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We investigated plasma concentrations of adrenocorticotropic hormone (ACTH), corticosterone and serotonin in juvenile and adult rats, as well as raphe serotonin levels and behavioral responses in the open field and elevated plus maze tests in adult rats, exposed to three sessions of neonatal hypobaric hypoxia (360 mm Hg, 2 h each, once a day) within days 8–10 postpartum. This noninvasive rat model of neonatal hypoxia (NH) simulates mild perinatal hypoxic injury in human fetuses and premature infants. At 3 months of age, NH-exposed rats exhibited reduced exploratory behavior and increased anxiety in both behavioral tests, accompanied by decreased serotonin levels in the raphe nuclei. In adult NH-exposed rats, plasma corticosterone and serotonin levels remained unaltered, while ACTH levels showed a significant decrease. Our findings suggest that early postnatal hypoxic stress disrupts the serotoninergic system and modifies the hypothalamic–pituitary–adrenocortical axis, leading to long-lasting behavioral deficits in adult rats. [ABSTRACT FROM AUTHOR]

Aim: Preterm infants frequently experience short apnoeas and periodic breathing. Animal studies have shown that repetitive hypoxia associated with periodic breathing can alter autonomic control. We aimed to elucidate if apnoea and periodic breathing were associated with changes in autonomic control assessed using heart rate variability, thus exacerbating the consequences of respiratory disturbance. Methods: Forty very preterm infants (15 M/25 F) were studied at 34.3 weeks post‐menstrual age with daytime polysomnography. Total power, low frequency (LF, sympathetic+parasympathetic activity) high frequency (HF, parasympathetic activity) and LF/HF (sympathovagal balance) were calculated. Results: Infants were divided into those with above and below the median total sleep time spent with respiratory events: Active sleep (AS) 13%, Quiet sleep (QS) 10%. In AS, including respiratory events, Total power (p < 0.05) and HF power (p < 0.05) were higher in the above median group. During AS excluding respiratory events, Total power (p < 0.05) and HF power (p = 0.061) were higher and LF power (p < 0.01) and LF/HF (p < 0.05) were lower in the above median group. There were no differences in HRV parameters in QS. Conclusion: This study provides new evidence that short apnoeas, particularly periodic breathing, which is currently not detected or treated in the neonatal unit can affect autonomic cardiovascular control. [ABSTRACT FROM AUTHOR]

In this article, we report a case of CTNNB1 syndrome (CTNNB1-NDD) in a child with cerebral palsy and also provide a literature review on the problem. CTNNB1 syndrome is an exceedingly rare and poorly studied disorder, which makes it particularly interesting due the difficulties associated with its diagnosis and description of the disease phenotype, as well as highly polymorphic clinical manifestations. Verification of the diagnosis is important to determine the prognosis of a child with cerebral palsy and visual impairment, as well as for reproductive planning in the family.

Background: Women of reproductive age frequently suffer from psychiatric disorders. The risk of developing anxiety, bipolar, and depressive disorders is especially significant during the perinatal period. Objectives: This article aims to identify and discuss the different psychiatric conditions that might affect pregnant women and update the mother's carers about the recent and updated bidirectional relationship between psychiatric disease and adverse pregnancy outcomes, As well as the most updates in diagnostic and management strategies. Methods: A thorough analysis of the literature was conducted using database searches in EMBASE, Science Direct, Google Scholar, Scopus, and PubMed to obtain the objectives and aim of the study. Results: The presence of maternal mental illness during pregnancy has been linked to preterm delivery, newborn hypoglycemia, poor neurodevelopmental outcomes, and disturbed attachment. Placental anomalies, small-for-gestational-age foetuses, foetal discomfort, and stillbirth are among more undesirable perinatal outcomes. Conclusions: Pregnancy-related psychiatric disorders are frequent. The outcomes for pregnant women, infants, and women's health are all improved by proper diagnosis and treatment of psychiatric problems.

Background: Preterm Premature rupture of membranes (PPROM) is the rupture of the membranes that encapsulate the amniotic fluid and the fetus before delivery, resulting in the amniotic fluid draining through the vagina. PPROM affects between 20% and 36% of all pregnancies. Objective: The aim of the current study was to assess the significance of the platelet/lymphocyte ratio (PLR) and the neutrophil/lymphocyte ratio (NLR) in PPROM. Patients and methods: A case control study was conducted on 70 women between 2020 and 2022 at the Obstetrics and Gynecology Department of Menufia University in Shebin Elkom, Egypt, and the Ministry of Health Hospital in Ashmoun, Egypt. Results: According to our findings, the optimal cutoff value for detecting PPROM for NLR was 4.658, with a sensitivity of 97% and a specificity of 29% at an AUC of 0.955. PLR's cutoff value was 133.415, with a sensitivity of 95% and a specificity of 98% at an AUC of 0.663. Conclusion: NLR and PLR values in the PPROM group are considerably greater than in healthy controls. [ABSTRACT FROM AUTHOR]

Abstract Hypoxia in the neonatal period is associated with early manifestations of adverse cardiovascular health in adulthood including higher risk of hypertension and atherosclerosis. We hypothesize that this occurs due to activation of lysyl oxidases (LOXs) and the remodeling of the large conduit vessels, leading to early arterial stiffening. Newborn C57Bl/6 mice were exposed to hypoxia (FiO2 = 11.5%) from postnatal day 1 (P1) to postnatal day 11 (P11), followed by resumption of normoxia. Controls were maintained in normoxia. Using in vivo (pulse wave velocity; PWV) and ex vivo (tensile testing) arterial stiffness indexes, we determined that mice exposed to neonatal hypoxia had significantly higher arterial stiffness compared with normoxia controls by young adulthood (P60), and it increased further by P120. Echocardiography performed at P60 showed that mice exposed to hypoxia displayed a compensated dilated cardiomyopathy. Western blotting revelated that neonatal hypoxia accelerated age‐related increase in LOXL2 protein expression in the aorta and elevated LOXL2 expression in the PA at P11 with a delayed decay toward normoxic controls. In the heart and lung, gene and protein expression of LOX/LOXL2 were upregulated at P11, with a delayed decay when compared to normoxic controls. Neonatal hypoxia results in a significant increase in arterial stiffness in early adulthood due to aberrant LOX/LOXL2 expression. This suggests an acceleration in the mechanical decline of the cardiovascular system, that contributes to increased risk of hypertension in young adults exposed to neonatal hypoxia that may increase susceptibility to further insults.

