Intrauterine growth restriction induces upregulation of aromatic amino acid decarboxylase (AADC) in piglets

INTRODUCTION: The importance of the intrauterine environment for the fetal brain development has been revealed by studies showing persistent behavioral abnormalities in prenatally stressed animals. Inadequate nutritional supply, mainly due to uteroplacental insufficiency or restricted maternal protein intake in the late gestation period, is mostly responsible for asymmetrical intrauterine growth restriction (IUGR). The immature dopaminergic system appears to be sensitive for inadequate prenatal nutritional supply followed by IUGR in offsprings, because the dopamine content in brainstem of fetal IUGR guinea-pigs is increased despite an unchanged oxygen delivery and an altered dopamine release persisted in IUGR born rats after maternal protein malnutrition. This, is suggested to contribute to etiological factors of the attention deficit hyperactivity disorder, a highly prevalent neurodevelopmental disorder with prefrontal and nigrostriatal dysfunction. However, the effects of IUGR on regional in vivo brain dopamine metabolism have yet not been determined. Therefore, we estimated the AADC activity, the ultimate enzyme in dopamine synthesis, together with the regional cerebral blood flow (CBF), the brain tissue PO₂ and the cerebral metabolic rate of oxygen (CMRO₂) in newborn normal weight (NW) and IUGR piglets.
METHODS: PET studies using FDOPA as tracer were performed in two groups of ten anesthetized (0.5% isoflurane, 70% N₂O, 30% O₂), 2-5 days old NW and IUGR piglets [1]. Blood pressure, gases, glucose and lactate, EEG and ECG were monitored. PET scans (three planes, 35 frames between 30 and 600 s) began simultaneously with the FDOPA injection (30-50 Mbq). 49 arterial blood samples were taken and plasma activity was measured. Plasma metabolites of FDOPA were determined by HPLC in 9 samples (between 2 and 120 min p.i.). The blood-brain clearance K₁ ^FDOPA, the clearance rate constant from brain k₂F^DOPA, the decarboxylation rate constant (k₃ ^FDOPA) and a constant for the clearance pathway (k_cl ^FDA+acids) of F-dopamine metabolites were calculated using a compartment model which corrects for the blood-brain transfer of 3-O-methyl-FDOPA [2]. Additionally, the cerebral blood flow (CBF) was measured with colored microspheres in both groups of animals [3].
RESULTS: In IUGR piglets the body weight was pronouncedly reduced (42% of NW group). Naturally occurring growth restriction in swine is asymmetrical with an increase in the mean ratio of brain weight to liver weight from 0.61±0.16 to 1.42±0.24 (P < 0.01). The reduction in brain weight was quite small (83 % of NW group). In contrast, the decrease in liver weight (35 % of NW group) was similar compared to that in body weight (42 % of NW group). All differences in organ weight were significant (P < 0.01). Physiological values measured for newborn NW and IUGR piglets were consistent with other data obtained from mildly anesthetized and artificially ventilated newborn piglets. The arterial blood pressure, the heart rate, and the arterial glucose content were mildly but significantly lower in IUGR piglets (P < 0.05). Other obtained physiological values such as the CMRO₂, the brain tissue PO₂, and the regional CBF were similar in NW and IUGR piglets. PET time curves of ¹⁸F activity accumulated in the striatum showed a distinctly higher tracer amount in IUGR piglets (P < 0.05). The regional transport of FDOPA to the brain indicated by K₁ ^FDOPA and PS^FDOPA, and the clearance rate of labelled metabolites from brain tissue (k_cl ^FDA+acids) were similar in both groups. However, the regional rate constants for backflux from the brain (k₂ ^FDOPA) was markedly increased in IUGR piglets in the striatum (72%) and the frontal cortex (83%) (P < 0.05). Furthermore, the