Fetal Brain Injury Following Prolonged Hypoxemia and Placental Insufficiency: A Review (original) (raw)
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Developmental Science, 2006
Hypoxia (H) and hypoxia-ischemia (HI) are major causes of foetal brain damage with long-lasting behavioral implications. The effect of hypoxia has been widely studied in human and a variety of animal models. In the present review, we summarize the latest studies testing the behavioral outcomes following prenatal hypoxia/hypoxia-ischemia in rodent models. Delayed development of sensory and motor reflexes during the first postnatal month of rodent life was observed by various groups. Impairment of motor function, learning and memory was evident in the adult animals. Activation of the signaling leading to cell death was detected as early as three hours following H/HI. An increase in the counts of apoptotic cells appeared approximately three days after the insult and peaked about seven days later. Around 14-20 days following the H/HI, the amount of cell death observed in the tissue returned to its basal levels and cell loss was apparent in the brain tissue. The study of the molecular mechanism leading to brain damage in animal models following prenatal hypoxia adds valuable insight to our knowledge of the central events that account for the morphological and functional outcomes. This understanding provides the starting point for the development and improvement of efficient treatment and intervention strategies.
Progress in Neurobiology, 1996
Hypoxia threatens brain function during the entire life-span starting from early fetal age up to senescence. This review compares the short-term, long-term and life-spanning effects of fetal chronic hypoxia and neonatal anoxia on several behavioural paradigms including novelty-induced spontaneous and learning behaviours. Furthermore, it reveals that perinatal hypoxia is an additional threat to neurodegeneration and decline of cognitive and other behaviours during the aging process. Prenatal hypoxia evokes a temporary delay of ingrowth of cholinergic and serotonergic fibres into the hippocampus and neocortex, and causes an enhanced neurodegeneration of 5-HT-ir axons during aging. Neonatal anoxia suppresses hippocampal ChAT activity and up-regulates muscarinic receptor sites for 3H-QNB and 3H-pirenzepine binding in the hippocampus in the early postnatal age. The altered development of axonal arborization and pre- and postsynaptic cholinergic functions may be an important underlying mechanism to explain the behavioural deficits. As far as the cellular mechanisms of perinatal hypoxia is concerned, our primary aim was to study the putative importance of Ca2+ homeostasis of developing neurons by means of pharmacological interventions and by measuring the development of immunoexpression of Ca(2+)-binding proteins. We assessed that nimodipine, an L-type calcium channel blocker, prevented or attenuated the adverse behavioural and neurochemical effects of perinatal hypoxias, while it enhanced the early postnatal development of ir-Ca(2+)-binding proteins. The results are discussed in the context of different related research areas on brain development and hypoxia and ischaemia.
The vulnerability of the fetal sheep brain to hypoxemia at mid-gestation
Developmental Brain Research, 1997
Our aim was to test the hypothesis that a brief episode of hypoxemia near mid-gestation in fetal sheep will result in damage to the fetal brain with the extent and type of damage in any particular region being related to the developmental processes occurring at the time of the insult. Hypoxemia was induced, sufficient to reduce arterial O content by approximately 50%, by restricting utero-placental blood flow 2
Experimental Neurology, 2014
a b s t r a c t Q3 2 3 Some psychiatric diseases in children and young adults are thought to originate from adverse exposures during 41 foetal life, including hypoxia and hypoxia/reoxygenation. The mechanism is not understood. Several authors 42 have emphasised that the placenta is likely to play an important role as the key interface between mother and 43 foetus. Here we have explored whether a first trimester human placenta or model barrier of primary human 44 cytotrophoblasts might secrete factors, in response to hypoxia or hypoxia/reoxygenation, that could damage 45 neurones. We find that the secretions in conditioned media caused an increase of [Ca 2+ ] i and mitochondrial 46 free radicals and a decrease of dendritic lengths, branching complexity, spine density and synaptic activity in dis-47 sociated neurones from embryonic rat cerebral cortex. There was altered staining of glutamate and GABA recep-48 tors. We identify glutamate as an active factor within the conditioned media and demonstrate a specific release of 49 glutamate from the placenta/cytotrophoblast barriers in vitro after hypoxia or hypoxia/reoxygenation. Injection 50 of conditioned media into developing brains of P4 rats reduced the numerical density of parvalbumin-containing 51 neurones in cortex, hippocampus and reticular nucleus, reduced immunostaining of glutamate receptors and 52 altered cellular turnover. These results show that the placenta is able to release factors, in response to altered 53 oxygen, that can damage developing neurones under experimental conditions. 54
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%.
