Trajectory of inflammatory and microglial activation markers in the postnatal rabbit brain following intrauterine endotoxin exposure

Zhi Zhang, Amar Jyoti, Bindu Balakrishnan, Monica Williams, Sarabdeep Singh, Diane C. Chugani, Sujatha Kannan

Research output: Contribution to journalArticlepeer-review

Abstract

Background Maternal infection is a risk factor for periventricular leukomalacia and cerebral palsy (CP) in neonates. We have previously demonstrated hypomyelination and motor deficits in newborn rabbits, as seen in patients with cerebral palsy, following maternal intrauterine endotoxin administration. This was associated with increased microglial activation, primarily involving the periventricular region (PVR). In this study we hypothesized that maternal intrauterine inflammation leads to a pro-inflammatory environment in the PVR that is associated with microglial activation in the first 2 postnatal weeks. Methods Timed pregnant New Zealand white rabbits underwent laparotomy on gestational day 28 (G28). They were randomly divided to receive lipopolysaccharide (LPS; 20 μg/kg in 1 mL saline) (Endotoxin group) or saline (1 mL) (control saline, CS group), administrated along the wall of the uterus. The PVR from the CS and Endotoxin kits were harvested at G29 (1 day post-injury), postnatal day1 (PND1, 3 day post-injury) and PND5 (7 days post-injury) for real-time PCR, ELISA and immunohistochemistry. Kits from CS and Endotoxin groups underwent longitudinal MicroPET imaging, with [ 11 C]PK11195, a tracer for microglial activation. Results We found that intrauterine endotoxin exposure resulted in pro-inflammatory microglial activation in the PVR of rabbits in the first postnatal week. This was evidenced by increased TSPO (translocator protein) expression co-localized with microglia/macrophages in the PVR, and changes in the microglial morphology (ameboid soma and retracted processes). In addition, CD11b level significantly increased with a concomitant decline in the CD45 level in the PVR at G29 and PND1. There was a significant elevation of pro-inflammatory cytokines and iNOS, and decreased anti-inflammatory markers in the Endotoxin kits at G29, PND1 and PND5. Increased [ 11 C]PK11195 binding to the TSPO measured in vivo by PET imaging in the brain of Endotoxin kits was present up to PND14–17. Conclusions Our results indicate that a robust pro-inflammatory microglial phenotype/brain milieu commenced within 24 h after LPS exposure and persisted through PND5 and in vivo TSPO binding was found at PND14–17. This suggests that there may be a window of opportunity to treat after birth. Therapies aimed at inducing an anti-inflammatory phenotype in microglia might promote recovery in maternal inflammation induced neonatal brain injury.

Original languageEnglish (US)
Pages (from-to)153-162
Number of pages10
JournalNeurobiology of Disease
Volume111
DOIs
StatePublished - Mar 2018

Keywords

  • Cerebral palsy
  • Cytokines
  • Maternal inflammation
  • Microglia
  • Neonatal brain injury
  • Periventricular leukomalacia
  • Rabbits

ASJC Scopus subject areas

  • Neurology

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