Morphologic studies have shown that the extent of tissue injury observed following ischemia largely reflects damage incurred during reperfusion and have identified specific populations of brain neurons that are exceptionally susceptible to damage and death. These selectively vulnerable neurons include the pyramidal neurons in layers 3 and 5 of the cortex and those found in the CA1 and hilus of the hippocampus. Minimal ultrastructural injury is seen in the brain during complete ischemia. Some margination and clumping of nuclear chromatin is seen by 10 to 15 min of complete ischemia. Mitochondria may be slightly swollen, but their structure does not show major degenerative alterations for up to 30 min of complete ischemia. Similarly, some swelling of the endoplasmic reticulum (ER) may be seen during ischemia, but the polyribosomes remain appropriately associated with the ER, and disaggregation of polyribosomes does not occur during complete ischemia. Nuclear and plasma membranes show a normal, well-defined bilaminar structure without evidence of holes or general structural disintegration.
In contrast to the paucity of morphologic findings, there are severe biochemical alterations. With the onset of cardiac arrest there is precipitous decline in brain oxygen content, which approaches zero within 6 to 12 s. The brain has very limited reserves of glucose, glycogen, or phosphocreatine; therefore, oxygen depletion leads to a sharp decline in tissue adenosine triphosphate (ATP) levels, which approach zero within 4 min. Anaerobic glycolysis and ATP depletion lead to lactic acidosis and hypoxanthine accumulation, respectively, during the ischemic phase. Since about 80 percent of the brain's ATP is used to maintain transmembrane ionic gradients for potassium, sodium, and calcium, these ionic gradients also decay rapidly. During complete ischemic anoxia, these ions equilibrate between the extra-and intracellular fluid within 5 to 10 min of the insult.
The high cytosolic calcium level, thought to be a major initiating event leading to cell death, 7 causes four key events: the activation of membrane phospholipase A2, proteolytic cleavage of xanthine dehydrogenase, activation of the proteolytic enzyme calpain, and release of excitatory neurotransmitters such as glutamate. Phospholipase A2 cleaves a fatty acid, primarily arachidonate, from the cell membrane lipids, yielding a free fatty acid and in the process damaging the membrane's structure. The proteolysis of xanthine dehydrogenase in brain endothelial cells produces xanthine oxidase, which will react with hypoxanthine to produce the superoxide radical (O2-) upon reperfusion. Proteins that are degraded by calpain during either ischemia or reperfusion include microtubule-associated 2, tubulin, neurofilament protein, spectrin, protein kinase C, calcium/calmodulin kinase II, and the translation initiation factors eIF4E and eIF4G.
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