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.
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