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Transcriptomics Responses to Hypoxia and Ketamine in Ovine Fetal Cerebral Cortex

ABSTRACT: Transient hypoxia in pregnancy stimulates a physiological reflex response that redistributes blood flow and defends oxygen delivery to the fetal brain. The chemoreceptor reflex that is responsible for this physiological response is dependent on glutamatergic neurotransmission which, in times of vigorous activity, could produce cell death secondary to calcium uptake. We designed the present experiment to test the hypotheses that transient hypoxia produces damage of the cerebral cortex and that ketamine, an antagonist of NMDA receptors, reduces the damage. Late-gestation, chronically catheterized fetal sheep were subjected to a 30 min period of ventilatory hypoxia that decreased fetal PaO2 from 17±1 to 10±1 mm Hg, or normoxia (PaO2 17±1 mm Hg), with or without pretreatment (10 min before hypoxia/normoxia) with ketamine (3 mg/kg, iv). One day (24 h) after hypoxia/normoxia, fetal cerebral cortex was removed and mRNA extracted for transcriptomics and systems biology analysis. Hypoxia stimulated a transcriptomics response consistent with a reduction in cellular metabolism and an increase in inflammation. Ketamine pretreatment reduced both of these responses. The inflammation response modeled with transcriptomic system biology was validated by immunohistochemistry and showed increased abundance of microglia/macrophages after hypoxia in the cerebral cortical tissue that ketamine significantly reduced. We conclude that transient hypoxia produces inflammation of the fetal cerebral cortex and that ketamine, in a standard clinical dose, reduces the inflammation response.

ORGANISM(S): Ovis aries

PROVIDER: GSE76110 | GEO | 2016/04/06

SECONDARY ACCESSION(S): PRJNA306253

REPOSITORIES: GEO

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Transcriptomics Responses to Hypoxia and Ketamine in Ovine Fetal Cerebral Cortex

Project description:Transient hypoxia in pregnancy stimulates a physiological reflex response that redistributes blood flow and defends oxygen delivery to the fetal brain. The chemoreceptor reflex that is responsible for this physiological response is dependent on glutamatergic neurotransmission which, in times of vigorous activity, could produce cell death secondary to calcium uptake. We designed the present experiment to test the hypotheses that transient hypoxia produces damage of the cerebral cortex and that ketamine, an antagonist of NMDA receptors, reduces the damage. Late-gestation, chronically catheterized fetal sheep were subjected to a 30 min period of ventilatory hypoxia that decreased fetal PaO2 from 17Â±1 to 10Â±1 mm Hg, or normoxia (PaO2 17Â±1 mm Hg), with or without pretreatment (10 min before hypoxia/normoxia) with ketamine (3 mg/kg, iv). One day (24 h) after hypoxia/normoxia, fetal cerebral cortex was removed and mRNA extracted for transcriptomics and systems biology analysis. Hypoxia stimulated a transcriptomics response consistent with a reduction in cellular metabolism and an increase in inflammation. Ketamine pretreatment reduced both of these responses. The inflammation response modeled with transcriptomic system biology was validated by immunohistochemistry and showed increased abundance of microglia/macrophages after hypoxia in the cerebral cortical tissue that ketamine significantly reduced. We conclude that transient hypoxia produces inflammation of the fetal cerebral cortex and that ketamine, in a standard clinical dose, reduces the inflammation response. 4 groups: hypoxia, hypoxia plus ketamine, normoxia, normoxia plus ketamine. Hypoxia produced by low PO2 in maternal inspired gas for 30 min, followed by normoxia recovery for 23.5 hours. Control fetuses maintained at normoxia for 30 min, followed by another 23.5 h of normoxia. Fetal frontal cerebral cortex collected for mRNA at end of 23.5 h recovery period.

