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Extracellular and intracellular acidosis occurs following hypoxic ischemia and has been considered as a primary cause of cell death.220 The possibility has been raised

FIGURE 4.3 Multiple pathways for hypoxic-ischemic neuronal apoptosis.

that intracellular acidification comprises an upstream event in the process of apop-tosis. The proton gradient across the mitochondrial inner membrane is collapsed in neurons deficient in oxygen and glucose, which can result in a complete loss of the mitochondrial membrane potential and render the outer mitochondrial membrane permeable to cytochrome c. The released cytochrome c in the cytosol binds to Apaf-1, activates procaspase-9, and leads to activation of downstream caspases such as caspase-3.42 Hypoxic ischemia or the apoptosis-inducing protein kinase inhibitor staurosporine causes acidification in the cytosol that promotes activation of cy-tochrome c-dependent caspases and acidic endonucleases.156 The intracellular acidification was shown to cause apoptosis in cultured neurons and haematopoietic cells.47,65 Growth factors and the antiapoptosis members of Bcl-2 prevent the cytoso-lic acidification, which likely results in attenuation of caspase activation and apop-tosis.65,109,195 It is possible that acidosis may mediate neuronal apoptosis following hypoxic-ischemic insults.

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