Introduction and aim. The objective of the study was to evaluate the effect of Mentat® an herbal formulation in experimental models of hypoxia-induced attention deficit hyperactive disorder (ADHD) like behavior in rats. Material and methods. Mentat® was evaluated at the dose of 100 and 200 mg/kg body weight. per oral., in two experimental models of hypoxia in Wistar rats. In the first model, after parturition, on a postnatal day 2 (PND-2), the pups were subjected to hypoxic exposure for 10 minutes to induce neonatal hypoxia. Pups were weaned from dams on PND-21 and subjected to drug treatments for 10 days. In the second model, phenytoin 150 mg/kg. b.wt. p.o. was administered orally to all pregnant animals throughout gestation to induce intrauterine hypoxia. Pups were subjected to assigned treatments after weaning. Behavioral and biochemical parameters relevant to ADHD were assessed. Results. In the positive control group, hypoxic exposure resulted in significant changes in cognitive and neurologic skills compared to normal control. Open field test, elevated plus maze test, and Acetylcholine esterase levels showed a significant increase in positive control compared to normal control. In treatment groups, there was a dose-dependent decrease in all the above parameters compared to positive control. Dopamine and Nor-epinephrine levels in brain homogenate were decreased in positive control which subsequently increased with Mentat® treatment. Conclusion. Mentat® showed a neuroprotective effect in different experimental models of ADHD. It may be recommended for the effective/preventive management of ADHD, especially associated with memory impairment and neurologic conditions. [ABSTRACT FROM AUTHOR]

Microglia are described as the immune cells of the brain, their immune properties have been extensively studied since first described, however, their neural functions have only been explored over the last decade. Microglia have an important role in maintaining homeostasis in the central nervous system by surveying their surroundings to detect pathogens or damage cells. While these are the classical functions described for microglia, more recently their neural functions have been defined; they are critical to the maturation of neurons during embryonic and postnatal development, phagocytic microglia remove excess synapses during development, a process called synaptic pruning, which is important to overall neural maturation. Furthermore, microglia can respond to neuronal activity and, together with astrocytes, can regulate neural activity, contributing to the equilibrium between excitation and inhibition through a feedback loop. Hypoxia at birth is a serious neurological condition that disrupts normal brain function resulting in seizures and epilepsy later in life. Evidence has shown that microglia may contribute to this hyperexcitability after neonatal hypoxia. This review will summarize the existing data on the role of microglia in the pathogenesis of neonatal hypoxia and the plausible mechanisms that contribute to the development of hyperexcitability after hypoxia in neonates. This article is part of the Special Issue on "Microglia". • Microglia are critical to the maturation of neurons during development. • Microglia respond to neuronal activity and regulate neural activity. • Hypoxia at birth inducesseizures and epilepsy later in life. • Microglia activation may contribute to the hyperexcitability. [ABSTRACT FROM AUTHOR]

ObjectiveMore women are obese at their first prenatal visit and then subsequently gain further weight throughout pregnancy than ever before. The impact on the infant’s development of neonatal hypoxic ischemic encephalopathy (HIE) has not been well studied. Using defined physiologic and neurologic criteria, our primary aim was to determine if maternal obesity conferred an additional risk of HIE.Study DesignData from the New York State Perinatal Data System of all singleton, term births in the Northeastern New York region were reviewed using the NIH obesity definition (Body Mass Index (BMI) ≥ 30 kg/m2). Neurologic and physiologic parameters were used to make the diagnosis of HIE. Physiologic criteria included the presence of an acute perinatal event, 10-min Apgar score ≤ 5, and metabolic acidosis. Neurologic factors included hypotonia, abnormal reflexes, absent or weak suck, hyperalert, or irritable state or evidence of clinical seizures. Therapeutic hypothermia was initiated if the infant met HIE criteria when assessed by the medical team. Logistic regression analysis was used to assess the effect of maternal body mass index on the diagnosis of HIE.ResultsIn this large retrospective cohort study we evaluated outcomes of 97,488 pregnancies. Infants born to obese mothers were more likely to require ventilatory assistance and have a lower 5-min Apgar score. After adjusting for type of delivery and maternal risk factors, infants of obese mothers were diagnosed with HIE more frequently than infants of non-obese mothers, OR 1.96 (1.33–2.89) (p = 0.001).ConclusionInfants of obese mothers were significantly more likely to have the diagnosis of HIE.

We assessed the quality of life and the amount of parental stress in families with children treated with therapeutic hypothermia (TH) after hypoxic ischemic encephalopathy (HIE). Our sample included 19 children (10 with mild HIE, 6 with moderate HIE, and 3 children with severe HIE) and their parents. The children were 6 to 9 years old. Parents completed two questionnaires (PedsQL-FIM and PSI-III). As a developmental outcome indicator we measured the children’s intelligence with WISC-IIISI and WPPSI-IIISI. The quality of life in participating families was better and parental stress did not differ significantly from normative values. Families have adapted to the risk factors for lower quality of life caused by the child’s illness, which is consistent with the theory of positive adaptation (the dual ABC-X model). Poor quality of family life and increased parental stress in some (but not all) areas were found in families with children of an under average IQ in comparison with families with children of an average or above average IQ. This finding is consistent with previous studies involving families of children with HIE and some other chronic diseases. Developmental outcomes of children with HIE treated with TH are different with specific characteristics and needs of children and their families. Further investigation should be focused on the early period, as parents often expressed uncertainty and fear experienced after a diagnosis and acute treatment of the child. Health care professionals need to inform parents about sources of help in the local environment, as well as those available at the national level. It is important for parents to obtain information and education, as well as receive professional therapeutic help when necessary. In order to provide optimum support to families of chronically ill children, adequate health and social policy is essential.