Future Perspectives for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
Miscellanea on Encephalopathies - A Second Look, 2012
The basal ganglia-thalamus pattern (BGT) affects bilaterally the deep gray nuclei and perirolandic cortex, occurring more often after an acute sentinel event, such as placental abruption, uterine rupture or umbilical cord prolapse. Hippocampus, brain stem and white matter may also be affected (de Vries & Groenendaal, 2010). BGT is associated with cerebral palsy in 70% of the survivors, and with epilepsy in 30-40% of HIE survivors. Visual impairments and dysarthria are also common in children with HIE and BGT injury (Martinez-Biarge et al., 2010). 2. The watershed predominant pattern (WS) is the second pattern of injury and involves the white matter, particularly the vascular watershed zones (anterior-middle cerebral artery and posterior-middle cerebral artery), and also the cortex when severe (de Vries & Groenendaal, 2010). WS is associated with cognitive deficits and epilepsy, but usually is not the cause of severe motor impairment (Martinez-Biarge et al., 2010). Besides the imaging studies performed in human infants, most of the observations related to the mechanisms of brain damage and brain plasticity after HIE came from preclinical studies using the Rice-Vannucci animal model of HIE. The model consists of unilateral common carotid artery ligation followed by systemic hypoxia (8% oxygen-balance nitrogen) in post-natal day 7 (P7) rats (Vannucci et al., 1999). The damage is restricted to the hemisphere ipsilateral to the common carotid artery occlusion, affecting the cerebral cortex, thalamus, striatum, hippocampus and subcortical white matter. Importantly, the HI animals develop several cognitive and motor deficits (Lubics et al., 2005). In this book chapter, we will discuss possible new treatments for HIE, focusing on neuroprotective strategies and on cell therapies. 2. Neuroprotective strategies for HIE Since, in most cases, the hypoxic-ischemic (HI) insult occurs near birth, it is feasible that neuroprotection could be achieved in the first few hours after birth. Accordingly, therapeutic hypothermia, when started within 6 hours of birth, modestly improves the neurologic outcome of full-term infants with moderate HIE and is becoming a standard therapy for this condition (Edwards et al., 2010). Besides the neurological improvement, therapeutic hypothermia was associated with a decreased injury in basal ganglia/thalamus and white matter in MRI scans (Rutherford et al., 2010), confirming the neuroprotective effect of this treatment, as observed in animal models of HIE (Gunn et al., 1997). However, given the limited benefits of therapeutic hypothermia, new neuroprotective treatments that could reduce or prevent the long-term neurodevelopmental sequelae of children with HIE, affecting one (or a combination) of the mechanisms that contribute to secondary brain injury, are urgently needed. The therapeutic window of hypothermia coincides with a latent phase, when cerebral energy metabolism returns to normal following perinatal asphyxia. Using phosphorus magnetic resonance spectroscopy (31 P-RMS), it was showed that brain energy metabolism returns to normal levels after a successful resuscitation. After 6-24 hours, this latent phase is followed by a secondary energy failure (Lorek et al., 1994), when there is a correlation between the degree of derangement of oxidative metabolism and the neurodevelopmental outcome (Martin et al., 1996). Thereby, it has been suggested that irreversible cell death occurs with a certain delay after HIE.
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.
