Tetrahydrobiopterin in the Prevention of Hypertonia in Hypoxic Fetal Brain

Objective: Tetrahydrobiopterin (BH4) deficiency is a cause of dystonia at birth. We hypothesized that BH4 is a developmental factor determining vulnerability of the immature fetal brain to hypoxic-ischemic injury and subsequent motor deficits in newborns. Methods: Pregnant rabbits were subjected to 40-minute uterine ischemia, and fetal brains were investigated for global and focal changes in BH4. Newborn kits were assessed by neurobehavioral tests following vehicle and sepiapterin (BH4 analog) treatment of dams. Results: Naive fetal brains at 70% gestation (E22) were severely deficient for BH4 compared with maternal and other fetal tissues. BH4 concentration rapidly increased normally in the perinatal period, with the highest concentrations found in the thalamus compared with basal ganglia, frontal, occipital, hippocampus, and parietal cortex. Global sustained 40-minute hypoxia-ischemia depleted BH4 in E22 thalamus and to a lesser extent in basal ganglia, but not in the frontal, occipital, and parietal regions. Maternal Supplementation prior to hypoxia-ischemia with sepiapterin increased BH4 in all brain regions and especially in the thalamus, but did not increase the intermediary metabolite, 7,8-BH2. Sepiapterin treatment also reduced incidence of severe motor deficits and perinatal death following E22 hypoxia-ischemia. Interpretation: We conclude that early developmental BH4 deficiency plays a critical role in hypoxic-ischemic brain injury. Increasing brain BH4 via maternal supplementation may be an effective strategy in preventing motor deficits from antenatal hypoxia-ischemia.