Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels
| Autor: | Jeong-Won Jeong, Sidhartha Tan, Jeannette Vasquez-Vivar, Amit Sharma, Karthikeyan Thirugnanam, Kehuan Luo, Zhongjie Shi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cerebellum Placenta Clinical Biochemistry Thalamus Ischemia Free radicals Placental insufficiency Fetal Hypoxia Sepiapterin Biochemistry 03 medical and health sciences 0302 clinical medicine Pregnancy Cortex (anatomy) Internal medicine Basal ganglia medicine Animals Hypertonia lcsh:QH301-705.5 Infant newborn lcsh:R5-920 business.industry Organic Chemistry Brain Tetrahydrobiopterin medicine.disease Biopterin Fetal brain 3. Good health body regions 030104 developmental biology medicine.anatomical_structure Endocrinology lcsh:Biology (General) Hypoxia-Ischemia Brain Cerebral palsy Female Rabbits medicine.symptom lcsh:Medicine (General) business 030217 neurology & neurosurgery medicine.drug Research Paper |
| Zdroj: | Redox Biology Redox Biology, Vol 29, Iss, Pp-(2020) |
| ISSN: | 2213-2317 |
| Popis: | 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. Graphical abstract Image 1 Highlights • Early driving events of hypertonia resulting from fetal brain injury, as occurs in cerebral palsy, are not understood. • MRI was used to assess hypoxia-ischemia (H–I) brain injury in rabbit fetuses that will manifest hypertonia. • A combination of predisposing low BH4 in thalamus, cerebellum, basal ganglia and cortex occurs in H–I induced hypertonia. • Expression of BH4 enzymes does not fully explain developmental brain regional differences. • Antenatal treatment with BH4 precursor protects brain from hypoxia-ischemia injury and death. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|