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- Ferrand-Drake, Michel
(author)
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Mechanisms of Mitochondria-Induced Brain Damage Following Ischemia and Hypoglycemia
- 2000
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Doctoral thesis (other academic/artistic)abstract
- 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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| 3. |
- Friberg, Hans, et al.
(author)
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Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death
- 1998
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In: The Journal of Neuroscience. - 0270-6474. ; 18:14, s. 5151-5159
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Journal article (peer-reviewed)abstract
- Induction of the mitochondrial permeability transition (MPT) has been implicated in cellular apoptosis and in ischemia-reperfusion injury. During MPT, a channel in the inner mitochondrial membrane, the mitochondrial megachannel, opens and causes isolated mitochondria to swell. MPT and mitochondrial swelling is inhibited by cyclosporin A (CsA), which may also inhibit apoptosis in some cells. Treatment with CsA (50 mg/kg, i.v.) showed a robust reduction of brain damage when administered 30 min before insulin- induced hypoglycemic isoelectricity of 30 min duration. Ultrastructural examination of the dentate gyrus revealed a marked swelling of dendrites and mitochondria during the hypoglycemic insult. In CsA-treated animals, mitochondria resumed a normal and contracted appearance during and after the hypoglycemic insult. Treatment with FK 506 (2 mg/kg, i.v.), a compound with immunosuppressive action similar to that of CsA, was not protective. Studies on the swelling kinetics of isolated mitochondria from the hippocampus showed that CsA, but not FK 506, inhibits calcium ion-induced MPT. We conclude that CsA treatment during hypoglycemic coma inhibits the MPT and reduces damage and that mitochondria and the MPT are likely to be involved in the development of hypoglycemic brain damage in the rat.
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