• Sick, Thomas (PI)
  • Rosenthal, Myron (PI)

Project: Research project

Project Details


During brain ischemia, metabolism and those activities requiring ATP, are
among the most severely altered. These changes initiate a cascade of
events that underlay ischemic cell death. Less well understood are
events during reperfusion after ischemia. This information is essential
since reperfusion, reoxygenation and mitochondrial recovery are
prerequisite to recovery of ion transport and electrical activities; yet
residual derangements form ischemia (or reperfusion!) may promote further
brain injury. Previous research from this laboratory and others has
suggested that derangements produced by ischemia and/or reperfusion limit
the supply of electrons to the electron transport chain. We believe that
this limitation is manifested by acute dysfunction of mitochondrial, ion
transport and electrical activities and that it modulates subsequent
recovery of electrophysiology and histopathology. This suggestion was
supported by our recent finding that increasing brain oxygenation after
ischemia exaggerated mitochondrial hyperoxidation but decreased evoked
potential (EP) amplitudes; while decreasing brain oxygenation enhanced
EP recovery. Since many of the derangements which characterize post-
ischemic pathophysiology and histopathology may be linked to
mitochondrial dysfunction, proposed research will increase understanding
of such dysfunction by testing four hypotheses: 1) changes in
mitochondrial, ion transport and E activities after ischemia predict
chronic pathophysiology and histopathology; 2) the intensity of
mitochondrial, ion transport and electrical derangements, and
histopathology after ischemia reflect decreases in high energy
intermediates; 3) Post-ischemic brain oxygenation influences ATP levels,
mitochondrial activity, E recovery, and histopathology; and 4) enhancing
reducing equivalent supply to the mitochondrial electron carriers after
ischemia decreases PIMHo and histopathology and improves functional
recovery. To test these hypotheses, mitochondrial, ion transport and
electrical activities will be monitored simultaneously by optical and
electrode techniques while metabolite levels and histopathology will be
defined by assay sampling and light microscopy. Advantages of combining
these approaches include that: a) the coupling among mitochondrial, ion
transport and electrical activities can be examined; b) they provide a
natural history of events to link acute changes with residual
pathophysiology and histopathology; and c) consequences of manipulating
post-ischemic events will be defined. In this manner, understanding of
ischemia-induced pathophysiology and histopathology will be increased to
provide a rational basis from which strategies for therapeutic
intervention can be targeted.
Effective start/end date8/1/771/31/98


  • National Institutes of Health: $268,014.00
  • National Institutes of Health


  • Medicine(all)
  • Neuroscience(all)


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