Valentina Vio,1,2 Ana L Riveros,1 Andrea Tapia-Bustos,2 Carolyne Lespay-Rebolledo,2 Ronald Perez-Lobos,2 Luis Muñoz,3 Paola Pismante,3 Paola Morales,2,4 Eyleen Araya,5 Natalia Hassan,1,6 Mario Herrera-Marschitz,2 Marcelo J Kogan1,7 1Department of Pharmacological and Toxicology Chemistry, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile; 2Program of Molecular and Clinical Pharmacology, Medical Faculty, Universidad de Chile, Santiago, Chile; 3Chemical Meteorology Section, Comisión Chilena de Energía Nuclear, Santiago, Chile; 4Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile; 5Departamento de Ciencias Quimicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago, Chile; 6Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación, Universidad Tecnológica Metropolitana, Santiago, Chile; 7Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile Background: Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated with systemic and neurological diseases. Despite the important role of poly (ADP-ribose) polymerase 1 (PARP-1) in the regulation of gene expression and DNA repair, overactivation of PARP-1 in asphyxia-exposed animals worsens the ATP-dependent energetic crisis. Inhibition of PARP-1 offers a therapeutic strategy for diminishing the effects of perinatal asphyxia. Methods: We designed a nanosystem that incorporates a specific siRNA for PARP-1 knockdown. The siRNA was complexed with gold nanorods (AuNR) conjugated to the peptide CLPFFD for brain targeting. Results: The siRNA was efficiently delivered into PC12 cells, resulting in gene silencing. The complex was administered intraperitoneally in vivo to asphyxia-exposed rat pups, and the ability of the AuNR-CLPFFD/siRNA complex to reach the brain was demonstrated. Conclusion: The combination of a nanosystem for delivery and a specific siRNA for gene silencing resulted in effective inhibition of PARP-1 in vivo. Keywords: neonatal hypoxia, siRNA delivery, PARP-1 knockdown, gold nanorods, in vivo administration, PC12, rats

Previous studies have suggested that xenon inhalation has neuroprotective and antiepileptic effects; however, the underlying mechanisms involved remain unclear. This study aimed to investigate the possible xenon inhalation mechanisms involved in the neuroprotection and antiepileptic effects. A neonatal hypoxic C57BL/6J mouse model was used for the experiments. Immediately after hypoxia treatment, the treatment group inhaled a xenon mixture (70% xenon/21% oxygen/9% nitrogen) for 60 min, while the hypoxia group inhaled a non-xenon mixture (21% oxygen/79% nitrogen) for 60 min. Seizure activity was recorded at designated time points using electroencephalography. Oxidative stress levels, iron levels, neuronal injury, and learning and memory functions were also studied. The results showed that hypoxia increased the levels of iron, oxidative stress, mitophagy, and neurodegeneration, which were accompanied by seizures and learning and memory disorders. In addition, our results confirmed that xenon treatment significantly attenuated the hypoxia-induced seizures and cognitive defects in neonatal C57 mice. Moreover, the increased levels of iron, oxidative stress, mitophagy, and neuronal injury were reduced in xenon-treated mice. This study confirms the significant protective effects of a xenon mixture on hypoxia-induced damage in neonatal mice. Furthermore, our results suggest that reducing oxidative stress levels and iron accumulation may be the underlying mechanisms of xenon activity. Studying the protective mechanisms of xenon will advance its applications in potential therapeutic strategies. Image 1 • Xenon exhibited an anti-seizure role in neonatal hypoxic mice. • Xenon reduced the neuronal injury and cognitive defect induced by neonatal hypoxia. • Xenon attenuated the levels of iron accumulation and oxidative stress in hypoxic mice. [ABSTRACT FROM AUTHOR]

Neuregulin 1 (NRG1)–induced activation of ErbB4 in parvalbumin (PV) inhibitory interneurons is reported to serve as a critical endogenous negative-feedback mechanism to repress brain epileptogenesis. Here, we investigated the seizure susceptibility and the role of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures for rats subject to early life hypoxia. Neonatal postnatal day 5 (P5) rats were exposed to intermittent hypoxia (IH) or control (CON) room air for 10 days. In the prefrontal cortex (PFC) of P54 rats, we determined the impact of neonatal IH exposures on the expression of PV, NRG1, ErbB4, and phosphorylated ErbB4 (p-ErbB4) during the seizure induction. Seizure susceptibility tests with the common convulsant agent pentylenetetrazole (PEN) at P54 revealed that rats subject to neonatal hypoxia exposure developed faster and more serious epileptic seizures. Neonatal IH exposures (1) decreased the number of PV cells in the PFC of P54 rats; (2) interrupted the expression of NRG1 gene; and (3) altered the activity of NRG1 on PV interneurons in the PFC after the seizure induction. Intracerebroventricular delivery of exogenous NRG1 before seizure induction by PEN significantly reduced the seizure susceptibility for neonatal IH-exposed rats. The ErbB4 inhibitor AG1478 inhibited the exogenous NRG1's effects on seizure susceptibility. Environmental enrichment (EE) rescued the abovementioned pathophysiological alterations and significantly attenuated the epileptic seizures after the seizure induction for neonatal IH-exposed rats. Our study indicated early life hypoxia exposure might increase the seizure susceptibility for rats and contribute to pathophysiological dysfunction of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures. EE might attenuate the increased seizure susceptibility for neonatal IH-exposed rats through rescuing pathophysiological alterations of NRG1-ErbB4 signaling in PV interneurons. [ABSTRACT FROM AUTHOR]

