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Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model

BACKGROUND: Creatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in near-term sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study...

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Autores principales: Tran, Nhi T., Muccini, Anna M., Hale, Nadia, Tolcos, Mary, Snow, Rod J., Walker, David W., Ellery, Stacey J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10097948/
https://www.ncbi.nlm.nih.gov/pubmed/37066075
http://dx.doi.org/10.3389/fncel.2023.1154772
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author Tran, Nhi T.
Muccini, Anna M.
Hale, Nadia
Tolcos, Mary
Snow, Rod J.
Walker, David W.
Ellery, Stacey J.
author_facet Tran, Nhi T.
Muccini, Anna M.
Hale, Nadia
Tolcos, Mary
Snow, Rod J.
Walker, David W.
Ellery, Stacey J.
author_sort Tran, Nhi T.
collection PubMed
description BACKGROUND: Creatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in near-term sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study investigated the effects of acute hypoxia with or without fetal creatine supplementation on neuropathology in multiple brain regions. METHODS: Near-term fetal sheep were administered continuous intravenous infusion of either creatine (6 mg kg(–1) h(–1)) or isovolumetric saline from 122 to 134 days gestational age (dGA; term is approx. 145 dGA). At 131 dGA, global hypoxia was induced by a 10 min umbilical cord occlusion (UCO). Fetuses were then recovered for 72 h at which time (134 dGA) cerebral tissue was collected for either RT-qPCR or immunohistochemistry analyses. RESULTS: UCO resulted in mild injury to the cortical gray matter, thalamus and hippocampus, with increased cell death and astrogliosis and downregulation of genes involved in regulating injury responses, vasculature development and mitochondrial integrity. Creatine supplementation reduced astrogliosis within the corpus callosum but did not ameliorate any other gene expression or histopathological changes induced by hypoxia. Of importance, effects of creatine supplementation on gene expression irrespective of hypoxia, including increased expression of anti-apoptotic (BCL-2) and pro-inflammatory (e.g., MPO, TNFa, IL-6, IL-1β) genes, particularly in the gray matter, hippocampus, and striatum were identified. Creatine treatment also effected oligodendrocyte maturation and myelination in white matter regions. CONCLUSION: While supplementation did not rescue mild neuropathology caused by UCO, creatine did result in gene expression changes that may influence in utero cerebral development.
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spelling pubmed-100979482023-04-14 Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model Tran, Nhi T. Muccini, Anna M. Hale, Nadia Tolcos, Mary Snow, Rod J. Walker, David W. Ellery, Stacey J. Front Cell Neurosci Neuroscience BACKGROUND: Creatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in near-term sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study investigated the effects of acute hypoxia with or without fetal creatine supplementation on neuropathology in multiple brain regions. METHODS: Near-term fetal sheep were administered continuous intravenous infusion of either creatine (6 mg kg(–1) h(–1)) or isovolumetric saline from 122 to 134 days gestational age (dGA; term is approx. 145 dGA). At 131 dGA, global hypoxia was induced by a 10 min umbilical cord occlusion (UCO). Fetuses were then recovered for 72 h at which time (134 dGA) cerebral tissue was collected for either RT-qPCR or immunohistochemistry analyses. RESULTS: UCO resulted in mild injury to the cortical gray matter, thalamus and hippocampus, with increased cell death and astrogliosis and downregulation of genes involved in regulating injury responses, vasculature development and mitochondrial integrity. Creatine supplementation reduced astrogliosis within the corpus callosum but did not ameliorate any other gene expression or histopathological changes induced by hypoxia. Of importance, effects of creatine supplementation on gene expression irrespective of hypoxia, including increased expression of anti-apoptotic (BCL-2) and pro-inflammatory (e.g., MPO, TNFa, IL-6, IL-1β) genes, particularly in the gray matter, hippocampus, and striatum were identified. Creatine treatment also effected oligodendrocyte maturation and myelination in white matter regions. CONCLUSION: While supplementation did not rescue mild neuropathology caused by UCO, creatine did result in gene expression changes that may influence in utero cerebral development. Frontiers Media S.A. 2023-03-30 /pmc/articles/PMC10097948/ /pubmed/37066075 http://dx.doi.org/10.3389/fncel.2023.1154772 Text en Copyright © 2023 Tran, Muccini, Hale, Tolcos, Snow, Walker and Ellery. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Tran, Nhi T.
Muccini, Anna M.
Hale, Nadia
Tolcos, Mary
Snow, Rod J.
Walker, David W.
Ellery, Stacey J.
Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model
title Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model
title_full Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model
title_fullStr Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model
title_full_unstemmed Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model
title_short Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model
title_sort creatine in the fetal brain: a regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10097948/
https://www.ncbi.nlm.nih.gov/pubmed/37066075
http://dx.doi.org/10.3389/fncel.2023.1154772
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