Prenatal Ischemia and White Matter Damage in Rats

Abstract

Ischemia/reperfusion injury to the developing brain is a major cause of neurologic abnormalities in preterm infants. To investigate the underlying mechanisms, we modified a previously described rat model of unilateral uterine-artery ligation on the 17th embryonic day (E17). Growth retardation was taken as an index of in utero ischemia, and pups born with a birth weight more than 2 standard deviations below that of controls were compared with the same-litter, normal-growth control pups born from the nonligated horn. Prenatal ischemia probably associated with hypoxia and followed by reperfusion at birth induced white matter damage at a developmental stage corresponding to extreme prematurity in humans. On P0 (day of birth), growth-retarded pups exhibited lesions in the cingular white matter and internal capsule with increased counts of activated microglial cells for 2 weeks compared with controls. Astrogliosis was detected in the injured white matter. On P3, increased apoptotic cell death was seen in O4-positive preoligodendrocytes, which were abnormally scarce on P7. Defective myelination, as assessed by myelin-binding-protein labeling, was detected until adulthood. The diffuse white matter damage in growth-retarded rats replicated the main features of white matter damage in human preterm infants.

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

“…The fetal sheep cerebrum has a predilection for relatively selective WMI under conditions of moderate cerebral ischemia [41], whereas rodents have a propensity for mixed cerebral injury such that substantial gray matter injury accompanies WMI [47][48][49][50][51][52]. This shortcoming, for example, limits the relevance of rodent hypoxia-ischemia models for the study of myelination disturbances associated with chronic human WMI.…”

SPIO‐enhanced magnetic resonance imaging study of placental perfusion in a rat model of intrauterine growth restriction

“…19,20 This ligation alters fetal growth in the horn with restricted perfusion, leading to a 20% reduction in the birthweight of live fetuses in the ligated horn at 22 days of gestation. [19][20][21][22][23] This model also induces brain injuries related to intrauterine growth restriction (IUGR) in pups, and also fetal deaths. [21][22][23] It is still used today, especially to study these brain injuries.…”

Effects of Antenatal Uteroplacental Hypoperfusion on Neonatal Microvascularisation and Excitotoxin Sensitivity in Mice

“…This finding suggests that AUVL may alter NMDA receptor function downstream from receptor expression. The timing of the effect of AUVL on ibotenate toxicity, with a protective effect initially and a deleterious effect later on, suggests a transient preconditioning mechanism (16,17). Previous work suggests that VEGFs and their receptors may play pivotal roles in various preconditioning paradigms (9,16,25,26).…”

“…This result does not constitute evidence for involvement in the protective effect of VEGFs and their receptors, whose mRNA expression declined between P2 and P10 in sham pups. Preconditioning strategies have different consequences depending on the age of the animal at the time of preconditioning and/or injury (12,17). Preconditioning induced by antenatal exposure to a low dose of lipopolysaccharide sensitizes the neonatal brain to hypoxia-ischemia but decreases the severity of brain injury in adult animals (13).…”

“…Olivier et al studied rat pups with vascular IUGR induced by unilateral uterine artery ligation on embryonic day (E) 17.5 and exposure to a cerebral excitotoxic insult on postnatal day 5 (PD5). White matter (WM) lesion size was smaller in pups with moderate growth restriction and larger in pups with severe growth restriction, compared with control animals (11,17). The mechanisms involved in this differential effect of antenatal ischemia remain partly unclear.…”