Abstract
In this study, we attempted to design a model using Sprague-Dawley rats to better reproduce perinatal systemic hypoxic-ischemic encephalopathy (HIE) in early preterm newborns. On day 21 of gestation, the uterus of pregnant rats were exposed and the blood supply to the fetuses of neonatal HIE groups were thoroughly abscised by hemostatic clamp for 5, 10 or 15 min. Thereafter, fetuses were moved from the uterus and manually stimulated to initiate breathing in an incubator at 37 °C for 1 hr in air. We showed that survival rates of offspring rats were decreased with longer hypoxic time. TUNEL staining showed that apoptotic cells were significant increased in the brains of offspring rats from the 10 min and 15 min HIE groups as compared to the offspring rats in the control group at postnatal day (PND) 1, but there was no statistical difference between the offspring rats in the 5 min HIE and control groups. The perinatal hypoxic treatment resulted in decreased neurons and increased cleaved caspase-3 protein levels in the offspring rats from all HIE groups at PND 1. Platform crossing times and the percentage of the time spent in the target quadrant of Morris Water Maze test were significantly reduced in the offspring rats of all HIE groups at PND 30, which were associated with decreased brain-derived neurotrophic factor levels and neuronal cells in the hippocampus of offspring rats at PND 35. These data demonstrated that perinatal ischemic injury led to the death of neuronal cells and long-lasting impairment of memory. This model reproduced hypoxic ischemic encephalopathy in early preterm newborns and may be appropriate for investigating therapeutic interventions.
Highlights
Hypoxic-ischemic encephalopathy (HIE) is the brain manifestation of systemic asphyxia [1,2]
The Log-rank test revealed that the survival rate of male offspring rats at postnatal day (PND) 35 from difference groups were control group > 5 min HIE group > 10 min HIE group > 15 min HIE group (Chi-Square = 15.344, df = 3, P = 0.002)
HIE significantly reduced the number of neuronal cells and resulted in smaller and irregularly arranged neurons in the brain of offspring rats from all HIE groups as compared to the offspring rats in the control group at PND 1 (Figure 2B)
Summary
Hypoxic-ischemic encephalopathy (HIE) is the brain manifestation of systemic asphyxia [1,2]. Clinical and pathological features of human perinatal brain lesions display striking variations according to the gestational ages [9]. Variations of brain damage according to gestational age have been reported in newborn rodents exposed to hypoxic-ischemia (HI) [10,11]. HI exposure of rats at post-natal day 1 (P1) corresponding to the human early preterm stage of brain development results in multifocal white-matter lesions [10]. HI exposure of rats at P7 or P12 corresponding respectively to the late preterm and full-term human brain stages of development results in severe parasagittal corticosubcortical infarcts [10]. We attempted to establish an animal model which might be better reproduce neonatal HIE in early preterm newborns to investigate therapeutic interventions
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