Reevaluation of Ischemic Neuronal Apoptosis

Wyllie reported that the genomic DNAwas cleaved into oligonucleosomal size in the course of apoptosis.256 This internucleosomal DNA fragmentation (or DNA ladders) has been shown using the agarose gel electrophoresis of DNA and the terminal de-oxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method and widely accepted to define apoptosis.66,256 In addition, apoptotic condensation of the nuclear chromatin has been demonstrated using membrane-permeable fluorochromes (e.g., Hoechst dye and propidium iodide) binding to DNA.41,172 As DNA ladders, TUNEL-positive neurons, and the chromatin condensation were observed in the process of neuronal death in the hypoxic-ischemic brain areas, apopto-sis as well as oncosis has been considered an additional type of hypoxic-ischemic neuronal death.140,142,147 However, similar patterns of DNA damage are observed in the process of necrotic cell, suggesting that analysis of DNA damage is not sufficient to define apoptosis.55,74,224 The electron microscopic examination reveals that neurons primarily undergo oncosis evident by swelling of cell body and mitochondria, translucent cytoplasm, scattering condensation of the nuclear chromatin, and fenes-tration of the plasma membrane with the preserved nuclear membrane following occlusion of the middle cerebral artery (Figure 4.4). The similar morphological patterns of degenerating neurons were reported in the hippocampal region following global forebrain ischemia.35,141 Taken together, hypoxic-ischemic insults to brain appear to produce neuronal cell oncosis possibly through mechanisms involving

FIGURE 4.4 Transmission electron micrographs of a normal neuron (A), a typical apoptotic neuron in the dentate gyrus 1 d after the intraventricular injection of colchicines (B), and neurons showing necrotic features 1 day after occlusion of middle cerebral artery for 60 min (C) and (D). Abbreviations: N = nucleus; PM = plasma membrane; Mi = mitochondria. Scale bar, 2.5 mm.

FIGURE 4.4 Transmission electron micrographs of a normal neuron (A), a typical apoptotic neuron in the dentate gyrus 1 d after the intraventricular injection of colchicines (B), and neurons showing necrotic features 1 day after occlusion of middle cerebral artery for 60 min (C) and (D). Abbreviations: N = nucleus; PM = plasma membrane; Mi = mitochondria. Scale bar, 2.5 mm.

excitotoxicity and oxidative stress (Table 4.1). While some biochemical and molecular events underlying apoptosis have been observed following focal cerebral ischemia and global forebrain ischemia, these may be overridden by fulminant necrotic pathway. The apoptosis component of hypoxic-ischemic neuronal death may be unveiled with blockade of excitotoxicity and oxidative stress.84

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