When cerebral blood flow is inadequate to sustain oxidative metabolism, an ischemic insult occurs which is characterized by a well described sequence of deteriorative changes in brain metabolic physiology which threaten irreversible damage. Although a variety of interrelated factors have been implicated in the progression to brain injury,relationships among these are not yet defined,effects of ischemia-induced changes upon recovery are not well understood and no mode of therapy has achieved general acceptance. Proposed studies are aimed toward factors that influence restoration of metabolic physiology (cell functions and metabolism,and relationships among these) following transient ischemia in mammalian brain. Specific protocols are focused upon tissue and intracellular activities manifested as extracellular oxygenation,mitochondrial electron transport,blood flow,ion transport and synaptic transmission since changes in these are consequences of ischemia and may underline secondary and irreversible effects of such insults. Proposed studies are based upon 'real-time', simultaneous optical and electrode indices of brain metabolic physiology. These will be measured (and sometimes manipulated) under 'steady-state' and 'active' conditions prior to,during and after ischemic insults. This approach offers four advantages: 1) the tightly coupled electrical,ion transport and metabolic activities in brain can be studied in terms of each other; 2) invasive sampling for biochemical assay can be avoided; 3) variations in extent and time course of ischemia-induced changes among animals can be accounted for; 4)they provide a natural history of events so that long-term effects can be correlated with prior events. Objectives and specific aims reflect research into: a) restoration of mitochondrial,ion transport and electrophysiology activity after ischemia; b) factors promoting,delaying or prohibiting recovery of these functions; c) factors underlying,or predictive of,secondary failure; and d) factors underlying, or predictive of,selective vulnerability to the consequences of cerebral ischemia. The fundamental premise of such research is that increased understanding of the effects of ischemia,and factors that promote or limit restoration of brain metabolic afterward,will lead to better management of cerebrovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS014325-14
Application #
3395480
Study Section
Neurology A Study Section (NEUA)
Project Start
1977-08-01
Project End
1994-01-31
Budget Start
1992-02-01
Budget End
1994-01-31
Support Year
14
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
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
Perez-Pinzon, M A; Vitro, T M; Dietrich, W D et al. (1999) The effect of rapid preconditioning on the microglial, astrocytic and neuronal consequences of global cerebral ischemia. Acta Neuropathol (Berl) 97:495-501
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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