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Neurovascular Unit Alterations in the Growth-Restricted Newborn Are Improved Following Ibuprofen Treatment

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Abstract

The developing brain is particularly vulnerable to foetal growth restriction (FGR) and abnormal neurodevelopment is common in the FGR infant ranging from behavioural and learning disorders to cerebral palsy. No treatment exists to protect the FGR newborn brain. Recent evidence suggests inflammation may play a key role in the mechanism responsible for the progression of brain impairment in the FGR newborn, including disruption to the neurovascular unit (NVU). We explored whether ibuprofen, an anti-inflammatory drug, could reduce NVU disruption and brain impairment in the FGR newborn. Using a preclinical FGR piglet model, ibuprofen was orally administered for 3 days from birth. FGR brains demonstrated a proinflammatory state, with changes to glial morphology (astrocytes and microglia), and blood-brain barrier disruption, assessed by IgG and albumin leakage into the brain parenchyma and a decrease in blood vessel density. Loss of interaction between astrocytic end-feet and blood vessels was evident where plasma protein leakage was present, suggestive of structural deficits to the NVU. T-cell infiltration was also evident in the parenchyma of FGR piglet brains. Ibuprofen treatment reduced the pro-inflammatory response in FGR piglets, reducing the number of activated microglia and enhancing astrocyte interaction with blood vessels. Ibuprofen also attenuated plasma protein leakage, regained astrocytic end-feet interaction around vessels, and decreased T-cell infiltration into the FGR brain. These findings suggest postnatal administration of ibuprofen modulates the inflammatory state, allowing for stronger interaction between vasculature and astrocytic end-feet to restore NVU integrity. Modulation of the NVU improves the FGR brain microenvironment and may be key to neuroprotection.

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Availability of Data and Material

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Abbreviations

BBB:

Blood-brain barrier

Cldn:

Claudin

CNS:

Central nervous system

Col IV:

Collagen IV

CXCL10:

C-X-C chemokine motif 10

DAPI:

4′,6-Diamidino-2-phenylindole

CD34:

Endothelial progenitor cells

FGR:

Foetal growth restriction

Gd:

Gadolinium

GFAP:

Glial fibrillary astrocytic protein

Iba-1:

Ionised calcium-binding adaptor molecule-1

Ibu:

Ibuprofen

IgG:

Immunoglobulin G

IL:

Interleukin

MRI:

Magnetic resonance imaging

NVU:

Neurovascular unit

NG:

Normally grown

OCLN:

Occludin

P:

Postnatal day

PBS:

Phosphate-buffered saline

RT:

Room temperature

TJ:

Tight junctions

TNF:

Tumour necrosis factor

ZO-1:

Zonula occludens

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Acknowledgments

The authors acknowledge the facilities and scientific and technical assistance of the National Imaging Facility, a National Collaborative Research Infrastructure Strategy (NCRIS) capability, at the Centre for Advanced Imaging, University of Queensland. The authors would also like to thank Lara Jones, Elliot Teo and John Luff for assistance with animal experimentation.

Funding

Financial support was provided by The National Health and Medical Research Council (Australia) (Grant ID: APP1147545), Royal Brisbane and Women’s Hospital Foundation, and Children’s Hospital Foundation (Grant ID 50217) grants.

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Authors and Affiliations

  1. UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

    Kirat K. Chand, Stephanie M. Miller, Lipsa Mohanty, Paul B. Colditz, Stella Tracey Bjorkman & Julie A. Wixey

  2. Perinatal Research Centre, Royal Brisbane and Women’s Hospital, Herston, Brisbane, QLD, 4029, Australia

    Jany Pienaar, Paul B. Colditz & Julie A. Wixey

  3. National Imaging Facility, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia

    Gary J. Cowin

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  1. Kirat K. Chand
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Contributions

KC was involved in obtaining funding and responsible for all laboratory aspects of the project, data analysis, interpretation, writing and editing the manuscript. SM was involved in conducting animal experiments and editing the manuscript. GC was involved in MRI acquisition, data analysis and editing the manuscript. LM undertook all western blotting and edited the manuscript. JP was involved in obtaining funding and editing the manuscript. PC was involved in obtaining funding, critical revision and editing the manuscript. STB was involved in obtaining funding, critical revision and editing the manuscript. JW was involved in obtaining funding, study conception and design, conducting animal experiments, acquiring data, critical revision and writing the manuscript.

Corresponding author

Correspondence to Julie A. Wixey.

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Ethics Approval

Animal care, handling and experiments were approved by the University of Queensland Animal Ethics Committee (MED/UQCCR/132/16/RBWH and UQCCR/249/18) and was carried out in accordance with National Health and Medical Research Council (NHMRC) guidelines (Australia) and ARRIVE guidelines.

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The authors declare no competing interests.

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Julie A. Wixey and Stella Tracey Bjorkman should be considered joint senior authors.

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Chand, K.K., Miller, S.M., Cowin, G.J. et al. Neurovascular Unit Alterations in the Growth-Restricted Newborn Are Improved Following Ibuprofen Treatment. Mol Neurobiol 59, 1018–1040 (2022). https://doi.org/10.1007/s12035-021-02654-w

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