{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:21:31Z","timestamp":1773307291982,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2009,5,28]],"date-time":"2009-05-28T00:00:00Z","timestamp":1243468800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2009,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Tetrahydrobiopterin (BH<jats:sub>4<\/jats:sub>) deficiency is a cause of dystonia at birth. We hypothesized that BH<jats:sub>4<\/jats:sub>is a developmental factor determining vulnerability of the immature fetal brain to hypoxic\u2010ischemic injury and subsequent motor deficits in newborns.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pregnant rabbits were subjected to 40\u2010minute uterine ischemia, and fetal brains were investigated for global and focal changes in BH<jats:sub>4<\/jats:sub>. Newborn kits were assessed by neurobehavioral tests following vehicle and sepiapterin (BH<jats:sub>4<\/jats:sub>analog) treatment of dams.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Naive fetal brains at 70% gestation (E22) were severely deficient for BH<jats:sub>4<\/jats:sub>compared with maternal and other fetal tissues. BH<jats:sub>4<\/jats:sub>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\u2010minute hypoxia\u2010ischemia depleted BH<jats:sub>4<\/jats:sub>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\u2010ischemia with sepiapterin increased BH<jats:sub>4<\/jats:sub>in all brain regions and especially in the thalamus, but did not increase the intermediary metabolite, 7,8\u2010BH<jats:sub>2<\/jats:sub>. Sepiapterin treatment also reduced incidence of severe motor deficits and perinatal death following E22 hypoxia\u2010ischemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We conclude that early developmental BH<jats:sub>4<\/jats:sub>deficiency plays a critical role in hypoxic\u2010ischemic brain injury. Increasing brain BH<jats:sub>4<\/jats:sub>via maternal supplementation may be an effective strategy in preventing motor deficits from antenatal hypoxia\u2010ischemia. Ann Neurol 2009;66:323\u2013331<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.21738","type":"journal-article","created":{"date-parts":[[2009,5,28]],"date-time":"2009-05-28T19:52:36Z","timestamp":1243540356000},"page":"323-331","source":"Crossref","is-referenced-by-count":27,"title":["Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain"],"prefix":"10.1002","volume":"66","author":[{"given":"Jeannette","family":"V\u00e1squez\u2010Vivar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Whitsett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Derrick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinhai","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sidhartha","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,10]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/bdrc.20095","article-title":"Destruction and reconstruction: hypoxia and the developing brain","volume":"81","author":"Barret RD","year":"2007","journal-title":"Birth Defects Res C Embryo Today"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.1985.tb04571.x"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1194-236"},{"key":"e_1_2_6_5_2","first-page":"1725","volume-title":"The Metabolic and Molecular Basis of Inherited Diseases","author":"Blau N","year":"2001"},{"key":"e_1_2_6_6_2","unstructured":"BlauN DhondtJL. 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