Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain.
OBJECTIVE
Tetrahydrobiopterin (BH(4)) deficiency is a cause of dystonia at birth. We hypothesized that BH(4) 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 BH(4). Newborn kits were assessed by neurobehavioral tests following vehicle and sepiapterin (BH(4) analog) treatment of dams.


RESULTS
Naive fetal brains at 70% gestation (E22) were severely deficient for BH(4) compared with maternal and other fetal tissues. BH(4) 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 BH(4) 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 BH(4) in all brain regions and especially in the thalamus, but did not increase the intermediary metabolite, 7,8-BH(2). Sepiapterin treatment also reduced incidence of severe motor deficits and perinatal death following E22 hypoxia-ischemia.


CONCLUSIONS
We conclude that early developmental BH(4) deficiency plays a critical role in hypoxic-ischemic brain injury. Increasing brain BH(4) via maternal supplementation may be an effective strategy in preventing motor deficits from antenatal hypoxia-ischemia.
Vásquez-Vivar
Jeannette
J
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA. jvvivar@mcw.edu
Whitsett
Jennifer
J
Derrick
Matthew
M
Ji
Xinhai
X
Yu
Lei
L
Tan
Sidhartha
S
D000818:Animals; D000831:Animals, Newborn; D001708:Biopterins / Q000031:analogs & derivatives* / Q000032:analysis / Q000172:deficiency / Q000627:therapeutic use; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D004195:Disease Models, Animal; D004421:Dystonia / Q000517:prevention & control*; D005260:Female; D047109:Fetal Development / Q000187:drug effects* / Q000502:physiology; D005311:Fetal Hypoxia / Q000188:drug therapy / Q000378:metabolism*; D005865:Gestational Age; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism*; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D009122:Muscle Hypertonia / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000172:deficiency / Q000627:therapeutic use; D011247:Pregnancy; D011622:Pterins / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits
D011622:Pterins; D001708:Biopterins; C016727:sepiapterin; D019001:Nitric Oxide Synthase; C003402:sapropterin