Neonatal hypoxia can induce the persisting brain dysfunctions and subsequently result in the behavioral abnormalities in adulthood. Improving mitochondrial functions were suggested as the effective strategy for brain functional recovery. In this study, we tested the effects of physical exercise, a well-established way benefits mitochondrion, for its functions to prevent hypoxia induced adult behavioral dysfunctions and the underlying molecular mechanism. Mice was induced with hypoxia and treadmill running were then administrated until the adulthood. The treadmill running resulted in the improved behavioral performance in depressive and anxiety tests together with the enhancement of hippocampal neurogenesis. We then detected treadmill running restored the mitochondrial morphology in adult neural stem cells (NSCs) as well as the ATP production in hippocampal tissue. In addition, activity of AMPK, which playing key roles in regulating mitochondrial functions, was also elevated by treadmill running. Blockage of AMPK with selective inhibitor compound C prohibited effects of treadmill running in attenuating neonatal hypoxia induced neurogenic impairment and antidepressant behavioral deficits in adulthood. In conclusion, treadmill running could prevent neonatal hypoxia induced adult antidepressant dysfunctions and neurogenic dampening via AMPK-mediated mitochondrial regulation. • Treadmill running restored early hypoxia induced depressive symptoms in adulthood. • Treadmill running promoted adult hippocampal neurogenesis in adult mice with early life hypoxic stress. • AMPK regulates treadmill running induced neuroprotection. [ABSTRACT FROM AUTHOR]

• Acute neonatal hypoxia resulted in upregulation of HIF1-α, GPx2 and GPx4 genes expression in rat brains. • Acute neonatal hypoxia led to delay in sensorimotor development and behavioural alterations in adolescent and adult rats. • NADA administration enhanced brain tissue redox capacity both in control rats and in rats exposed to hypoxia. • NADA treatment from P2 to P5 significantly improved sensorimotor development and memory retention in hypoxic rats. • The long-lasting beneficial effects of NADA are mediated, at least in part, by its antioxidant properties. Perinatal hypoxia-ischemia is one of the most common causes of perinatal brain injury and subsequent neurological disorders in children. The aim of this work was to evaluate the potential antioxidant and neuroprotective effects of N-arachidonoyl-dopamine (NADA) in the model of acute neonatal hypoxia (ANH) in rat pups. Male and female Wistar rats were exposed to a hypoxic condition (8% oxygen for 120 min) at postnatal day 2 (P2). Transcription factor HIF1-α and glutathione peroxidases GPx2 and GPx4 gene expression was increased in rat brains in the hypoxic group compared to control 1.5 h but not 4 days after ANH. There were no post-hypoxic changes in reduced (GSH) and oxidised (GSSG) glutathione levels in the brain of rat pups 1.5 h and 4 d after hypoxia. Hypoxic rats displayed retarded performance in the righting reflex and the negative geotaxis tests. ANH resulted in increased ambulation in Open field test and impaired retention in the Barnes maze task under stressful conditions as compared with the control group. Treatment with NADA significantly attenuated the delayed development of sensorimotor reflexes and stress-evoked disruption of memory retention in hypoxic rats but had no effect on the hypoxia-induced hyperactivity. In rats exposed to hypoxia, treatment with NADA decreased GPx2 gene expression and increased GSH/GSSG ratio in whole brains 1.5 h after ANH. These results suggest that the long-lasting beneficial effects of NADA on hypoxia-induced neurobehavioural deficits are mediated, at least in part, by its antioxidant properties. [ABSTRACT FROM AUTHOR]

Neonatal asphyxia occurs due to reduction in oxygen supply to vital organs in the newborn. Rapid restoration of oxygen to the lungs after a long period of asphyxia can cause lung injury and decline of respiratory function, which result from the activity of molecules that induce vascular changes in the lung such as nitric oxide (NO) and vascular endothelial growth factors (VEGF). In this study, we evaluated the pulmonary and vascular morphometry of rats submitted to the model of neonatal asphyxia and mechanical ventilation, their expression of pulmonary VEGF, VEGF receptors (VEGFR-1/VEGFR-2), and endothelial NO synthase (eNOS). Neonate Sprague-Dawley rats (CEUA #043/2011) were divided into four groups (n=8 each): control (C), control submitted to ventilation (CV), hypoxia (H), and hypoxia submitted to ventilation (HV). The fetuses were harvested at 21.5 days of gestation. The morphometric variables measured were body weight (BW), total lung weight (TLW), left lung weight (LLW), and TLW/BW ratio. Pulmonary vascular measurements, VEGFR-1, VEGFR-2, VEGF, and eNOS immunohistochemistry were performed. The morphometric analysis showed decreased TLW and TLW/BW ratio in HV compared to C and H (P

Perinatal hypoxia–ischaemia is one of the leading factors that negatively influence the development of the central nervous system. Our aim was to investigate the effects of sex on the outcomes of acute neonatal hypoxia (ANH) in rat pups. Male and female Wistar rats were exposed to a hypoxic condition (8% oxygen for 120 min) at postnatal day 2 (P2). Immediately after ANH an increase in HIF1-α gene expression was observed in the rat brains, independently of sex. Brain-derived neurotrophic factor (BDNF) and glutathione peroxidase-4 gene expression was increased in female animals only. Hypoxic pups of both sexes showed a decreased reduced/oxidised glutathione (GSH/GSSG) ratio in the blood and only males had an increased GSH content in the whole brain immediately after hypoxia. Furthermore, an increased BDNF content in the brain was found in both male and female rat pups at 0 h and in serum 4 h after hypoxia, but at 4 h after hypoxia only males had an increased BDNF level in the brain. Only hypoxic males displayed retarded performance in the righting reflex, but in a negative geotaxis test hypoxic pups of both sexes had an increased turnaround time. Moreover, hypoxic female but not male pups demonstrated less weight gain than control littermates for the entire observation period (until P18). These results demonstrate that ANH at P2 leads to both molecular and physiological impairments in a sex-specific manner and the described model could be used to represent mild hypoxic brain damage in very preterm infants. [ABSTRACT FROM AUTHOR]

Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O 2 . Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period. [ABSTRACT FROM AUTHOR]

Small remnants of the right valve of the sinus venosus are commonly found in adults, but the incidence and risk associated with these embryonic remnants in neonates are not well studied. The following report describes a cyanotic neonate with a large Eustachian valve remnant creating a functional cor triatriatum dexter who was initially diagnosed with persistent pulmonary hypertension of the newborn. The cyanosis in this infant improved over the first postnatal week with conservative management, but she suffered multifocal subcortical stroke, likely related to her intracardiac shunt. The clinical presentation and questions regarding long-term management of this rare diagnosis are explored. [ABSTRACT FROM AUTHOR]

