Research article summary (published 30 Aug 2009):

Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain.

Full Abstract

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. INTERPRETATION: 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.

Author information

Author/s: Vásquez-Vivar, Jeannette (J); Whitsett, Jennifer (J); Derrick, Matthew (M); Ji, Xinhai (X); Yu, Lei (L); Tan, Sidhartha (S);

Affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA. jvvivar(-atsign-)mcw.edu

Grants: NS051402 (Agency:NINDS NIH HHS) ; NS054017 (Agency:NINDS NIH HHS) ; NS43285 (Agency:NINDS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Annals of neurology (Ann Neurol), published in United States. (Language: eng)

Reference: 2009-Sep; vol 66 (issue 3) : pp 323-31

Dates: Created 2009/10/14; Completed 2009/10/29;

PMID: 19798726, status: MEDLINE (last retrieval date: 10/29/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Animals, Newborn Biopterin - analogs & derivatives; analysis; deficiency; therapeutic use Brain - embryology; metabolism Brain Chemistry - drug effects Disease Models, Animal Dystonia - prevention & control Female Fetal Development - drug effects; physiology Fetal Hypoxia - drug therapy; metabolism

Fetal Hypoxia - drug therapy; metabolism Gestational Age Humans Hypoxia-Ischemia, Brain - drug therapy; metabolism Maternal-Fetal Exchange - drug effects Muscle Hypertonia - prevention & control Nitric Oxide Synthase - analysis; deficiency; therapeutic use Pregnancy Pterins - pharmacology; therapeutic use Rabbits

Associated Chemicals: Pterins (0) ; sepiapterin (17094-01-8) ; 5,6,7,8-tetrahydrobiopterin (17528-72-2) ; Biopterin (22150-76-1) ; Nitric Oxide Synthase (EC 1.14.13.39)

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