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Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the...

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Autores principales: Cho, Kenta H. T., Zeng, Nina, Anekal, Praju V., Xu, Bing, Fraser, Mhoyra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181613/
https://www.ncbi.nlm.nih.gov/pubmed/32327682
http://dx.doi.org/10.1038/s41598-020-63770-6
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author Cho, Kenta H. T.
Zeng, Nina
Anekal, Praju V.
Xu, Bing
Fraser, Mhoyra
author_facet Cho, Kenta H. T.
Zeng, Nina
Anekal, Praju V.
Xu, Bing
Fraser, Mhoyra
author_sort Cho, Kenta H. T.
collection PubMed
description In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1–4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection.
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spelling pubmed-71816132020-04-27 Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep Cho, Kenta H. T. Zeng, Nina Anekal, Praju V. Xu, Bing Fraser, Mhoyra Sci Rep Article In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1–4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection. Nature Publishing Group UK 2020-04-23 /pmc/articles/PMC7181613/ /pubmed/32327682 http://dx.doi.org/10.1038/s41598-020-63770-6 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Cho, Kenta H. T.
Zeng, Nina
Anekal, Praju V.
Xu, Bing
Fraser, Mhoyra
Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep
title Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep
title_full Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep
title_fullStr Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep
title_full_unstemmed Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep
title_short Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep
title_sort effects of delayed intraventricular tlr7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181613/
https://www.ncbi.nlm.nih.gov/pubmed/32327682
http://dx.doi.org/10.1038/s41598-020-63770-6
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