Development of intracellular acidosis during cerebral ischemia and generation of free radicals during reperfusion are two mechanisms of brain injury that have received increasing attention in recent years. The overall goal of this proposal is to investigate the role of intracellular pH and oxygen-derived free radicals on the recovery of cerebral high energy phosphates, blood flow and electrical function following ischemia. We will use in vivo 31P nuclear magnetic resonance spectroscopy to track the recovery of cerebral ATP, phosphocreatine (PCr) and intracellular pH (pHi). We will simultaneously measure cerebral blood flow (CBF), 02 uptake, somatosensory evoked potentials (SEP), and electroencephalogram (EEG). We will study both complete and incomplete global cerebral ischemia produced by intracranial pres- sure elevations in dogs. To titrate recovery of electrical function (from normal to poor restoration), three ischemic durations will be produced so that effects of interventions can be studied in an injury-dose dependent manner. We will first determine whether the initial rate of recovery of ATP and PCr, as marker of mitochondrial function, correlate better with electrical recovery than steady state recovery level of ATP and PCr following various durations of complete and incomplete ischemia. We will then examine the influence of pHi achieved during ischemia and its rate of normalization during reperfusion on the rate of recovery of ATP, PCr, SEP, and EEG, To manipulate pHi, blood glucose levels will be varied, thereby altering lactic acid production. Complete ischemia will be compared to incomplete ischemia, where the range of pHi alterations should be greater because of sustained glucose delivery during ischemia. The influence of hyperventilation, a clinical intervention frequently used, on recovery of pHi, ATP. PCr, EEG and SEP will also be studied. We will investigate the role of oxygen-derived free radicals first by measuring the time course of cortical appearance and disappearance of superoxide anion during reperfusion, and second by demonstrating that free radical scavengers and inhibitors suppress superoxide appearance during reperfusion. We will then evaluate the efficacy of scavenger administration on the restoration of CBF, SEP, EEG, ATP and PCr. Finally, we will determine if acidosis potentiates free radical appearance and if scavengers can effectively reverse this detrimental effect of acidosis. These studies should enhance our understanding of ischemic-reperfusion injury mechanisms in brain.
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