title: Ketamine decreases inflammatory and immune pathways after transient hypoxia in late gestation 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. We designed the present experiment to test the hypotheses that transient hypoxia produces damage of the cerebral cortex and that ketamine, an antagonist ofNMDAreceptors and a known anti-inflammatory agent, reduces the damage. Late gestation, chronically catheterized fetal sheep were subjected to a 30-min period of ventilatory hypoxia that decreased fetal PaO2from 17 ± 1 to 10 ± 1 mmHg, or normoxia (PaO217 ± 1 mmHg), with or without pretreatment (10 min before hypoxia/normoxia) with ketamine (3 mg/kg, i.v.). One day (24 h) after hypoxia/normoxia, fetal cerebral cortex was removed andmRNAextracted for transcriptomics and systems biology analysis (n = 3-5 per group). Hypoxia stimulated a transcriptomic 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 systems 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.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida change@ufl.edu.
authors.forename: Eileen I
authors.identifier: http://orcid.org/0000-0002-3444-7260
authors.initials: EI
authors.lastname: Chang
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Zárate
authors.affiliation: CEPROCOR, National Scientific and Technical Research Council (CONICET), Córdoba, Argentina.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Rabaglino
authors.affiliation: Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, Florida.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Richards
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Arndt
authors.affiliation: Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, Florida.
authors.forename: Maureen
authors.initials: M
authors.lastname: Keller-Wood
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005311:Fetal Hypoxia / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005865:Gestational Age; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D012756:Sheep; D049490:Systems Biology; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D007649:Ketamine
keywords: Fetal hypoxia; frontal cortex; immune response; ketamine