Animal models of hypoxic-ischemic brain damage in the newborn
Seminars in Pediatric Neurology, 2004
Controversy continues over which animal model to use as a reflection of human disease states. With respect to perinatal brain disorders, scientists must contend with a disease in evolution. In that regard, the perinatal brain is at risk during a time of extremely rapid development and maturation, involving processes that are required for normal growth. Interfering with these processes, as
Chronic intrauterine hypoxia alters neurodevelopment in fetal sheep
The Journal of Thoracic and Cardiovascular Surgery, 2019
Objective: We tested the hypothesis that chronic fetal hypoxia, at a severity present in many types of congenital heart disease, would lead to abnormal neurodevelopment. Methods: Eight mid-gestation fetal sheep were cannulated onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid-filled environment for 22 ± 2 days under normoxic or hypoxic conditions. Total parenteral nutrition was provided. Control fetuses (n = 7) were harvested at gestational age 133 ± 4 days. At necropsy, brains were fixed for histopathology. Neurons were quantified in white matter tracts, and the thickness of the external granular layer of the cerebellum was measured to assess neuronal migration. Capillary density and myelination were quantified in white matter. Data were analyzed with unpaired Student t tests or 1-way analysis of variance, as appropriate. Results: Oxygen delivery was reduced in hypoxic fetuses (15.6 ± 1.8 mL/kg/min vs 24.3 ± 2.3 mL/kg/min, P <.01), but umbilical blood flow and caloric delivery were not different between the 2 groups. Compared with normoxic and control animals, hypoxic fetuses had reduced neuronal
International Journal of Developmental Neuroscience, 1996
The effects of acute perinatal ischemia-hypoxia on fetal liver and brain energy metabolism, fetal brain total free fatty acid concentration and subsequent offspring behavior were investigated in rats. Ischemia-hypoxia was induced at term either by ligation of the uterine blood vessels or submersion of the entire uterine horn in warmed saline. Fetuses of the adjacent horn served as within-dam controls for all assessments and fetuses of dams which had not undergone the surgical stress served as independent controls for enzyme assays, lschemia-hypoxia was associated with reduced activity of fatty acid synthase in the liver and brain. Total free fatty acid concentration significantly increased in the fetal hypoxic brain. Pups not used for enzyme analyses were cross-fostered for behavioral assessments. Relative to the enzymatic alterations, there were few behavioral alterations associated with ischemia-hypoxia. At postnatal day 30, rats made hypoxic by ligation of the uterine blood vessels had decreased caudate nucleus and brain stem weights relative to within-dam controls. At postnatal day 85, rats made hypoxic by submersion of the uterine horn had decreased olfactory bulb weight. The results of this study indicate an initial acute response to a brief period of ischemia-hypoxia at term pregnancy in the fetal rat brain and liver. Published by Perinatal cerebral ischemia-hypoxia remains a problem for preterm neonates 19'21'34 and has been associated with the later development of diabetes insipidus, cerebral palsy, seizure susceptibility, mental retardation and learning disabilities. 5'24 In experimental animal models, hypoxic conditions during gestation have been shown to result in neural, hepatic and behavioral alterations in the offspring. 28'34 The long-lasting and/or permanent effects of ischemia-hypoxia are of direct importance to the human problem and it is also vital to ascertain the acute effects of ischemia-hypoxia. Basic cellular function, such as enzyme activity is likely to be affected by perinatal ischemia-hypoxia. Indeed, such potential alterations might predict later consequences. However, we are unaware of any studies that have assessed hepatic enzyme activity and few studies have examined the immediate effects of perinatal ischemia-hypoxia on brain enzymatic activity. To date, only Shen et al. have examined the immediate effects of ischemia-hypoxia on brain enzyme activity without allowing reperfusion. In that study, cytochrome oxidase was reduced in the hippocampus after 2--12 rain of ischemia-hypoxia. Finally, it is unclear what the effects of ischemia-hypoxia are on the enzyme activity of other organs, such as the liver.