Cerebral hypoxia causes selective neuronal damage by complex and incompletely understood mechanisms. In this proposal, CO hypoxia and re- oxygenation will be used to study some of the pathophysiological mechanisms involved in hypoxic neuronal injury. We will focus on the hypothesis that significant neuronal damage during and after CO hypoxia is caused by intracellular production of reactive oxygen species, particularly from mitochondrial sources, which contributes to both necrotic and programmed cell death (apoptosis).
The Specific Aims are: 1) Assess the extent of ROS production and oxidative stress during and after CO hypoxia in hypoxia sensitive and resistant brain regions in the rat in vivo, 2) Assess sources and mechanisms of ROS production and oxidative stress during and after CO hypoxia in hypoxia sensitive and resistant brain regions in vivo, 3) Investigate the extent and mechanisms by which increases in brain PO2 alter ROS production and oxidative stress in normal brain and after exposure to CO hypoxia in vivo, and 4) Investigate effects of CO hypoxia and interventions which alter oxidative stress after CO hypoxia on changes in brain function and neuropathology in the rat. The proposed studies are expected to demonstrate that oxidative stress from mitochondrial sources during and after CO hypoxia contribute substantially to neuronal degeneration in vulnerable brain regions, and that this effect can be ameliorated by pharmacological use of hyperbaric oxygen and specific interventions that minimize oxidative stress.
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