MOLECULAR MECHANISMS ISCHEMIA REPERFUSION BRAIN INJURY

University Of Maryland Baltimore, Baltimore MD

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Abstract

The overall goal of this ongoing project is to gain a more complete understanding of the roles that mitochondrial dysfunction and oxidative molecular alterations play in ischemia/reperfusion brain injury. The specific aims are designed to amplify the most important conclusions made during the last few years and to test the following hypotheses using a combination of a clinically relevant animal model of transient global ischemia, neuronal and astrocytic cell culture models of hypoxic and excitotoxic delayed cell death, and subcellular models of mitochondrial stress. 1. Brain mitochondria release the apoptosis factor cytochrome c in response to elevated Ca2+, oxidative stress, and the presence of specific cell death proteins by membrane permeability transition independent and dependent mechanisms that can be controlled by unique neuroprotective agents. 2. Oxidative alterations to mitochondrial proteins and lipids is a common pathway by which elevated intracellular Ca2+, reactive oxygen species and metabolic derangements cause mitochondrial functional alterations during both acute ischemia and during reperfusion. 3. Early reperfusion-dependent loss of pyruvate dehydrogenase is a sensitive marker of selective neuronal vulnerability to oxidative stress and delayed cell death. 4. Delayed, post-ischemic hyperbaric oxygen therapy reduces oxidative injury and death in selectively vulnerable neurons through increasing expression of antioxidant defense mechanisms present in mitochondria and in other cellular compartments. The significance of these studies is that they will define the molecular mechanisms by which mitochondria are injured during cerebral ischemia and reperfusion, they will explicate the modes by which mitochondrial dysfunction promotes neural cell death, they will help identify novel targets for neuroprotection, and they will further test the neuroprotective potential of both pre- and postischemic hyperbaric oxygen therapy.