Transient Rise of Glucose Uptake in the Fetal Rat Brain after Brief Episodes of Intrauterine Ischemia

Abstract

In a rat model of intrauterine growth retardation and fetal brain ischemia, the maternal-fetal circulation was obstructed for up to 40 min in 20-day gestational age rats by occluding (restriction) the uterine blood vessels supplying the placenta. After restriction, flow was returned (reperfusion) for designated times. A time-dependent depletion of cerebral pyruvate levels (from 0.2 ± 0.02 to 0.06 ± 0.01 pmol/g wet weight) accompanied by an elevation in lactate concentration (from 1.95 ± 0.03 to 7.00 ± 0.56 umol/g wet weight) was observed after 20 min restriction. During 20 min, reperfusion lactate levels continued to increase, then gradually decreased as the reperfusion continued for approximately 2 h. A drastic increase in the lactate/pyruvate ratio (from 10 to 117) suggested that the fetal brain was relying on anaerobic glycolysis to meet its energy demands. In addition, a time-dependent decrease in fetal brain phosphocreatine (PCr) content from 2.54 ± 0.26 to 1.52 ± 0.15 mM was observed after 20 min of maternal-fetal blood flow obstruction. ATP levels gradually decreased after 20 min restriction from 1.62 ± 0.13 to 0.59 ± 0.09 mM. After 30 min reperfusion ATP, PCr and pyruvate returned to their normal values. These metabolic changes observed are concordant with the ability of the ischemic fetal brain to sustain adequate levels of ATP for energy-requiring cellular processes. The capacity of glucose transporters to facilitate transport of glucose into brain tissue was assessed ex vivo, using [³H]2-deoxyglucose (2D-Glu). A statistically significant increase of 2D-Glu uptake, from 48.9 ± 2.3 to 69.5 ± 4.5 pmol/mg (42%) was noticed in fetal brains after 20 min restriction. Kinetic analysis revealed a 2.2-fold increase in the maximal uptake of [³H]-2D-Glu after 20 min blood flow restriction. Facilitation of specific glucose transporters triggered by oxygen depletion and glucose reduction, may contribute to the partial resistance of the fetal brain to ischemia and account for the moderate decrease in ATP energy levels.

Direct administration and utilization of [1-13C]glucose by fetal brain and liver tissues under normal and ischemic conditions:1H,31P, and13C NMR studies

“…An ADP/ATP ratio of 0.34 was calculated which appeared to be a little higher than expected for a normal high energy charge. In a previous study we also detected somewhat lower absolute ATP concentrations (Kunievsky et al, 1994) than those reported by Vannucci and Duffy (1976) for the fetal brain. The ADP/ATP ratio in the fetal liver was 0.49 in the control samples and as expected no PCr was detected (Fig.…”

“…In this particular set of experiments [1-13 C]glucose was injected at the end of the 20 min maternal fetal blood occlusion, just before circulation was restored. Under these conditions, the energy status as indicated by the levels of phosphocreatine, ATP, pyruvate and lactate was not significantly different between 15 min and 20 min restriction (Kunievsky et al, 1994). The flux of the 13 C label reflects therefore glucose metabolism during the reperfusion period.…”

“…Using this model we showed an enhanced uptake of 2-deoxyglucose (2-DOG) by fetal brain slices subjected to ischemic episodes in utero as a mechanism to sustain adequate levels of ATP for energy-requiring cellular processes (Kunievsky et al, 1994). To extend this work we have now used nuclear magnetic resonance (NMR) spectroscopy to get a detailed insight into the fetal rat brain and liver energy metabolism under normal and ischemic conditions.…”

AMP-activated protein kinase-mediated glucose transport as a novel target of tributyltin in human embryonic carcinoma cells

“…18,19 The fetal brain has been reported to rely on anaerobic glycolysis to meet its energy demands. 20 Thus, GLUT is considered essential in the early organogenesis period. GLUT1, a major subtype of GLUT in fetal tissue, has been shown to mediate organogenesis in rat embryos.…”