IL-1 Receptor Blockade Prevents Fetal Cortical Brain Injury but Not Preterm Birth in a Mouse Model of Inflammation-Induced Preterm Birth and Perinatal Brain Injury

Authors

  • Kirstin Leitner,

    1. Department of Obstetrics and Gynecology, Maternal and Child Health Research Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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  • Mofeedah Al Shammary,

    1. Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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  • Michael McLane,

    1. Department of Obstetrics and Gynecology, Maternal and Child Health Research Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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  • Michael V. Johnston,

    1. Department of Neuroscience, Kennedy Krieger Institute, Baltimore, MD, USA
    2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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  • Michal A. Elovitz,

    1. Department of Obstetrics and Gynecology, Maternal and Child Health Research Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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  • Irina Burd

    Corresponding author
    1. Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    2. Department of Neuroscience, Kennedy Krieger Institute, Baltimore, MD, USA
    3. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • Correspondence

      Irina Burd, Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University Hospital, Phipps 228, 600 North Wolfe Street, Baltimore, MD 21287, USA.E-mail: iburd@jhmi.edu

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Abstract

Problem

Exposure to intrauterine inflammation, associated with preterm birth, has been linked to a devastating spectrum of neurobehavioral disorders. Mechanisms of this injury are unknown. Using a mouse model of intrauterine inflammation, we have observed a disruption of fetal neuronal morphology along with a marked elevation of interleukin (IL)-1β in the fetal brain and placenta. In this study, we hypothesized that IL-1 plays a key role in perinatal brain injury.

Method of study

Utilizing a mouse model of inflammation-induced preterm birth, we investigated the role of IL-1 in fetal cortical injury as well as preterm birth. In these studies, dams received systemic treatment with IL-1 receptor antagonist prior to administration of intrauterine inflammation.

Results

Systemic maternal antagonism of IL-1 improved fetal cortical neuronal injury associated with the exposure to intrauterine inflammation, without affecting the phenotype of preterm birth. IL-1 receptor antagonist blocked activation of neuronal nitric oxide synthase in perinatal cortex, a key enzyme implicated in neurotoxicity.

Conclusion

Our data suggest that fetal cortical brain injury and preterm birth may occur by divergent mechanisms. Furthermore, our studies indicate maternal administration of IL-1 receptor antagonist (IL-1RA) blocked neuronal nitric oxide synthase activation observed in the brain cortex and, we speculate, that this alteration in activation leads to demonstrated decreased neurotoxicity.

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