The goal of this investigation is to determine whether tissue acidosis plays a critical role in the development of ischemic damage and, if so, by which biochemical mechanisms. Using a model of reversible, unilateral hypoxia-ischemia in the mouse, we will first develop a regional, quantitative method for brain pH. Second, ischemic alterations of brain pH will be correlated with the accumulation of lactate during hypoxia-ischemia and with postischemic recovery of energy metabolism. Third, the pH changes during hypoxia-ischemia will be modified (a) by administering CO2 and (b) by partially inhibiting the glycolytic pathway in order to alter the recovery of energy metabolism. Finally, the ischemic change in glycolytic intermediates other than lactate will be determined in glucose-pretreated animals to detect deleterious alterations not related to acidosis. The second major aim is to identify the biochemical processes which are affected by acidosis/glucose-pretreatment. Because NADH is acid-labile, we will measure brain levels of NADH, NAD+, and their degradation products using enzymatic methods and high performance liquid chromatography (HPLC). In addition, we will attempt to alter the size of the NAD pool by administering the precursor, nicotinamide, and a false precursor, 6-amino-nicotinamide. The effect of acidosis/glucose-pretreatment on brain levels of Adenyl, Guanyl, Uridyl, and Cytidyl Nucleotides during and after hypoxia-ischemia will be determined using HPLC. Finally, the degradative activity of acid phosphatase will be assayed in hypoxic-ischemic brain using both in vitro and in vivo methods.
| Welsh, F A; Marcy, V R; Sims, R E (1991) NADH fluorescence and regional energy metabolites during focal ischemia and reperfusion of rat brain. J Cereb Blood Flow Metab 11:459-65 |
| Welsh, F A; Harris, V A (1991) Postischemic hypothermia fails to reduce ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab 11:617-20 |
| Welsh, F A; Sims, R E; Harris, V A (1990) Mild hypothermia prevents ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab 10:557-63 |
| Katayama, Y; Welsh, F A (1989) Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain. J Neurochem 52:1817-22 |
| Welsh, F A; Sakamoto, T; McKee, A E et al. (1987) Effect of lactacidosis on pyridine nucleotide stability during ischemia in mouse brain. J Neurochem 49:846-51 |
