis; caspase; cortex; mitochondria; necrosis; stroke
Copyright © 2001 Society for Neuroscience 0270-6474/01/21187127-08$05.00/0
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