Intrauterine growth restriction induces up-regulation of cerebral aromatic amino acid decarboxylase activity in newborn piglets: [18F]fluorodopa positron emission tomographis study.

There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. However, the relevant enzyme activities have not been measured in the living neonatal brain together with brain oxidative metabolism. Therefore, fluorine-18-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) was used together with positron emission tomography to estimate the activity of the aromatic amino acid decarboxylase in the brain of 10 newborn IUGR piglets (2 to 5 d old; body weight, 908 +/- 109 g) and in 10 normal-weight (3 to 5 d old; body weight, 2142 +/- 373 g) newborn piglets. The regional transport of FDOPA to the brain and the clearance rate of labeled metabolites from brain tissue were broadly similar in the two groups. However, the regional rate constant for back flux from the brain was markedly increased in IUGR piglets for striatum (72%) and frontal cortex (83%) (p < 0.05). Furthermore, the rate constant for conversion of FDOPA to fluorodopamine was markedly increased (between 48% in cerebellum and 91% in mesencephalon, p < 0.05) in all brain regions of IUGR piglets studied. Thus, it is suggested that IUGR induces an up-regulation of aromatic amino acid decarboxylase activity that is not related to alterations in brain oxidative metabolism.

Relation between brain tissue pO2 and dopamine synthesis of basal ganglia--a 18FDOPA-PET study in newborn piglets.

Perinatal hypoxic-ischemic cerebral injury is a major determinant of neurologic morbidity and mortality in the neonatal period and later in childhood. There is evidence that the dopaminergic system is sensitive to oxygen deprivation. However, the respective enzyme activities have yet not been measured in the living neonatal brain. In this study, we have used 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography (PET) to estimate the activity of the aromatic amino acid decarboxylase (AADC), the ultimate enzyme in the synthesis of dopamine, in the brain of newborn piglets under normoxic and moderate asphyxial conditions. The study was performed on 8 newborn piglets (2-5 days old). In each piglet PET studies were performed under control conditions and during 2-hour asphyxia. Simultaneously, brain tissue pO2 was recorded, cerebral blood flow (CBF) was measured with colored microspheres and cerebral metabolic rate of oxygen (CMRO2) was determined. Asphyxia was induced by lowering the inspired fraction of oxygen from 0.35 to 0.10 and adding about 6% CO2 to the inspired gas. Asphyxia elicited a more than 3-fold increase of the CBF (p < 0.01) so that CMRO2 remained unchanged throughout the asphyxial period. Despite this, brain tissue pO2 was reduced from 19 +/- 4 mm Hg to 6 +/- 3 mm Hg (p < 0.01). Blood-brain transfer of FDOPA as well as permeability-surface area product (PS) from striatum were unchanged. Striatal synthesis rate of fluoro-dopamine from FDOPA (k3) was, however, significantly increased (p < 0.01). This increase of the AADC activity is associated with reduced brain tissue pO2. Asphyxia-induced CBF increase impedes an alteration of brain oxidative metabolism.

Upregulation of the aromatic amino acid decarboxylase under neonatal asphyxia.

Perinatal hypoxic-ischemic cerebral injury is a major determinant of neurologic morbidity and mortality in the neonatal period and later in childhood. There is evidence that the dopaminergic system is sensitive to asphyxia. However, the respective enzyme activities have not yet been measured in the living neonatal brain. In this study, we have used 18F-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron-emission tomography (PET) to estimate the activity of the aromatic amino acid decarboxylase (AADC), the ultimate enzyme in the synthesis of dopamine (DA), in the brain of newborn piglets. Simultaneously, the cerebral blood flow (CBF) was measured with colored microspheres. Asphyxia elicited an up to threefold increase of the CBF. Despite this, the blood-brain transfer of FDOPA as well as the clearance rate constants from brain were unchanged. However, the synthesis rate of FDA from FDOPA was significantly increased in frontal cortex, striatum, and midbrain. This increase of the AADC activity and the decrease of monoamine oxidase activity may contribute to the increase of extracellular DA during asphyxia which is expected to be involved in severe disturbances of neuronal metabolism, e.g., by generating free radicals.

Simultaneous measurement of [18F]FDOPA metabolism and cerebral blood flow in newborn piglets.

Available information on the dopamine (DA) metabolism of the immature brain is rare. In order to establish a useful animal model we have performed PET experiments in anesthetized neonatal pigs using 6-[18F]-fluoro-L-DOPA (FDOPA) as tracer. In this study, we have simultaneously determined the cerebral blood flow and the rate constant of FDOPA conversion by the aromatic amino acid decarboxylase, the ultimate enzyme in the synthesis of dopamine. The estimated values of FDOPA decarboxylation in the basal ganglia were similar to values calculated in adult animals and humans. However, in contrast to those studies a significant decarboxylation was also found in the frontal cortex and the cerebellum. HPLC analysis of brain samples also revealed extensive and rapid metabolism of FDOPA in the five investigated brain regions. At 8 min after tracer injection about 80% of FDOPA was already converted to FDA and its metabolites. Surprisingly, a rather high fraction (16-21%) of [18F]-fluoro-3-methoxytyramine was found which may indicate a low storage capacity of vesicular DA at this perinatal stage. It is suggested that the findings are related to the ontogenetic development of the dopaminergic system. The knowledge of the regulation of the DA metabolism in the immature brain may have implications for the understanding of neurodevelopmental effects of perinatal oxygen deprivation.