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

Research output: Contribution to journalArticle

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)-1ß 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 mouse model 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-1ß 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.

Original languageEnglish (US)
Pages (from-to)230-239
Number of pages10
JournalBiology of Reproduction
Volume97
Issue number2
DOIs
StatePublished - Aug 1 2017

Keywords

  • GLP-1
  • GnRH
  • Kisspeptin
  • Leptin

ASJC Scopus subject areas

  • Cell Biology

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