A rat model of severe neonatal hypoxic-ischemic brain injury (original) (raw)
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Development of a postnatal 3-day-old rat model of mild hypoxic-ischemic brain injury
Brain Research, 2003
Improvements in both obstetric and paediatric care have been responsible for a continuing reduction in mortality in extremely premature infants. However, higher survival rates have been at the expense of more long-term neurological damage. Various animal models have been developed to study the effect of hypoxic-ischemic insults on the brain. However, established models like the postnatal day 7 rat model represent damage found in term infants rather than in preterm infants of 24-28 weeks' gestation, and produce a severe form of injury resulting in high mortality rates. In this study we developed a reliable model of minor hypoxic-ischemic brain injury in postnatal day 3 rats. At this maturity, the pattern of damage represents that expected in a preterm infant suffering a non-lethal perinatal insult. We found that minor changes in duration of insult and both temperature and humidity produced wide fluctuations in the degree of injury observed. By maintaining strict control over experimental conditions including duration of insult, temperature and humidity, we produced a reliable model of minor injury primarily affecting all five areas of the cerebral cortex, and also the thalamus (area 7) and basal ganglia (area 8). Differences were significant compared to normal controls and sham-operated animals (p < 0.05). These areas represent the primary motor, insular, visual and temporal cortices. The overall mortality rate in this study was 12.3%.
Hypoxia-ischemia induced neurological dysfunction and brain injury in the neonatal rat
Behavioural Brain Research, 2005
Bilateral carotid artery occlusion (BCAO) followed by exposure to a hypoxic condition (8% oxygen for 10 or 15 min) was performed in postnatal day 4 SD rats. Brain injury and myelination changes were examined on postnatal day 21 (P21) and tests for neurobehavioral toxicity were performed from P3 to P21. BCAO followed by 10 or 15 min hypoxic insult resulted in mild and severe, respectively, brain injury, reduction in mature oligodendrocytes and tyrosine hydroxylase positive neurons and impaired myelination as indicated by decreased myelin basic protein immunostaining in the P21 rat brain. Hypoxia-ischemia also affected physical development (body weight gain and eye opening) and neurobehavioral performance, such as righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, responses in the elevated plus-maze and passive avoidance. BCAO followed by 15 min of hypoxia caused more severely impaired neurobehavioral performance as compared with BCAO followed by 10 min of hypoxia in the rat. The overall results demonstrate that hypoxia-ischemiainduced brain injury not only persists, but also is linked with neurobehavioral deficits in juvenile rats. The present data also indicate that the degree of brain injury and the deficits of neurobehavioral performance in the rat are dependent on the hypoxic-ischemic condition, i.e., the exposure time to hypoxia.
Neuroscience Letters, 2001
Hypoxic-ischemic (HI) injury in neonatal mice is associated with signi®cant cell loss in hippocampus, striatum and deep layers of the cortex. The pattern of cell death in hippocampus after a moderate focal ischemic-global hypoxic insult is studied through morphologic changes in dying neurons at both the light and ultrastructural levels. Light microscopy at 24 h showed a number of injured neurons, as evidenced by dark, round, condensed nuclei, primarily in CA1 through CA3. Nuclei appeared punctate and cytoplasm vacuolated. Electron microscopy revealed that the punctate appearance of the nuclei corresponded to clumped chromatin. At 7 days after HI, injured neurons were shrunken and had a uniformly dark, angular appearance. While dying cells had an appearance consistent with apoptosis on light microscopy, cells were neither necrotic nor apoptotic at the ultrastructural level. q
Neurobiology of Disease, 2001
We used silver staining to demonstrate neuronal cell body, axonal, and terminal degeneration in brains from p7 rat pups recovered for 0, 1.5, 3, 6, 24, 48, 72 h, and 6 days following hypoxia-ischemia. We found that initial injury is evident in ipsilateral forebrain by 3 h following hypoxia-ischemia, while injury in ventral basal thalamus develops at 24 h. A secondary phase of injury occurs at 48 h in ipsilateral cortex, but not until 6 days in basal ganglia. Initial injury in striatum and cortex is necrosis, but in thalamus the neurodegeneration is primarily apoptosis. Degeneration also occurs in bilateral white matter tracts, and in synaptic terminal fields associated with apoptosis in regions remote from the primary injury. These results show that hypoxia-ischemia in the developing brain causes both early and delayed neurodegeneration in specific systems in which the morphology of neuronal death is determined by time, region, and potentially by patterns of neuronal connectivity.
Early biochemical effects after unilateral hypoxia-ischemia in the immature rat brain
International Journal of Developmental Neuroscience, 2011
Perinatal hypoxia-ischemia (HI) gives rise to inadequate substrate supply to the brain tissue, resulting in damage to neural cells. Previous studies at different time points of development, and with different animal species, suggest that the HI insult causes oxidative damage and changes Na + , K + -ATPase activity, which is known to be very susceptible to free radical-related lipid peroxidation. The aim of the present study was to establish the onset of the oxidative damage response in neonatal Wistar rats subjected to brain HI, evaluating parameters of oxidative stress, namely nitric oxide production, lipoperoxidation by thiobarbituric acid reactive substances (TBA-RS) production and malondialdehyde (MDA) levels, reactive species production by DCFH oxidation, antioxidant enzymatic activities of catalase, glutathione peroxidase, superoxide dismutase as well as Na + , K + -ATPase activity in hippocampus and cerebral cortex. Rat pups were subjected to right common carotid ligation followed by exposure to a hypoxic atmosphere (8% oxygen and 92% nitrogen) for 90 min. Animals were sacrificed by decapitation 0, 1 and 2 h after HI and both hippocampus and cerebral cortex from the right hemisphere (ipsilateral to the carotid occlusion) were dissected out for further experimentation. Results show an early decrease of Na + , K + -ATPase activity (at 0 and 1 h), as well as a late increase in MDA levels (2 h) and superoxide dismutase activity (1 and 2 h after HI) in the hippocampus. There was a late increase in both MDA levels and DCFH oxidation (1 and 2 h) and an increase in superoxide dismutase activity (2 h after HI) in cortex; however Na + , K + -ATPase activity remained unchanged. We suggest that neonatal HI induces oxidative damage to both hippocampus and cortex, in addition to a decrease in Na + , K + -ATPase activity in hippocampus early after the insult. These events might contribute to the later morphological damage in the brain and indicate that it would be essential to pursue neuroprotective strategies, aimed to counteract oxidative stress, as early as possible after the HI insult.
