Carbohydrate and Energy Metabolism in the Brain of Rats With Thromboxane A2-Induced Fetal Growth Restriction

Abstract

Fetal growth restriction (FGR) remains a cause of perinatal brain injury, sometimes leading to neurological and intellectual impairment. Although the mechanisms and pathophysiology of CNS injuries have not been elucidated completely, it is possible carbohydrate and energy metabolism may have an important role in the FGR brain. In this study, FGR was induced in rats by administration of synthetic thromboxane A 2 (STA 2 ). Pups were delivered by cesarean section. After killing, samples were obtained from the fetuses of both control and FGR rats for evaluation of carbohydrate and energy metabolism in brain tissue. Lactate and pyruvate levels in brain were reduced significantly in the FGR group. Glucose content in brain tissue tended to be increased in the FGR group. In contrast, glycogen content in brain tissue tended to be lower in the FGR group. However, these differences in glucose and glycogen content did not reach statistical significance. Brain high-energy reserves, including ATP, ADP, AMP, and phosphocreatine (P-Cr), were similar in the control and FGR groups. Gluconeogenesis compensated for chronic fetal hypoxia and decreased glycogen storage. Energy metabolism in the FGR brain is likely to be disrupted as a consequence of lower reserves of energy substrates. (Pediatr Res 70: 21-24, 2011) F etal growth restriction (FGR) is an important cause of perinatal morbidity and mortality. Surviving small-for-GA (SGA) infants have a higher incidence of neurological impairments including mental retardation and educational and/or behavioral problems (1-3). Several authors have reported that perinatal hypoxic ischemic brain damage may contribute to an increased prevalence of motor, cognitive, and affective disabilities in children born with FGR (4 -6). However, the mechanisms underlying these disabilities have not yet been fully elucidated.Various prenatal factors may affect fetal growth. Pregnancyinduced hypertension (PIH) is an especially important factor in FGR fetuses. In PIH, increasing umbilical vessel resistance causes limitations in uteroplacental blood flow. As a consequence, the supply of oxygen and nutrition to the fetus may decrease (7). FGR fetuses are frequently hypoxic and hypoglycemic (8). During labor, uterine contractions can further compromise placental blood flow and oxygen supply to the FGR fetus, thereby increasing the risk of an intrapartum hypoxic-ischemic event and subsequent brain injury (9). Several authors have also reported that FGR fetuses are not only at great risk of perinatal hypoxic ischemic events but also may be more susceptible to hypoxic-ischemic brain damage, compared with appropriate-for-GA (AGA) fetuses (9,10).Several studies have investigated the mechanisms of brain injuries in FGR model animals (11-13). Manipulations to induce FGR in animal models included surgical ligation of vessels supplying the uteroplacental unit (12) and maternal starvation (11). However, these models do not necessarily reflect the pathophysiology of FGR. It has been suggested that plasma levels ...

Acute hypoglycemia results in reduced cortical neuronal injury in the developing IUGR rat

“…Furthermore, the sensitivity to insulin was similar in both the IUGR/HG and NG/HG groups (Figure 1). Although studies employing a variety of IUGR animal models, including the bilateral uterine artery surgery used here, have shown fetal hypoglycemia and disrupted glucoregulation at birth (1,3,14), the blood glucose concentrations and hepatic gluconeogenic enzyme activity normalize by 10 days of age in the rat (12) consistent with our findings of normal fasting blood glucose concentrations in P14 IUGR rat pups. Likewise, in our experimental groups receiving saline (IUGR/CON and NG/CON) there was no difference in blood glucose concentrations during the 4 hr study period (Figure 1).…”

“…Whether or not IUGR infants are at an increased risk for hypoglycemic brain injury is unknown. Neurodevelopmental deficits have been described in school-aged children who were born IUGR with respect to learning and memory, cognition, attention and behavior, suggesting functional deficits in the cerebral cortex and hippocampus (3-6). The cerebral cortex and hippocampus are particularly vulnerable to hypoglycemic brain injury in both humans and rodents (7-9) with the cortex being more susceptible to injury than the hippocampus in the developing rat brain (7,10,11).…”

“…Animal models of IUGR describe altered carbohydrate and energy metabolism, blunted glucoregulation, and ineffective ketone body response to hypoglycemia (3,12-14) suggesting that the IUGR brain may be at greater risk of injury during periods of low glucose availability. Conversely, there is evidence that fetal metabolic adaptations as a result of IUGR might be protective during periods of perinatal or postnatal nutrient insufficiency by prioritizing limited resources to the brain over less metabolically active peripheral tissues.…”

Role for the thromboxane A2 receptor β-isoform in the pathogenesis of intrauterine growth restriction

“…Previous studies on the pathogenic role of TXA 2 in IUGR were performed in small animal models 25 26 27 where TPβ expression is absent. These data suggest that appropriate activation of TPα may promote healthy placentation and angiogenesis; however, overstimulation of TPα may result in ligand-induced receptor desensitization 45 46 47 essentially creating an environment devoid of TP activation.…”

“…TXA 2 overproduction by placentae and platelets is prevalent in human pregnancies complicated by cigarette smoking 22 , diabetes mellitus 23 and alcohol consumption 24 which are associated with IUGR. Furthermore, infusion of TXA 2 analogues (such as U46619 and STA 2 ) into rodents produces a IUGR-like syndrome characterised by a 10–15% reduction in pup weight, which persisted until 28 and 77 days post-partum for male and female offspring, respectively 25 26 27 . The pups from these pregnancies exhibit a pattern of growth restriction characteristic of asymmetrical IUGR with reduced body/liver weight with sparing of brain changes in weight or energy metabolites 25 28 29 .…”