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Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult. PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1α (HIF-1α) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-κB subunit p65, overexpression of the pro-inflammatory cytokines IL-1β and TNF-α, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss evidence showing that (i) inhibition of PARP-1 overactivation by nicotinamide and (ii) inhibition of extrasynaptic NMDA receptor overactivation by memantine can prevent the short- and long-term consequences of PA. These hypotheses have been evaluated in a rat preclinical model of PA, aiming to identify the metabolic cascades responsible for the long-term consequences induced by the insult, also assessing postnatal vulnerability to recurrent oxidative insults. Thus, we present and discuss evidence demonstrating that PA induces long-term changes in metabolic pathways related to energy and oxidative stress, priming vulnerability of cells with both the neuronal and the glial phenotype. The effects induced by PA are region dependent, the substantia nigra being particularly prone to cell death. The issue of short- and long-term consequences of PA provides a framework for addressing a fundamental issue referred to plasticity of the CNS, since the perinatal insult triggers a domino-like sequence of events making the developing individual vulnerable to recurrent adverse conditions, decreasing his/her coping repertoire because of a relevant insult occurring at birth. [ABSTRACT FROM AUTHOR]

Animal models are valuable tools for screening novel therapies for patients who suffer from epilepsy. However, a wide array of models are necessary to cover the diversity of human epilepsies. In humans, neonatal hypoxia (or hypoxia-ischemia) is one of the most common causes of epilepsy early in life. Hypoxia-induced seizures (HS) during the neonatal period can also lead to spontaneous seizures in adulthood. This phenomenon, i.e., early-life hypoxia leading to adult epilepsy − is also seen in experimental models, including rats. However, it is not known which anti-seizure medications are most effective at managing adult epilepsy resulting from neonatal HS. Here, we examined the efficacy of three anti-seizure medications against spontaneous seizures in adult rats with a history of neonatal HS: (1) phenobarbital (PHB), the oldest epilepsy medicine still in use today; (2) levetiracetam (LEV); and (3) tiagabine (TGB). Both LEV and TGB are relatively new anticonvulsant drugs that are ineffective in traditional seizure models, but strikingly effective in other models. We found that PHB and LEV decreased seizures in adult rats with a history of HS, whereas TGB exacerbated seizures. These divergent drug effects indicate that the HS model may be useful for differentiating the clinical efficacy of putative epilepsy therapies. [ABSTRACT FROM AUTHOR]

While extensive studies report that neonatal hypoxia-ischemia (HI) induces long-term cognitive impairment via inflammatory responses in the brain, little is known about the role of early peripheral inflammation response in HI injury. Here we used a neonatal hypoxia rodent model by subjecting postnatal day 0 (P0d) rat pups to systemic hypoxia (3.5 h), a condition that is commonly seen in clinic neonates, Then, an initial dose of minocycline (45 mg/kg) was injected intraperitoneally (i.p.) 2 h after the hypoxia exposure ended, followed by half dosage (22.5 mg/kg) minocycline treatment for next 6 consecutive days daily. Saline was injected as vehicle control. To examine how early peripheral inflammation responded to hypoxia and whether this peripheral inflammation response was associated to cognitive deficits. We found that neonatal hypoxia significantly increased leukocytes not only in blood, but also increased the monocytes in central nervous system (CNS), indicated by presence of C-C chemokine receptor type 2 (CCR2+)/CD11b+CD45+ positive cells and CCR2 protein expression level. The early onset of peripheral inflammation response was followed by a late onset of brain inflammation that was demonstrated by level of cytokine IL-1β and ionized calcium binding adapter molecule 1(Iba-1; activated microglial cell marker). Interrupted blood-brain barrier (BBB), hypomyelination and learning and memory deficits were seen after hypoxia. Interestingly, the cognitive function was highly correlated with hypoxia-induced leukocyte response. Notably, administration of minocycline even after the onset of hypoxia significantly suppressed leukocyte-mediated inflammation as well as brain inflammation, demonstrating neuroprotection in systemic hypoxia-induced brain damage. Our data provided new insights that systemic hypoxia induces cognitive dysfunction, which involves the leukocyte-mediated peripheral inflammation response.

The hypothesis of enhanced vulnerability following perinatal asphyxia was investigated with a protocol combining in vivo and in vitro experiments. Asphyxia-exposed (AS) (by 21 min water immersion of foetuses containing uterine horns) and caesarean-delivered control (CS) rat neonates were used at P2-3 for preparing triple organotypic cultures (substantia nigra, neostriatum and neocortex). At DIV 18, cultures were exposed to different concentrations of HO (0.25-45 mM), added to the culture medium for 18 h. After a 48-h recovery period, the cultures were either assessed for cell viability or for neurochemical phenotype by confocal microscopy. Energy metabolism (ADP/ATP ratio), oxidative stress (GSH/GSSG) and a modified ferric reducing/antioxidant power assay were applied to homogenates of parallel culture series. In CS cultures, the number of dying cells was similar in substantia nigra, neostriatum and neocortex, but it was several times increased in AS cultures evaluated under the same conditions. A HO challenge led to a concentration-dependent increase in cell death (>fourfold after 0.25 mM of HO) in CS cultures. In AS cultures, a significant increase in cell death was only observed after 0.5 mM of HO. At higher than 1 mM of HO (up to 45 mM), cell death increased several times in all cultures, but the effect was still more prominent in CS than in AS cultures. The cell phenotype of dying/alive cells was investigated in formalin-fixed cultures exposed to 0 or 1 mM of HO, co-labelling for TUNEL (apoptosis), MAP-2 (neuronal phenotype), GFAP (astroglial phenotype) and TH (tyrosine hydroxylase; for dopamine phenotype), counterstaining for DAPI (nuclear staining), also evaluating the effect of a single dose of nicotinamide (0.8 nmol/kg, i.p. injected in 100 μL, 60 min after delivery). Perinatal asphyxia produced a significant increase in the number of DAPI/TUNEL cells/mm, in substantia nigra and neostriatum. One millimolar of H0 increased the number of DAPI/TUNEL cells/mm by ≈twofold in all regions of CS and AS cultures, an effect that was prevented by neonatal nicotinamide treatment. In substantia nigra, the number of MAP-2/TH-positive cells/mm was decreased in AS compared to CS cultures, also by 1 mM of H0, both in CS and AS cultures, prevented by nicotinamide. In agreement, the number of MAP-2/TUNEL-positive cells/mm was increased by 1 mM HO, both in CS (twofold) and AS (threefold) cultures, prevented by nicotinamide. The number of MAP-2/TH/TUNEL-positive cells/mm was only increased in CS (>threefold), but not in AS (1.3-fold) cultures. No TH labelling was observed in neostriatum, but 1 mM of HO produced a strong increase in the number of MAP-2/TUNEL-positive cells/mm, both in CS (>2.9-fold) and AS (>fourfold), decreased by nicotinamide. In neocortex, HO increased the number of MAP-2/TUNEL-positive cells/mm, both in CS and AS cultures (≈threefold), decreased by nicotinamide. The ADP/ATP ratio was increased in AS culture homogenates (>sixfold), compared to CS homogenates, increased by 1 mM of H0, both in CS and AS homogenates. The GSH/GSSG ratio was significantly decreased in AS, compared to CS cultures. One millimolar of HO decreased that ratio in CS and AS homogenates. The present results demonstrate that perinatal asphyxia induces long-term changes in metabolic pathways related to energy and oxidative stress, priming cell vulnerability with both neuronal and glial phenotype. The observed effects were region dependent, being the substantia nigra particularly prone to cell death. Nicotinamide administration in vivo prevented the deleterious effects observed after perinatal asphyxia in vitro, a suitable pharmacological strategy against the deleterious consequences of perinatal asphyxia. [ABSTRACT FROM AUTHOR]

