The Temporal Relationship between Blood–Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia

Arya Jithoo, Tayla R. Penny, Yen Pham, Amy E. Sutherland, Madeleine J. Smith, Maria Petraki, Michael C. Fahey, Graham Jenkin, Atul Malhotra, Suzanne L. Miller, Courtney A. McDonald

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1 Citation (Scopus)


Blood–brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia–ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). At 6, 12, 24, and 72 h (h) post-HI, brains were collected to assess neuropathology and BBB dysfunction. A significant breakdown of the BBB was observed in the HI injury group compared to the sham group from 6 h in the cortex and hippocampus (p < 0.001), including a significant increase in albumin extravasation (p < 0.0033) and decrease in basal lamina integrity and tight-junction proteins. There was a decrease in resting microglia (p < 0.0001) transitioning to an intermediate state from as early as 6 h post-HI, with the intermediate microglia peaking at 12 h (p < 0.0001), which significantly correlated to the peak of microbleeds. Neonatal HI insult leads to significant brain injury over the first 72 h that is mediated by BBB disruption within 6 h and a transitioning state of the resident microglia. Key BBB events coincide with the appearance of the intermediate microglial state and this relationship warrants further research and may be a key target for therapeutic intervention.

Original languageEnglish
Article number660
Number of pages23
Issue number8
Publication statusPublished - Apr 2024


  • astrocytes
  • blood–brain barrier
  • hypoxia–ischemia
  • microglia
  • neuroinflammation

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