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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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University of Miami School of Medicine
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Perez-Pinzon, M A; Born, J G (1999) Rapid preconditioning neuroprotection following anoxia in hippocampal slices: role of the K+ ATP channel and protein kinase C. Neuroscience 89:453-9
Centeno, J M; Orti, M; Salom, J B et al. (1999) Nitric oxide is involved in anoxic preconditioning neuroprotection in rat hippocampal slices. Brain Res 836:62-9
Sick, T J; Xu, G; Perez-Pinzon, M A (1999) Mild hypothermia improves recovery of cortical extracellular potassium ion activity and excitability after middle cerebral artery occlusion in the rat. Stroke 30:2416-21;discussion 2422
Sick, T J; Tang, R; Perez-Pinzon, M A (1999) Cerebral blood flow does not mediate the effect of brain temperature on recovery of extracellular potassium ion activity after transient focal ischemia in the rat. Brain Res 821:400-6
Perez-Pinzon, M A; Xu, G P; Born, J et al. (1999) Cytochrome C is released from mitochondria into the cytosol after cerebral anoxia or ischemia. J Cereb Blood Flow Metab 19:39-43
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Feng, Z C; Sick, T J; Rosenthal, M (1998) Oxygen sensitivity of mitochondrial redox status and evoked potential recovery early during reperfusion in post-ischemic rat brain. Resuscitation 37:33-41
Perez-Pinzon, M A; Mumford, P L; Carranza, V et al. (1998) Calcium influx from the extracellular space promotes NADH hyperoxidation and electrical dysfunction after anoxia in hippocampal slices. J Cereb Blood Flow Metab 18:215-21
Sick, T J; Feng, Z C; Rosenthal, M (1998) Spatial stability of extracellular potassium ion and blood flow distribution in rat cerebral cortex after permanent middle cerebral artery occlusion. J Cereb Blood Flow Metab 18:1114-20
Perez-Pinzon, M A; Mumford, P L; Sick, T J (1998) Prolonged anoxic depolarization exacerbates NADH hyperoxidation and promotes poor electrical recovery after anoxia in hippocampal slices. Brain Res 786:165-70

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