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26 July 2017 P2X7 receptor blockade prevents preterm birth and perinatal brain injury in a mouse model of intrauterine inflammation
Michael E. Tsimis, Jun Lei, Jason M. Rosenzweig, Hattan Arif, Yahya Shabi, Wael Alshehri, Connie C. Talbot, K. Maravet Baig-Ward, James Segars, Ernest M. Graham, Irina Burd
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Abstract

The P2X7 is an adenosine triphosphate (ATP)-gated ion channel involved in several facets of immune activation and neuronal function through its importance in interleukin (IL)-1β secretion. We hypothesized that blockade of P2X7 would prevent perinatal brain injury associated with exposure to intrauterine (IU) inflammation. Dams received 45 mg/kg of Brilliant Blue G (BBG), a specific P2X7 receptor (P2X7R) antagonist, on gestation day 17 (E17) prior to administration of lipopolysaccharide (LPS) or phosphate-buffered saline (PBS). Furthermore, we utilized embryo transfer experiments to delineate whether the P2X7 was the key mediator of IU inflammation-associated brain injury on maternal or fetal sides. In these experiments, P2X7–/– dams were embryo-transferred wild type embryos and wild type dams were embryo-transferred P2X7–/– embryos. In the mousemodel of intrauterine inflammation, pharmacologic blockade of P2X7R reduced preterm birth rate, improved offspring performance on neuromotor tests as well as the dendritic arborization and density of cortical neurons. Embryo transfer experiments demonstrated the importance of maternal P2X7R in IU inflammation-mediated effects on offspring. Both genetic and pharmacologic blockade of IL-1β signaling, by targeting maternal P2X7R, ameliorated perinatal brain injury following exposure to IU inflammation. Specific targeting of maternal P2X7R may provide a clinically useful tool to prevent both preterm birth and prematurity-associated perinatal brain injury, and further studies are urgently needed.

Summary Sentence

Brilliant Blue G, a specific P2X7 channel blocker, prevents preterm birth and perinatal brain injury associated with exposure to intrauterine inflammation suggesting a role for IL-1β in both regulation of preterm birth and neuronal damage.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Michael E. Tsimis, Jun Lei, Jason M. Rosenzweig, Hattan Arif, Yahya Shabi, Wael Alshehri, Connie C. Talbot, K. Maravet Baig-Ward, James Segars, Ernest M. Graham, and Irina Burd "P2X7 receptor blockade prevents preterm birth and perinatal brain injury in a mouse model of intrauterine inflammation," Biology of Reproduction 97(2), 230-239, (26 July 2017). https://doi.org/10.1093/biolre/iox081
Received: 17 January 2017; Accepted: 25 July 2017; Published: 26 July 2017
JOURNAL ARTICLE
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KEYWORDS
developmental biology
developmental origins of health and disease
gene expression
immunology
placenta
pregnancy
transgenic/knockout model
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