2016-04-06 | E-GEOD-76110 | biostudies-arrayexpress

Transcriptomics Responses to Hypoxia and Ketamine in Ovine Fetal Hippocampus

Project description:Transient hypoxia in pregnancy stimulates a physiological reflex response that redistributes blood flow and defends oxygen delivery to the fetal brain. The chemoreceptor reflex that is responsible for this physiological response is dependent on glutamatergic neurotransmission which, in times of vigorous activity, could produce cell death secondary to calcium uptake. We designed the present experiment to test the hypotheses that transient hypoxia produces damage of the hippocampus and that ketamine, an antagonist of NMDA receptors, reduces the damage. Late-gestation, chronically catheterized fetal sheep were subjected to a 30 min period of ventilatory hypoxia that decreased fetal PaO2 from 17±1 to 10±1 mm Hg, or normoxia (PaO2 17±1 mm Hg), with or without pretreatment (10 min before hypoxia/normoxia) with ketamine (3 mg/kg, iv). One day (24 h) after hypoxia/normoxia, fetal hippocampus was removed and mRNA extracted for transcriptomics and systems biology analysis. Hypoxia stimulated a transcriptomics response consistent with a an increase in inflammation (e.g., cytokine binding and response to LPS). Ketamine pretreatment reduced these responses. The inflammation response modeled with transcriptomic system biology was validated by immunohistochemistry and showed increased abundance of microglia/macrophages after hypoxia in the hippocampal tissue that ketamine significantly reduced. We conclude that transient hypoxia produces inflammation of the fetal hippocampus and that ketamine, in a standard clinical dose, reduces the inflammation response.

2017-08-31 | GSE97916 | GEO

A Systems Biology Understanding of Hypothalamic Inflammation Following Transient Hypoxia in the Late-Gestation Fetal Sheep

Project description:The physiological response to hypoxia in the fetus has been extensively studied with regard to redistribution of fetal combined ventricular output and sparing of oxygen delivery to fetal brain and heart. However, little is known about the biochemical and molecular response of the fetal brain to transient hypoxia. The present study was designed to use transcriptomics and systems biology modeling to identify major biological responses of the fetal hypothalamus to transient hypoxia. We also investigated the effect of ketamine, an FDA approved anesthetic that has anti-inflammatory properties in various tissues. Chronically catheterized fetal sheep (122±5 days gestation) were subjected to 30 min hypoxia (relative reduction in PaO2 ~50 %) caused by infusion of nitrogen into the inspired gas of the pregnant ewe. Messenger RNA was isolated from fetal hypothalamus collected 24 hours after hypoxia, and was analyzed for gene expression using the Agilent 15.5k ovine microarray. Hypoxia increased expression of 280 and decreased expression of 357 genes. Genes increased by hypoxia were associated with immune responses, consistent with stimulation by lipopolysaccharide. Pretreatment of the fetuses with ketamine reduced immune/inflammation responses. Immunohistochemical analysis revealed that the number of microglia/macrophages in the anterior hypothalamus was increased by hypoxia and that the increase was blunted by ketamine. We conclude that transient hypoxia stimulates an inflammatory/immune response in the fetal hypothalamus and that transcriptomics/systems biology modeling is a useful and valid tool for investigation of biological function in the fetal sheep.

2017-07-31 | GSE82016 | GEO

Ketamine suppresses hypoxia-induced inflammatory responses in the late-gestation ovine fetal kidney cortex