Perinatal asphyxia (PA) is associated to delayed cell death, affecting neurocircuitries of basal ganglia and hippocampus, and long-term neuropsychiatric disabilities. Several compensatory mechanisms have been suggested to take place, including cell proliferation and neurogenesis. There is evidence that PA can increase postnatal neurogenesis in hippocampus and subventricular zone (SVZ), modulated by dopamine, by still unclear mechanisms. We have studied here the effect of selective dopamine receptor agonists on cell death, cell proliferation and neurogenesis in organotypic cultures from control and asphyxia-exposed rats. Hippocampus and SVZ sampled at 1-3 postnatal days were cultured for 20-21 days. At day in vitro (DIV) 19, cultures were treated either with SKF38393 (10 and 100 µM, a D agonist), quinpirole (10 µM, a D agonist) or sulpiride (10 μM, a D antagonist) + quinpirole (10 μM) and BrdU (10 μM, a mitosis marker) for 24 h. At DIV 20-21, cultures were processed for immunocytochemistry for microtubule-associated protein-2 (MAP-2, a neuronal marker), and BrdU, evaluated by confocal microscopy. Some cultures were analysed for cell viability at DIV 20-21 (LIVE/DEAD kit). PA increased cell death, cell proliferation and neurogenesis in hippocampus and SVZ cultures. The increase in cell death, but not in cell proliferation, was inhibited by both SKF38393 and quinpirole treatment. Neurogenesis was increased by quinpirole, but only in hippocampus, in cultures from both asphyxia-exposed and control-animals, effect that was antagonised by sulpiride, leading to the conclusion that dopamine modulates neurogenesis in hippocampus, mainly via D receptors. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension is a fatal disease characterized by a progressive increase in pulmonary artery pressure accompanied by pulmonary vascular remodeling and increased vasomotor tone. Although some biological pathways have been identified in neonatal hypoxia-induced pulmonary hypertension (PH), little is known regarding the role of growth factors in the pathogenesis of PH in neonates. In this study, using a model of hypoxia-induced PH in neonatal mice, we demonstrate that the growth factor insulin-like growth factor-1 (IGF-1), a potent activator of the AKT signaling pathway, is involved in neonatal PH. After exposure to hypoxia, IGF-1 signaling is activated in pulmonary endothelial and smooth muscle cells in vitro , and the IGF-1 downstream signal pAKT S473 is upregulated in lungs of neonatal mice. We found that IGF-1 regulates ET-1 expression in pulmonary endothelial cells and that IGF - 1 expression is regulated by histone deacetylases (HDACs). In addition, there is a differential cytosine methylation site in the IGF - 1 promoter region in response to neonatal hypoxia. Moreover, inhibition of HDACs with apicidin decreases neonatal hypoxia-induced global DNA methylation levels in lungs and specific cytosine methylation levels around the pulmonary IGF - 1 promoter region. Finally, HDAC inhibition with apicidin reduces chronic hypoxia-induced activation of IGF-1/pAKT signaling in lungs and attenuates right ventricular hypertrophy and pulmonary vascular remodeling. Taken together, we conclude that IGF-1, which is epigenetically regulated, is involved in the pathogenesis of pulmonary hypertension in neonatal mice. This study implicates a novel HDAC/IGF-1 epigenetic pathway in the regulation of hypoxia-induced PH and warrants further study of the role of IGF-1 in neonatal pulmonary hypertensive disease. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to estimate the association between time from uterine incision to delivery and hypoxic neonatal outcomes in nonanomalous term infants. Methods All women undergoing in-labor term cesarean deliveries (CDs) in the first 2 years of an ongoing prospective cohort study were included. The primary exposure was time in seconds from uterine incision to delivery. The primary outcome was a composite of hypoxia-associated neonatal outcomes, defined as at least one of: seizures, hypoxic ischemic encephalopathy, need for hypothermia treatment, and death within 7 days. Results Of 812 patients who underwent in-labor CD, the composite hypoxia outcome occurred in 18 (2.2%) neonates. There was no significantdifference in the rateofhypoxic morbidity with increasing increments of 60 seconds from uterine incision to delivery (p = 0.35). There was a significantly increased risk of hypoxic morbidity in those delivered in the highest quintile (>240 seconds) compared with those in the lowest quintile (≤60 seconds) in cesareans performed for an indication other than nonreassuring fetal status (relative risk, 5.58; 95% confidence interval, 1.30-23.91). Conclusion Overall, duration from uterine incision to delivery for in-labor cesareans of nonanomalous term infants was not associated with an increase in risk of hypoxia-associated morbidities. [ABSTRACT FROM AUTHOR]

