Mechanism of the delayd neuronal death : a mitochondrial

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Brief period of global brain ischemia causes cell death in hippocampal CA1 pyramidal neurons days after reperfusion in rodents and human. Hippocampal CA1 neuronal death usually occurs 3-4 days after an initial ischemic insult. Such delay is seeential for the mechanism of this type of cell death. However, previous hypotheses have not well explained the reason of the delay and the exact mechanism of the cell death. On the other hand, disturbance of mitochondrial (mt) gene expression could be an alternative. Reductions of a mt RNA level and the activity of a mt protein, encoded partly by mt DNA,occurred exclusively in the CA1 neurons at the early stage of reperfusion, and were aggravated in the course of time. In contrast, the activity of a nuclear DNA-encoded mt enzyme and the level of mt DNA remained intact in the CA1 cells until the death. Immunohistochemical stainings for cytoplasmic dynein and kinesin, that are involved in the shuttle movement of mitochondria between cell body and the periphery, also showed early and progressive decreases after ischemia, and the decreases were found exclusively in the vulnerable CA1 subfield.Disturbance of mt DNA expression may be due to dysfunction of the mt shuttle system, and could cause progressive failure of energy production of the CA1 neurons that eventually results in the cell death. Thus, mitochondrial hypothesis could provide a new and fantastic potential to elucidate the mechanism of the delayd neuronal death of hippocampal CA1 neurons.