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Chronic ischemia preferentially causes white matter injury in the neonatal rat brain
1Department of Pediatrics/Newborn Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.zcai@ped.umsmed.edu
Insights
Bilateral carotid artery occlusion in rat pups caused chronic ischemic brain injuries, primarily affecting white matter. These injuries resemble human periventricular leukomalacia, suggesting immature oligodendrocytes are vulnerable targets.
Area of Science:
- Neuroscience
- Developmental Biology
- Pathology
Background:
- Chronic ischemic brain injuries in newborns can lead to long-term neurological deficits.
- Periventricular leukomalacia (PVL) is a common form of white matter injury in premature infants.
- Understanding the mechanisms of ischemic white matter injury is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the effects of chronic ischemia on white matter development in early postnatal life.
- To identify the cellular targets and inflammatory responses involved in ischemic white matter injury.
- To compare the observed white matter damage in a rat model to human PVL.
Main Methods:
- Bilateral carotid artery occlusion (BCAO) was performed on postnatal day 1 in rat pups.
- Histological analysis (immunostaining for ED1, OX42, O4, O1, MBP) was used to assess white matter integrity and cell types.
- Quantitative analysis of white matter rarefaction and lateral ventricle size was conducted.
- Myelin basic protein (MBP) mRNA expression was measured using RT-PCR.
Main Results:
- BCAO induced preferential white matter injury in the corpus callosum, subcortex, and internal capsule, sparing cortical neurons.
- White matter rarefaction and enlarged lateral ventricles were observed in BCAO rats, mimicking human PVL.
- Increased activation of microglia/macrophages and reduced numbers of immature oligodendrocytes were noted in injured white matter.
- Decreased MBP and MBP mRNA expression indicated impaired myelin formation in BCAO rat brains.
Conclusions:
- Immature oligodendrocytes and pre-oligodendrocytes are susceptible to chronic ischemic insults.
- Activated microglia/macrophages may play a role in the pathogenesis of ischemic white matter injury.
- This rat model effectively replicates key features of human periventricular leukomalacia, offering a platform for further research.
Abstract:
Chronic ischemic brain injuries were studied in 7- and 14-day-old rat pups, which were subjected to bilateral carotid artery occlusion (BCAO) on postnatal day 1. BCAO preferentially injured white matter in the corpus callosum, subcortex and internal capsule areas while largely spared cortical neurons. White matter rarefaction in the corpus callosum was observed in 12 out of the 17 BCAO rat brains and significantly enlarged lateral ventricles were found in five out of seven P14 BCAO rat brains. These white matter changes were similar to injuries found in newborn infants with periventricular leukomalacia (PVL). White matter injuries in the 7-day-old BCAO rat brain were accompanied with increased activation of microglia/macrophages, as indicated by ED1 and OX42 positive immunostaining. Immature oligodendrocytes in the 7-day-old BCAO rat brain, as indicated by O4+/O1+ staining, were much fewer than in the sham-operated rat brain. Immunostaining for myelin basic protein (MBP) at the fimbria hippocampus and the internal capsule areas in the 7-day-old BACO rat brain was also much less than in the control rat brain. Consistent with the immunostaining data, MBP mRNA expression in the 7-day-old, but not in the 14-day-old, BCAO rat brain was significantly less than in the control rat brain. The overall results suggest that pre-oligodendrocytes and immature oligodendrocytes might be major targets for chronic ischemic insults and activated microglia/macrophages are possibly involved in the process of white matter injury.