Transient Global Cerebral Ischemia Produces Morphologically Necrotic, Not Apoptotic Neurons

Abstract

Brief global cerebral ischemia results in relatively selective brain damage that matures over hours to many days. The most thoroughly studied structure is the hippocampal CA1 sector as these pyramidal neurons typically die 2–4 days after the insult. Other brain regions are also damaged, especially with prolonged ischemia and in true cardiac arrest models. Nonetheless, most studies target the CA1 zone to understand the molecular mechanisms of global ischemic injury and to evaluate putative neuroprotectants, leading to a number of existing studies of the morphological features of cell death after global ischemia. Cerebral ischemic cell death, including that of CA1 neurons, was long considered to be necrotic. Recently, however, some investigators have tacitly accepted that this cell death is apoptotic. This can partly be attributed to the biochemical evidence supporting the involvement of apoptotic mechanisms such as caspase activation and apoptosis-inducing factor release from mitochondria. Moreover, several studies claim that cell death appears morphologically apoptotic. If morphological criteria for necrosis and apoptosis are strictly applied to this biological problem, however, one may conclude that these are predominantly necrotic features. Thus, in our opinion, neuronal death after global cerebral ischemia in adult animals more closely resembles necrosis than either apoptosis or autophagy-induced cell death. Indeed, conclusive evidence for apoptotic neurons is lacking from light and electron microscopy studies. Nonetheless, the occurrence of programmed cell death mechanisms following cerebral ischemia, along with some signs of excessive autophagy, argues against the traditional view that global ischemia only induces necrosis in a completely unregulated, cytoclastic manner.

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