Persistent pulmonary hypertension of the newborn (PPHN) is defined as the failure of normal pulmonary vascular relaxation at birth. Hypoxia is known to impede postnatal disassembly of the actin cytoskeleton in pulmonary arterial myocytes, resulting in elevation of smooth muscle α-actin and γ-actin content in elastic and resistance pulmonary arteries in PPHN compared with age-matched controls. This review examines the original histological characterization of PPHN with attention to cytoskeletal structural remodeling and actin isoform abundance, reviews the existing evidence for understanding the biophysical and biochemical forces at play during neonatal circulatory transition, and specifically addresses the role of the cortical actin architecture, primarily identified as γ-actin, in the transduction of mechanical force in the hypoxic PPHN pulmonary circuit. [ABSTRACT FROM AUTHOR]

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Neonatal anoxia in rodents has been used to understand brain changes and cognitive dysfunction following asphyxia. This study investigated the time-course of cellular and subcellular changes and hippocampal cell death in a non-invasive model of anoxia in neonatal rats, using Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL) to reveal DNA fragmentation, Fluoro-Jade® B (FJB) to show degenerating neurons, cleaved caspase-3 immunohistochemistry (IHC) to detect cells undergoing apoptosis, and transmission electron microscopy (TEM) to reveal fine ultrastructural changes related to cell death. Anoxia was induced by exposing postnatal day 1 (P1) pups to a flow of 100% gaseous nitrogen for 25 min in a chamber maintained at 37 °C. Control rats were similarly exposed to this chamber but with air flow instead of nitrogen. Brain changes following anoxia were evaluated at postnatal days 2, 14, 21 and 60 (P2, P14, P21 and P60). In addition, spatial reference memory following anoxia and control treatments was evaluated in the Morris water maze, starting at P60. Compared to their respective controls, P2 anoxic rats exhibited (1) higher TUNEL labeling in cornus ammonis (CA) 1 and the dentate gyrus (DG), (2) higher FJB-positive cells in the CA2–3, and (3) somato-dendritic swelling, mitochondrial injury and chromatin condensation in irregular bodies, as well as other subcellular features indicating apoptosis, necrosis, autophagy and excitotoxicity in the CA1, CA2–3 and DG, as revealed by TEM. At P14, P21 and P60, both groups showed small numbers of TUNEL-positive and FJB-positive cells. Stereological analysis at P2, P14, P21 and P60 revealed a lack of significant differences in cleaved caspase-3 IHC between anoxic and control subjects. These results suggest that the type of hippocampal cell death following neonatal anoxia is likely independent of caspase-3 activation. Neonatal anoxia induced deficits in acquisition and performance of spatial reference memory in the Morris water maze task. Compared to control subjects, anoxic animals exhibited increased latencies and path lengths to reach the platform, as well as decreased searching specifically for the platform location. In contrast, no significant differences were observed for swimming speeds and frequency within the target quadrant. Together, these behavioral results indicate that the poorer performance by anoxic subjects is related to spatial memory deficits and not to sensory or motor deficits. Therefore, this model of neonatal anoxia in rats induces hippocampal changes that result in cell losses and impaired hippocampal function, and these changes are likely related to spatial memory deficits in adulthood. [ABSTRACT FROM AUTHOR]

Abstract: We investigated whether the effect of neonatal hypoxia on amphetamine-induced hyperlocomotion can reproduce the ontogenic (age of onset) properties of schizophrenia. Neonatal hypoxia enhanced amphetamine-induced hyperlocomotion in adult mice and decreased it in adolescent mice. These findings provide ontogenic validity for this very simple animal model of schizophrenia. [Copyright &y& Elsevier]

Abstract: Cholinergic system is important for respiratory control from the first days of life. Disturbances in cholinergic pathway due to early life stress like hypoxic shock can adversely affect the ventilatory response. The present study evaluates neonatal hypoxic insult mediated cholinergic disturbances and the role of glucose, oxygen and epinephrine resuscitation. The changes in total muscarinic, muscarinic M1, M2, M3 receptors and the enzymes involved in acetylcholine metabolism – cholineacetyl transferase and acetylcholine easterase in the cerebellum were analyzed. Hypoxic stress decreased cerebellar muscarinic receptor density with a decreased muscarinic M1, M2 and M3 receptor gene expression. The metabolic shift in the acetylcholine synthesis and release is indicated by the decreased cholineacetyl transferase mRNA expression and increased acetylcholine esterase gene expression. Glucose, acting as a precursor for acetyl choline synthesis and an immediate energy source, helps in reversing the cholinergic disturbances in hypoxic neonates. The limitation of immediate oxygenation and epinephrine administration in ameliorating cholinergic disturbances in hypoxic neonates was also reported. This will help in devising a better resuscitation program for the management of neonatal hypoxia. [Copyright &y& Elsevier]

