Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels

Hypertonia is pathognomonic of cerebral palsy (CP), often caused by brain injury before birth. To understand the early driving events of hypertonia, we utilized magnetic resonance imaging (MRI) assessment of early critical brain injury in rabbit fetuses (79% term) that will predict hypertonia after...

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Main Authors: Jeannette Vasquez-Vivar, Zhongjie Shi, Jeong-Won Jeong, Kehuan Luo, Amit Sharma, Karthikeyan Thirugnanam, Sidhartha Tan
Format: Article
Language:English
Published: Elsevier 2020-01-01
Series:Redox Biology
Online Access:http://www.sciencedirect.com/science/article/pii/S2213231719311978
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author Jeannette Vasquez-Vivar
Zhongjie Shi
Jeong-Won Jeong
Kehuan Luo
Amit Sharma
Karthikeyan Thirugnanam
Sidhartha Tan
author_facet Jeannette Vasquez-Vivar
Zhongjie Shi
Jeong-Won Jeong
Kehuan Luo
Amit Sharma
Karthikeyan Thirugnanam
Sidhartha Tan
author_sort Jeannette Vasquez-Vivar
collection DOAJ
description Hypertonia is pathognomonic of cerebral palsy (CP), often caused by brain injury before birth. To understand the early driving events of hypertonia, we utilized magnetic resonance imaging (MRI) assessment of early critical brain injury in rabbit fetuses (79% term) that will predict hypertonia after birth following antenatal hypoxia-ischemia. We examined if individual variations in the tetrahydrobiopterin cofactor in the parts of the brain controlling motor function could indicate a role in specific damage to motor regions and disruption of circuit integration as an underlying mechanism for acquiring motor disorders, which has not been considered before. The rabbit model mimicked acute placental insufficiency and used uterine ischemia at a premature gestation. MRI during the time of hypoxia-ischemia was used to differentiate which individual fetal brains would become hypertonic. Four brain regions collected immediately after hypoxia-ischemia or 48 h later were analyzed in a blinded fashion. Age-matched sham-operated animals were used as controls. Changes in the reactive nitrogen species and gene expression of the tetrahydrobiopterin biosynthetic enzymes in brain regions were also studied. We found that a combination of low tetrahydrobiopterin content in the cortex, basal ganglia, cerebellum, and thalamus brain regions, but not a unique low threshold of tetrahydrobiopterin, contributed etiologically to hypertonia. The biggest contribution was from the thalamus. Evidence for increased reactive nitrogen species was found in the cortex. By 48 h, tetrahydrobiopterin and gene expression levels in the different parts of the brain were not different between MRI stratified hypertonia and non-hypertonia groups. Sepiapterin treatment given to pregnant dams immediately after hypoxia-ischemia ameliorated hypertonia and death. We conclude that a developmental tetrahydrobiopterin variation is necessary with fetal hypoxia-ischemia and is critical for disrupting normal motor circuits that develop into hypertonia. The possible mechanistic pathway involves reactive nitrogen species. Keywords: Infant newborn, Cerebral palsy, Hypertonia, Sepiapterin, Free radicals, Fetal brain
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spelling doaj.art-1376f2796b4340429b7abd991d0a8df52022-12-22T01:43:39ZengElsevierRedox Biology2213-23172020-01-0129Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levelsJeannette Vasquez-Vivar0Zhongjie Shi1Jeong-Won Jeong2Kehuan Luo3Amit Sharma4Karthikeyan Thirugnanam5Sidhartha Tan6Department of Biophysics and Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI, USADepartment of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USADepartment of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USADepartment of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USANeonatology Division, Children's Hospital of Michigan, Detroit, MI, USADepartment of Biophysics and Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI, USADepartment of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Neonatology Division, Children's Hospital of Michigan, Detroit, MI, USA; Corresponding author. Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Street, Detroit, MI, 48201, USA.Hypertonia is pathognomonic of cerebral palsy (CP), often caused by brain injury before birth. To understand the early driving events of hypertonia, we utilized magnetic resonance imaging (MRI) assessment of early critical brain injury in rabbit fetuses (79% term) that will predict hypertonia after birth following antenatal hypoxia-ischemia. We examined if individual variations in the tetrahydrobiopterin cofactor in the parts of the brain controlling motor function could indicate a role in specific damage to motor regions and disruption of circuit integration as an underlying mechanism for acquiring motor disorders, which has not been considered before. The rabbit model mimicked acute placental insufficiency and used uterine ischemia at a premature gestation. MRI during the time of hypoxia-ischemia was used to differentiate which individual fetal brains would become hypertonic. Four brain regions collected immediately after hypoxia-ischemia or 48 h later were analyzed in a blinded fashion. Age-matched sham-operated animals were used as controls. Changes in the reactive nitrogen species and gene expression of the tetrahydrobiopterin biosynthetic enzymes in brain regions were also studied. We found that a combination of low tetrahydrobiopterin content in the cortex, basal ganglia, cerebellum, and thalamus brain regions, but not a unique low threshold of tetrahydrobiopterin, contributed etiologically to hypertonia. The biggest contribution was from the thalamus. Evidence for increased reactive nitrogen species was found in the cortex. By 48 h, tetrahydrobiopterin and gene expression levels in the different parts of the brain were not different between MRI stratified hypertonia and non-hypertonia groups. Sepiapterin treatment given to pregnant dams immediately after hypoxia-ischemia ameliorated hypertonia and death. We conclude that a developmental tetrahydrobiopterin variation is necessary with fetal hypoxia-ischemia and is critical for disrupting normal motor circuits that develop into hypertonia. The possible mechanistic pathway involves reactive nitrogen species. Keywords: Infant newborn, Cerebral palsy, Hypertonia, Sepiapterin, Free radicals, Fetal brainhttp://www.sciencedirect.com/science/article/pii/S2213231719311978
spellingShingle Jeannette Vasquez-Vivar
Zhongjie Shi
Jeong-Won Jeong
Kehuan Luo
Amit Sharma
Karthikeyan Thirugnanam
Sidhartha Tan
Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels
Redox Biology
title Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels
title_full Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels
title_fullStr Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels
title_full_unstemmed Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels
title_short Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels
title_sort neuronal vulnerability to fetal hypoxia reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels
url http://www.sciencedirect.com/science/article/pii/S2213231719311978
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