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.
Original language | English |
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Article number | e12741 |
Journal | Physiological Reports |
Volume | 4 |
Issue number | 6 |
DOIs | |
Publication status | Published - Mar 2016 |
Externally published | Yes |
Keywords
- Animals
- Anti-Inflammatory Agents/pharmacology
- Cerebral Cortex/drug effects
- Disease Models, Animal
- Female
- Fetal Hypoxia/drug therapy
- Gene Expression Profiling/methods
- Gene Expression Regulation
- Gestational Age
- Hypoxia, Brain/drug therapy
- Inflammation Mediators/immunology
- Ketamine/pharmacology
- Neuroprotective Agents/pharmacology
- Oligonucleotide Array Sequence Analysis
- Pregnancy
- RNA, Messenger/metabolism
- Sheep
- Systems Biology
- Time Factors