Mechanisms of Mitochondria-Induced Brain Damage Following Ischemia and Hypoglycemia

Detta är en avhandling från Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, 221 85 Lund, Sweden

Sammanfattning: Mechanisms of Mitochondria-Induced Brain Damage Following Ischemia and Hypoglycemia Following prolonged disruption of blood flow to the central nervous system (CNS), or energy deprivation by other means, such as hypoglycemia, some cells will inevitably degenerate. It has been, and still is, the subject of considerable debate and intense research on brain ischemia, as to the mode of cell death, i.e. do neurons (and other cells in the CNS) die as the result of a cell death program (apoptosis)? Are there similarities in the mechanisms, which seem to play an important role for executing cell death in apoptosis vs. the mechanisms, which are responsible for ischemic and hypoglycemic cell death? This thesis brings up some of the questions related to this issue. The time course of DNA fragmentation and its relation to morphological signs of cell death was studied. The role of the mitochondrial permeability transition (MPT), which is a state where an increase in permeability of the inner mitochondrial membrane causes mitochondrial swelling, was examined following hypoglycemia. The possible roles of caspase-3, the apoptotic "signature" protease, and calpain, a protease involved in both necrotic and apoptotic cell death, were investigated. We conclude that following hypoglycemia an induction of the MPT occurs and that following hypoglycemia and transient forebrain global ischemia, calpain and caspase-3 are activated. In both cases, caspase-3 activation precedes the development of DNA fragmentation. The activation of caspase-3, calpain, and DNA fragmentation, are processes only seen in degenerated or dying cells and are all prevented by blockade of MPT. In summary, neuronal cell death induced as a result of hypoglycemia and possibly ischemia, can be mediated through mitochondria-dependent cell death mechanisms.

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