Continuation is proposed of current efforts to sequentially monitor changes of intracellular brain pH and lactate as well as PCr, Pi and ATP levels with multinuclear in-vivo NMR spectroscopy (MRS) during transient global ischemia (TGI) and reperfusion in ventilated, physiologically monitored rats. Our previous studies have described the extent of variable changes in PCr/ATP, Pi/PCr and lactate/n-acetyl aspartate (NAA) peak ratios that may define metabolic thresholds for recovery during 1 hr reperfusion after 6, 15 and 30 min. ischemic episodes. A new model of basilar and temporary bilateral carotid occlusion in ventilated, physiologically monitored rats will be used to produce a more complete and uniform but less severe metabolic insult that obliterates the EEG signal due to almost complete reduction in CBF so that metabolic mechanisms of potentially preventable secondary ischemic brain injury can be elucidated. Using a double-tuned surface coil interleaved 31P and 1H spectra will be obtained at 5 min. intervals for 4 hrs to quantify metabolic alterations before during and after TGI. In vitro experiments will describe the time course and severity of delayed metabolic alterations during 4-24 hrs reperfusion after 15 or 30 min TGI. Outcome measures after TGI will include mortality, neurological function, histology, autoradiographic CBF and CMRG measurements (14C-IAP or 2DG), and neurochemistry (H2O, cation, arachidonic acid, thromboxane, leukotrienes and lipid peroxidation assays). Modification of lactic acidosis and possible protection from infarction after TGI by hypoglycemia, dichloroacetate, deep anesthesia with isoflurane or barbiturates, and treatment with mannitol or opiate antagonists will be evaluated. The relative roles and interactions of CBF reduction, substrate availability, ATP and PCr depletion, lactic acidosis due to anaerobic glycolysis and delayed hypoperfusion or cytotoxic reactions in production of infarction after TGI will be assessed. If MRS studies can detect a dynamic lactate threshold that identifies irreversible ischemic brain injury, a non-invasive in-vivo method for distinguishing infarction from edema could be developed for potential clinical application.
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