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.

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Glial fibrillary acidic protein (GFA) has been visualized by direct peroxidase antiperoxidase (APA) immunohistochemistry in various vertebrates (cyclostomes, teleosts, amphibians, reptiles, birds, and several placental mammals). In this study GFA-immunoreactivity (GFA-I) was observed in all species examined except in cyclostomes and amphibians. Two types of immunoreactive elements were observed: astrocytes and long processes without visible somata. Astrocytic cells with GFA-I were first found in the snake, and more cells were in birds where the pattern of distribution was similar to that of mammals. Within mammals, few differences in the manner of localization were observed among different species, except in the corpus callosum and the ependymal and subependymal layers. Long straight processes were observed in the lower submammalians--the lamprey, carp, and turtle. They radiated through the neuropil from the ventricular wall and followed nerve fiber bundles in the white matter. An uncommon feature was observed in the turtle brain, which possessed very intense GFA-I within the ependymal layer. The presence of GFA-containing profiles in the ependyma of adult animals is discussed in relation to GFA-positive structures seen in the human brain during ontogeny or under certain pathological conditions.