Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain

Abstract

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. Ann Neurol 2009;66:323–331