Persistent inflammation and white matter damage in the preterm brain: Insights from a novel ovine model of chronic inflammation

Abdul Razak¹, Amy E Sutherland², Yen Pham³, Tamara Yawno⁴, Ilias Nitsos⁵, Lindsay Zhou⁶, Tegan A White⁷, Charmaine Rock⁸, Rod W Hunt⁹, Atul Malhotra¹⁰, Beth J Allison¹¹, Suzanne L Miller¹², Courtney A McDonald¹³

Affiliations

¹ Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. Electronic address: abdul.razak@monash.edu.
² The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: amy.sutherland@hudson.org.au.
³ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: yennie.pham@hudson.org.au.
⁴ Department of Paediatrics, Monash University, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: tamara.yawno@hudson.org.au.
⁵ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: ilias.nitsos@hudson.org.au.
⁶ Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. Electronic address: lindsay.zhou1@monash.edu.
⁷ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: Tegan.White@monash.edu.
⁸ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: Charmaine.Rock@monash.edu.
⁹ Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Cerebral Palsy Alliance Research, Brain and Mind Centre, University of Sydney, Sydney, Australia. Electronic address: rod.hunt@monash.edu.
¹⁰ Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. Electronic address: atul.malhotra@monash.edu.
¹¹ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: beth.allison@hudson.org.au.
¹² The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: suzie.miller@monash.edu.
¹³ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: courtney.mcdonald@monash.edu.

PMID: 40714018
DOI: 10.1016/j.expneurol.2025.115397

Free article

Persistent inflammation and white matter damage in the preterm brain: Insights from a novel ovine model of chronic inflammation

Abdul Razak et al. Exp Neurol. 2025 Nov.

Free article

. 2025 Nov:393:115397.

doi: 10.1016/j.expneurol.2025.115397. Epub 2025 Jul 24.

Authors

Affiliations

¹ Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. Electronic address: abdul.razak@monash.edu.
² The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: amy.sutherland@hudson.org.au.
³ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: yennie.pham@hudson.org.au.
⁴ Department of Paediatrics, Monash University, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: tamara.yawno@hudson.org.au.
⁵ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: ilias.nitsos@hudson.org.au.
⁶ Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. Electronic address: lindsay.zhou1@monash.edu.
⁷ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: Tegan.White@monash.edu.
⁸ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: Charmaine.Rock@monash.edu.
⁹ Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Cerebral Palsy Alliance Research, Brain and Mind Centre, University of Sydney, Sydney, Australia. Electronic address: rod.hunt@monash.edu.
¹⁰ Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. Electronic address: atul.malhotra@monash.edu.
¹¹ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: beth.allison@hudson.org.au.
¹² The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: suzie.miller@monash.edu.
¹³ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia; Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. Electronic address: courtney.mcdonald@monash.edu.

PMID: 40714018
DOI: 10.1016/j.expneurol.2025.115397

Abstract

Background: Preterm brain injury involves persistent inflammation, making it a potential therapeutic target. Current large animal models focus on short-term outcomes, limiting understanding of long-term effects. We developed an ovine model of inflammation-induced preterm brain injury to assess long-term neuropathology at an age equivalent to early cerebral palsy diagnosis in human infants.

Methods: Fetal sheep were instrumented at gestational day (d) 90-91 (term is 148d): one group received lipopolysaccharide (LPS 200 ng; n = 9) on 96d, 97d, and 98d (0.65 gestation, ∼25-26 weeks human brain development), and a control group received saline (n = 8). Birth was induced on 138d, and lambs were euthanised within 24 h of birth. Brains were evaluated for white matter injury, microglial/macrophage activation and astrogliosis in the subcortical (SCWM), periventricular (PVWM), and cortical (CWM) white matter, subventricular zone (SVZ), and corpus callosum (CC).

Results: Antenatal LPS administration was associated with significant persistent microglial/macrophage activation in the PVWM (P = 0.04), SCWM (P = 0.01), and CWM (P = 0.006). Furthermore, LPS exposure was associated with reduced oligodendrocyte cell number in the PVWM (P = 0.02), SCWM (P = 0.001), and CWM (P = 0.0001), and reduced myelination in CWM (CNPase, P < 0.0001 and MBP, P = 0.04) and SVZ (MBP, P = 0.05). No difference in astrogliosis or microhaemorrhages was observed.

Conclusion: We demonstrated that in a large animal model of inflammation-induced intrauterine preterm brain injury, long-term persistent inflammation occurs, along with significant white matter injury, including loss of oligodendrocytes and reduced myelination in multiple white matter regions. This model paves the way for long-term evaluation of promising therapeutics and behavioral assessment in this clinically relevant model of persistent preterm brain injury.

Keywords: Brain injury; Inflammation; Ovine model; Preterm white matter injury; Tertiary phase.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Abdul Razak reports financial support was provided by Australian Lions Cord Blood Foundation. Abdul Razak reports financial support was provided by The Royal Australasian College of Physicians. Abdul Razak reports a relationship with Monash Children’s Hospital that includes: employment. Abdul Razak reports a relationship with Joan Kirner Women’s and Children’s Hospital that includes: employment. Abdul Razak reports a relationship with Medtrain that includes: speaking and lecture fees. Abdul Razak reports a relationship with Newborn cell therapy symposium that includes: travel reimbursement. Atul Malhotra reports financial support was provided by Australian Lions Cord Blood Foundation. Atul Malhotra reports a relationship with Cincanniti Children’s Hospital that includes: travel reimbursement. Atul Malhotra reports a relationship with GE Healthcare that includes: travel reimbursement. Atul Malhotra reports a relationship with European Society for Paediatric Research that includes: travel reimbursement. Atul Malhotra reports a relationship with Kuwait Department of Health that includes:. Atul Malhotra reports a relationship with Fetal Neonatal Physiological Society that includes: travel reimbursement. Atul Malhotra reports a relationship with Delphi Innovation conference that includes: travel reimbursement. Atul Malhotra reports a relationship with NeoPaed Conference that includes: travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Persistent inflammation and white matter damage in the preterm brain: Insights from a novel ovine model of chronic inflammation

Affiliations

Persistent inflammation and white matter damage in the preterm brain: Insights from a novel ovine model of chronic inflammation

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous