Delayed or secondary energy failure causes cell death either by the genetically programmed process of apoptosis or by the explosive destruction of cellular membranes
NMDA I Channel I Open
NMDA I Channel I Open
called necrosis (Figure 2.1)110,111. Although a great deal of work remains to be done in specific models of ischemia in neonates, a general conceptual outline is available based on both animal and cell culture experiments.112 Apoptosis appears to be far more prominent in neonatal animal models of hypoxic ischemia than in the adult, and cell death is expressed in a continuum from apoptosis to necrosis at this age.113-117 In neonates it is common to observe "hybrid" cells that have morphologic features of both apoptosis and necrosis.118,119 The same continuum is observed in the immature brain when excitotoxic amino acids are injected directly into the brain.118 Evidence that a pan-caspase inhibitor is strongly protective against hypoxic-ischemic damage in the 7-day-old rat model suggests that apoptosis plays a major role in cell death at this age.120,121 In the neonatal rat model of hypoxic ischemia, NMDA antagonists prevent activation of caspase 3 in the brain.122 In the same model, apoptosis persists for more than a week after the insult, suggesting that new cells continue to commit to apoptosis over that time.119 Postmortem neuropathology from neonates who have died after hypoxic ischemia also demonstrates prominent apoptosis.113 This may be related to the fact that cellular programs for apoptosis are more active in the immature brain because they are used normally to remove redundant neurons.
Regarding Figure 2.1, synaptic dysfunction involving accumulation of glutamate and other amino acids and depolarization of neuronal membranes leads to excessive calcium entry into neurons and some glia. Production of oxygen-free radicals leads to mitochondrial dysfunction and secondary energy failure over hours to days after the insult. Consumption of NAD+ by activation of PARP poly(ADP-ribose) polymerase may contribute to mitochondrial dysfunction by reducing energy intermediates. Activation of caspases by mitochondrial dysfunction can lead to apoptosis. The nature and intensity of mitochondrial dysfunction may help to determine whether neurons die by necrosis, with total destruction of neuronal membranes, or apoptosis, which involves nuclear condensation and cytoplasmic shrinkage with membranes left intact until phagocytosis.
Experiments in cell culture suggests that the severity of mitochondrial energy failure may have a connection to the decision that cells make for apoptosis or necro-sis.110,111,123 Ankarcrona et al. found that the expression of apoptosis or necrosis in cultured neurons was related to the severity of energy failure produced by NMDA, with necrosis associated with more intense excitotoxic insults.110 Less severe insults may impair metabolism and stimulate mitochondria to release cytochrome C and other proteins to activate caspase 3 and apoptosis by the intrinsic pathway.124 Recent evidence suggests that hypoxic-ischemic injury in neonatal rats is also associated with activation of the extrinsic Fas death receptor pathway associated with cleavage of procaspase 8 and downstream activation of caspase 3.125 Activation of other proteases such as the interleukin 1 P converting enzyme (ICE) family also appear to be important in triggering apoptosis after hypoxic ischemia injury in neonates, providing a connection to cytokine-mediated inflammatory pathways.126,127 The calpain protease system is also activated by hypoxia-ischemia.126 This information suggests ways in which the nature and severity of energy disorders in the neonatal brain influence the decision for apoptosis or necrosis.
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