Faculty Collaboration Database

Developmental susceptibility of neurons to transient tetrahydrobiopterin insufficiency and antenatal hypoxia-ischemia in fetal rabbits. Free Radic Biol Med 2014 Feb;67:426-36

Date

12/10/2013

Pubmed ID

24316196

Pubmed Central ID

PMC3945116

DOI

10.1016/j.freeradbiomed.2013.11.026

Scopus ID

2-s2.0-84891668871 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

Tetrahydrobiopterin (BH4) is important for normal brain development as congenital BH4 deficiencies manifest movement disorders at various childhood ages. BH4 transitions from very low levels in fetal brains to higher "adult" levels postnatally, with the highest levels in the thalamus. Maternal supplementation with the BH4 precursor sepiapterin reduces postnatal motor deficits and perinatal deaths after 40-min fetal hypoxia-ischemia (HI) at 70% gestation, suggesting that brain BH4 is important in improving function after HI. We tested the hypothesis that the intrinsically low concentrations of BH4 made fetal neurons vulnerable to added insults. Brains were obtained from naïve fetal rabbits or after 40-min HI, at 70% (E22) and 92% gestation (E29). Neuronal cultures were prepared from basal ganglia, cortex, and thalamus, regions with different intrinsic levels of BH4. Cultures were grown with or without added BH4 for 48h. Cell survival and mitochondrial function were determined by flow cytometry. At E22, thalamic cells had the lowest survival rate in a BH4-free milieu, in both control and HI groups, whereas BH4 supplementation ex vivo increased neuronal survival only in HI cells. Neuronal survival was similar in all regions without BH4 at E29. BH4 supplementation increased cell survival and cells with intact mitochondrial membrane potential, from basal ganglia and cortex, but not thalamus. After E29 HI, however, the benefit of BH4 was limited to cortical neurons. We conclude that BH4 is important for fetal neuronal survival after HI especially in the premature thalamus. Supplementation of BH4 has a greater benefit at an earlier gestational age.

Author List

Yu L, Vásquez-Vivar J, Jiang R, Luo K, Derrick M, Tan S

Author

Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Age Factors
Animals
Animals, Newborn
Basal Ganglia
Cell Survival
Cerebral Cortex
Disease Susceptibility
Female
Fetus
Gestational Age
Hypoxia-Ischemia, Brain
Membrane Potential, Mitochondrial
Mitochondria
Neurons
Organ Specificity
Phenylketonurias
Pregnancy
Primary Cell Culture
Rabbits
Thalamus