Apoptotic Pathways Cell Morphology

Apoptosis represents an actively regulated form of cell death, whereas necrosis is considered to represent a passive form of cell death secondary to the loss of energy metabolism. Because energy metabolism usually recovers initially after reperfusion, but can decline hours later depending on ischemic duration, the role of apoptotic and necrotic mechanisms can be interrelated temporally in a complex fashion. With complete or near-complete global cerebral ischemia, most neurons that die have a necrotic appearance. Neurons that display classic apop-totic morphology are uncommon (124), unless the blood flow reduction is moderate or brief (125 ) . Apoptotic morphology is more common in models of hypoxia-ischemia in immature rodents (126). This age-dependent pattern probably reflects the increased expression of many of the apoptosis-regulatory proteins in immature brain, which normally undergo increased baseline apoptosis (127) . However, the lack of pure apoptotic morphology in mature brain after ischemia does not mean that molecular mechanisms of apoptosis are not contributing to cell death. The processing of cell death signaling proteins may be modified by disturbed energy metabolism and free radical damage to the ER, Golgi apparatus, mitochondria, and nuclear membranes. Within neuronal subpopulations, multiple mechanisms may contribute to cell death, with each mechanism operating over different time courses and modifying the cell's response to other cell death pathways. Thus, hybrids of cell death mechanisms can display different morphologies along a necrosis-apoptosis continuum (128,129). Moreover, broad-spectrum caspase inhibitors are capable of ameliorating hippocampal damage from global ischemia (130-132), thereby implicating apoptotic signaling.

Studies of excitotoxicity in neuronal cell culture indicate that AMPA-induced cell death is partially dependent on apoptotic mechanisms (133). Large, discrete, irregularly shaped clusters of chromatin appear to be a hybrid between the large, uniformly rounded shape of apoptotic bodies versus the multiple, small chromatin clumps appearing in necrotic and NMDA-induced cell death (128,129). NMDA-induced cell death also yields a sequence of ultrastructural changes, including dilation of rough ER, disaggregation of polyribosomes, Golgi vesicula-tion, and mitochondrial swelling (128). After global ischemia, neurons in striatum undergo rapid cell death with an appearance that resembles NMDA and non-NMDA excitotoxic cell death (128,129). Delayed degeneration of pyramidal neurons in hippocampus and of Purkinje neurons in cerebellum does not typically display classic apoptotic morphology (134-1362. Interestingly, degenerating granule neurons in hippocampal dentate gyrus and granule neurons in cerebellar cortex display an apoptotic appearance at 1 day of reperfusion and often precede the necrotic appearance of pyramidal and Purkinje neurons. In immature rats and pigs subjected to hypoxia-ischemia, necrotic morphology is prominent in striatum and cerebral cortex, whereas delayed apoptotic morphology appears in thalamic sensory nuclei, apparently as a result of target deprivation (128,137,138). Thus, the mechanisms of cell death vary among specific neuronal populations with different temporal profiles and are influenced by connectivity and developmental maturity.

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