Persistent inflammation and white matter damage in the preterm brain: Insights from a novel ovine model of chronic inflammation
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Published on: May 18, 2010
Abdul Razak1, Amy E Sutherland2, Yen Pham2
1Department of Paediatrics, Monash University, Melbourne, Australia; Monash Newborn, Monash Children's Hospital, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia.
Insights
Inflammation in preterm brain injury causes long-term white matter damage, including oligodendrocyte loss and reduced myelination. This ovine model allows for evaluating new therapies for preterm brain injury.
Area of Science:
- Neuroscience
- Developmental Biology
- Perinatal Medicine
Background:
- Preterm brain injury is characterized by persistent inflammation, a key factor in its long-term consequences.
- Existing large animal models inadequately capture the long-term neuropathology of preterm brain injury.
- A novel ovine model was developed to study inflammation-induced preterm brain injury and its long-term effects.
Purpose of the Study:
- To establish and validate a large animal model for investigating long-term neuropathology following inflammation-induced preterm brain injury.
- To assess the impact of antenatal inflammation on white matter integrity and myelination in the preterm ovine brain.
- To provide a platform for evaluating potential therapeutic interventions for preterm brain injury.
Main Methods:
- Fetal sheep were exposed to lipopolysaccharide (LPS) or saline during mid-gestation (0.65 gestation).
- Brain tissues were analyzed post-birth (138 days gestation) for white matter injury markers.
- Evaluated parameters included microglial/macrophage activation, astrogliosis, oligodendrocyte cell counts, and myelination in various white matter regions.
Main Results:
- Antenatal LPS exposure led to persistent microglial/macrophage activation in the periventricular, subcortical, and cortical white matter.
- Significant reduction in oligodendrocyte cell numbers was observed in multiple white matter regions.
- Myelination was reduced in the cortical white matter and subventricular zone following LPS exposure.
Conclusions:
- The ovine model successfully replicates long-term inflammation and white matter injury seen in human preterm brain injury.
- This model demonstrates persistent inflammation, oligodendrocyte loss, and reduced myelination, crucial indicators of preterm brain injury.
- The developed model is suitable for long-term evaluation of therapeutics and behavioral assessments in a clinically relevant context.
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.