Project description:Acute fetal hypoxia is a form of fetal stress that stimulates renal vasoconstriction and ischemia as a consequence of the physiological redistribution of combined ventricular output. We have demonstrated that hypoxia in late ovine gestation induces inflammation in the brain that is ameliorated by treatment with ketamine. We hypothesized that the fetal kidney would also respond to hypoxia with an increase in the expression of inflammatory genes, and that ketamine (an N-Methyl-D-aspartate receptor antagonist) would reduce or block this response. Enriched biological processes for the 427 upregulated genes were immune and inflammatory responses and for the 946 down-regulated genes were metabolic processes. Ketamine countered the effects of hypoxia on upregulated immune/inflammatory responses as well as the down-regulated metabolic responses. We conclude that our transcriptomics modeling predicts that hypoxia activates inflammatory pathways and reduces metabolism in the fetal kidney cortex, and ketamine blocks or ameliorates this response. The results suggest that ketamine may have therapeutic potential for protection from ischemic renal damage. At the time of surgery, fetuses were randomly assigned to one of the four groups (n=3-4/group): normoxic control, normoxia+ketamine, hypoxic control, and hypoxia+ketamine. Hypoxia was induced for 30 min in chronically catheterized fetal sheep (125Â±3 d; term=145-147d), with or without ketamine (3 mg/kg) administered intravenously to the fetus 10 min prior to hypoxia. Fetuses were euthanized 24 hours after the onset of hypoxia, and the kidney cortex were collected for RNA extraction and gene array studies. Gene expression was analyzed using ovine Agilent 15.5 k array and validated with qPCR. Significant differences in gene expression between groups were determined with t-statistics using the limma package for R (Pâ¤0.05).

2016-09-01 | E-GEOD-66920 | biostudies-arrayexpress

Ketamine suppresses hypoxia-induced inflammatory responses in the late-gestation ovine fetal kidney cortex

2016-09-01 | GSE66920 | GEO

Ovis aries

Project description:Transcriptomics Responses to Hypoxia and Ketamine in Ovine Fetal Cerebral Cortex

| PRJNA306253 | ENA

The Genomics of the Fetal Hypothalamic Cellular Response to Transient Hypoxia: Endocrine, Immune, and Metabolic Responses

Project description:Fetuses respond to transient hypoxia (a common stressor in utero) with cellular responses that are appropriate for promoting survival of the fetus. The present experiment was performed to identify the acute genomic responses of the fetal hypothalamus to transient hypoxia. Three fetal sheep were exposed to 30 min of hypoxia and hypothalamic mRNA extracted from samples collected 30 min after return to normoxia. These samples were compared to those from 4 normoxic control fetuses using the Agilent 019921 ovine array. Differentially-regulated genes were analyzed by network analysis and by gene ontology analysis, identifying statistically significant overrepresentation of biological processes. Real-time PCR of selected genes supported the validity of the array data. Hypoxia induced increased expression of genes involved in response to oxygen stimulus, RNA splicing, anti-apoptosis, vascular smooth muscle proliferation, and positive regulation of Notch receptor target. Downregulated genes were involved in metabolism, antigen receptor-mediated immunity, macromolecular complex assembly, S-phase, translation elongation, RNA splicing, protein transport, and post-transcriptional regulation. We conclude that these results emphasize that the cellular response to hypoxia involves reduced metabolism, the involvement of the fetal immune system, and the importance of glucocorticoid signaling. 3 Ventilatory Hypoxia (VH) and 4 Control (con) fetuses. All fetuses were chronically catheterized and in late gestation. Hypoxia produced by low PO2 in maternal inspired gas for 30 min, followed by normoxia recovery for 30 min. Control fetuses maintained at normoxia for 30 min, followed by another 30 min of normoxia. Hypothalami collected for mRNA at end of normoxic recovery period.

2014-01-16 | E-GEOD-43371 | biostudies-arrayexpress

Genome wide RNA Sequencing of whole C. elegans RNA

Project description:We report genes induced under transient hypoxia in an ELT-2 dependent manner Adult C. elegans were exposed to transient hypoxia and fed ELT-2 RNAi. Normoxia and Empty Vector RNAi were performed as controls

2014-08-27 | E-GEOD-60825 | biostudies-arrayexpress

The Genomics of the Fetal Hypothalamic Cellular Response to Transient Hypoxia: Endocrine, Immune, and Metabolic Responses

2014-01-16 | GSE43371 | GEO

Methylation studies in baboons.

Project description:DNA methylation data from Papio hamadryas (baboons) profiled on the mammalian methylation array (HorvathMammalMethylChip40) which focuses on highly conserved CpGs across mammalian species. Seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age.

2023-08-05 | GSE190661 | GEO

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