Mechanisms of Mitochondria-Induced Brain Damage Following Ischemia and Hypoglycemia

Research output: ThesisDoctoral Thesis (compilation)

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.

Details

Authors
  • Michel Ferrand-Drake
Research areas and keywords

Subject classification (UKÄ)

  • Neurosciences

Keywords

  • cyclosporin A, neuronal death, calpain, caspase, mitochondrial permeability transition, necrosis, apoptosis, cerebral ischemia, hypoglycemia, Neurology, neuropsychology, neurophysiology, Neurologi, neuropsykologi, neurofysiologi
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2000 Feb 11
Publisher
  • Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, 221 85 Lund, Sweden
Print ISBNs91-628-4002-9
Publication statusPublished - 2000
Publication categoryResearch

Bibliographic note

Defence details Date: 2000-02-11 Time: 09:00 Place: Segerfalkssalen, Wallenberg Neurocenter External reviewer(s) Name: Zhivotovsky, Boris Title: Professor Affiliation: Institutionen för Miljömedicin, Avdelningen för Toxikologi, Karolinska Institutet, Stockholm --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Brain Research (0131000120)