Neuropathology of remote hypoxic-ischemic damage in the immature rat
Acta neuropathologica, 1991
This study was undertaken to determine: (a) the duration of hypoxia required to produce brain damage in immature rats with unilateral carotid artery ligation (Levine technique); (b) the regions of immature brain most vulnerable to hypoxia-ischemia (HI); and (c) the neuropathology of the remote HI insult. To this end, 7-day postnatal rats, subjected to unilateral carotid artery ligation combined with hypoxia of varying durations (45, 60, 75 or 90 min), were killed at 30 days of postnatal age and their brains examined by light microscopy. The results indicated that a longer duration of HI was more likely to produce brain lesions and that the extent and severity of the lesions closely correlated with the length of HI. Shorter intervals of HI primarily damaged the cerebral cortex and hippocampus, while longer periods resulted in more extensive damage and were often associated with cavitary lesions of the cerebral hemisphere. Comparison of HI brain damage produced by the Levine technique in immature and adult rats suggested that in immature rats: (a) the cavitary lesions were common; (b) the non-cavitary cortical lesions had a tendency to show a vertical band-like distribution -a pattern never seen in adults; and (c) the lesions often showed mineralization. The similarities between these experimentally produced HI cerebral lesions and those observed in the developing human brain, such as ulegyria and porencephaly, are discussed.
Stroke, 2012
Background and Purpose— Hypothermia (HT) for neonatal hypoxic-ischemic encephalopathy is advised to start within the first 6 hours after birth. There is some clinical evidence that HT is more effective against moderate than against severe hypoxic-ischemic encephalopathy, but it is unknown whether delayed HT beyond 6 hours is effective or even injurious. Methods— One-hundred seven 7-day-old rat pups underwent unilateral hypoxia-ischemia of moderate severity. Pups were randomized to receive 5 hours of normothermia (NT) or HT starting immediately, 3 hours, 6 hours, or 12 hours after the 90-minute hypoxic period. One-hundred five 7-day-old rat pups underwent severe hypoxia-ischemia lasting 150 minutes, followed by the same group design as mentioned. Relative area loss of the left/right hemisphere was measured after 1 week of survival. Results— In the moderate NT group, the mean area loss of the left hemisphere was 40.5%. The area loss was significantly decreased to 24.8% with immediate ...
Neurology research international, 2012
Understanding the evolution of neonatal hypoxic/ischemic is essential for novel neuroprotective approaches. We describe the neuropathology and glial/inflammatory response, from 3 hours to 100 days, after carotid occlusion and hypoxia (8% O(2), 55 minutes) to the C57/BL6 P7 mouse. Massive tissue injury and atrophy in the ipsilateral (IL) hippocampus, corpus callosum, and caudate-putamen are consistently shown. Astrogliosis peaks at 14 days, but glial scar is still evident at day 100. Microgliosis peaks at 3-7 days and decreases by day 14. Both glial responses start at 3 hours in the corpus callosum and hippocampal fissure, to progressively cover the degenerating CA field. Neutrophils increase in the ventricles and hippocampal vasculature, showing also parenchymal extravasation at 7 days. Remarkably, delayed milder atrophy is also seen in the contralateral (CL) hippocampus and corpus callosum, areas showing astrogliosis and microgliosis during the first 72 hours. This detailed and lon...
Late Measures of Brain Injury After Neonatal Hypoxia-Ischemia in Mice
Stroke, 2004
Background and Purpose-This work was undertaken to determine to what degree long-term neurofunctional outcome of neonatal hypoxic-ischemic (HI) brain injury in mice correlates with anatomical extent of cerebral damage assessed by magnetic resonance imaging (MRI) and histopathology. Methods-On postnatal day 7, mice were subjected to HI. At 7 to 9 weeks after HI neurofunctional outcome was assessed by water-maze, rota-rod, and open-field test performance, followed by cerebral MRI and histopathology evaluation. Results-At 10 weeks after HI, MRI revealed ipsilateral brain atrophy alone or with porencephalic cyst formation and contralateral ventriculomegaly. Adult HI-affected mice, especially those that developed a porencephalic cyst, demonstrated significant neurofunctional deficit compared with age-matched naïve mice. HI-affected mice with ipsilateral cerebral atrophy but without porencephaly demonstrated no or an intermediate level of neurofunctional deficit. Neurobehavioral assessment of mice subjected to HI insult revealed a strong correlation between degree of brain injury and functional neurohandicap. Conclusions-This is the first study to demonstrate that long-term neurofunctional outcome in mice after a neonatal HI correlates tightly with anatomical pattern/extent of cerebral damage, defined by MRI and histopathology. (Stroke. 2004; 35:2183-2188.)