As a consequence of obstetric complications, neonatal hypoxia has been discussed as an environmental factor in the pathophysiology of schizophrenia. However, the biological consequences of hypoxia are unclear. The neurodevelopmental hypothesis of schizophrenia suggests that the onset of abnormal brain development and neuropathology occurs perinatally, whereas symptoms of the disease appear in early adulthood. In our animal model of chronic neonatal hypoxia, we have detected behavioral alterations resembling those known from schizophrenia. Disturbances in cell proliferation possibly contribute to the pathophysiology of this disease. In the present study, we used postnatal rats to investigate cell proliferation in several brain areas following neonatal hypoxia. Rats were repeatedly exposed to hypoxia (89 % N, 11 % O) from postnatal day (PD) 4-8. We then evaluated cell proliferation on PD 13 and 39, respectively. These investigations were performed in the anterior cingulate cortex (ACC), caudate-putamen (CPU), dentate gyrus, and subventricular zone. Rats exposed to hypoxia exhibited increased cell proliferation in the ACC at PD 13, normalizing at PD 39. In other brain regions, no alterations have been detected. Additionally, hypoxia-treated rats showed decreased CPU volume at PD 13. The results of the present study on the one hand support the assumption of chronic hypoxia influencing transient cell proliferation in the ACC, and on the other hand reveal normalization during ageing. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to describe and evaluate an experimental model of neonatal normocapnic hypoxia and resuscitation. Methods: Ten male Landrace/Large White neonatal piglets were studied. Following anaesthesia and intubation, the animals were mechanically ventilated. Surgical procedures included catheterization of the right internal jugular vein and the carotid artery. After stabilization with 21% O2, normocapnic hypoxia was induced by decreasing the inspired O2 to 6-8%. When piglets developed bradycardia (heart rate < 60 beats/min), reoxygenation was initiated by administering 21% O2. Arterial blood samples were taken during baseline, hypoxia and reoxygenation in order to measure interleukine-6 and interleukine-8. Results: Nine out of ten animals were successfully resuscitated (one of these required chest compressions and a dose of adrenaline) and one died despite resuscitation efforts. After returning to baseline haemodynamic values, euthanasia was performed using thiopental overdose. Conclusions: Haemodynamic fluctuations at baseline, during normocapnic hypoxia and reoxygenation in Landrace/Large White piglets are comparable to that in human neonates, making the breed a favorable model of human neonatal hypoxia investigation. [ABSTRACT FROM AUTHOR]

Abstract: Hypoxia in neonates causes dysfunction of excitatory and inhibitory neurotransmission resulting in permanent brain damage. The present study is to understand the cerebellar GABAA receptor alterations and neuroprotective effect of glucose supplementation prior to current sequence of resuscitation – oxygen and epinephrine supplementation in hypoxic neonatal rats. Hypoxic insult caused a significant decrease in GABAA receptor number along with down regulated expression of GABAAα1, GABAAα5, GABAAδ and GABAAγ3 receptor subunits in the cerebellum which accounts for the respiratory inhibition. Hypoxic rats supplemented with glucose alone and with oxygen showed a reversal of the receptor alterations and changes in GABAA receptor subunits expression to near control. Glucose can reduce ATP-depletion-induced alterations in GABA receptors, thereby assisting in overcoming the neuronal damage caused by hypoxia. Resuscitation with oxygen alone and epinephrine was less effective in reversing the receptor alterations. The reduction in the GABAA receptors functional regulation during hypoxia plays an important role in cerebellar damage. Resuscitation with glucose alone and glucose with oxygenation to hypoxic neonatal rats helps in protecting the brain from severe hypoxic damage. [Copyright &y& Elsevier]

Abstract: Background: There is a growing population of adults with repaired cyanotic congenital heart disease. These patients have increased risk of impaired cardiac health and premature death. We hypothesized that hypoxia in early life before surgical intervention causes lasting changes in left ventricular structure and function with physiological implications in later life. Methods: Sprague–Dawley rats reared initially hypoxic conditions (FiO2 =0.12) for days 1–10 of life were compared to rats reared only in ambient air. Cellular morphology and viability were compared among LV cardiomyocytes and histological analyses were performed on LV myocardium and arterioles. Intracellular calcium transients and cell shortening were measured in freshly-isolated cardiomyocytes, and mitochondrial hexokinase 2 (HK2) expression and activity were determined. Transthoracic echocardiography was used to assess LV function in anesthetized animals. Results: Cardiomyocytes from adult animals following hypoxia in early life had greater cellular volumes but significantly reduced viability. Echocardiographic analyses revealed LV hypertrophy and diastolic dysfunction, and alterations in cardiomyocyte calcium transients and cell shortening suggested impaired diastolic calcium reuptake. Histological analyses revealed significantly greater intima–media thickness and decreased lumen area in LV arterioles from hypoxic animals. Alterations in mitochondrial HK2 protein distribution and activity were also observed which may contribute to cardiomyocyte fragility. Conclusions: Hypoxia in early life causes lasting changes in left ventricular structure and function that may negatively influence myocardial and vascular responses to physiological stress in later life. These data have implications for the growing population of adults with repaired or palliated cyanotic congenital heart disease. [Copyright &y& Elsevier]

Hypoxia in neonates disrupts the oxygen flow to the brain, essentially starving the brain and preventing it from performing vital biochemical processes important for central nervous system development. Hypoxia results in a permanent brain damage by gene and receptor level alterations mediated through neurotransmitters. The present study evaluated GABA, GABAA, GABAB receptor functions and gene expression changes in glutamate decarboxylase in the corpus striatum of hypoxic neonatal rats and the treatment groups with glucose, oxygen and epinephrine. Since GABA is the principal neurotransmitter involved in hypoxic ventilatory decline, the alterations in its level under hypoxic stress points to an important aspect of respiratory control. Following hypoxic stress, a significant decrease in total GABA, GABAA and GABAB receptors function and GAD expression was observed in the striatum, which accounts for the ventilator decline. Hypoxic rats treated with glucose alone and with oxygen showed a reversal of the receptor alterations and changes in GAD to near control. Being a source of immediate energy, glucose can reduce the ATP-depletion-induced changes in GABA and oxygenation helps in overcoming reduction in oxygen supply. Treatment with oxygen alone and epinephrine was not effective in reversing the altered receptor functions. Thus, our study point to the functional role of GABA receptors in mediating ventilatory response to hypoxia and the neuroprotective role of glucose treatment. This has immense significance in the proper management of neonatal hypoxia for a better intellect in the later stages of life. [ABSTRACT FROM AUTHOR]

Responses of the endocrine system are vital in revealing the mechanisms of respiratory activities. The present study focused on changes in insulin and triiodothyronine concentration in serum, its receptors in the hearts of hypoxic neonatal rats and glucose, oxygen, and epinephrine resuscitated groups. The insulin concentration was significantly increased with a significant upregulation of receptors in hypoxic neonates. Triiodothyronine content and its receptors were significantly decreased in serum and the hearts of hypoxic neonates. The change in hormonal levels is an adaptive modification of the endocrine system to encounter the stress. The effectiveness of glucose resuscitation to hypoxic neonates was also reported. [ABSTRACT FROM AUTHOR]

Abstract: Alterations in neurotransmitters and its receptors expression induce brain injury during neonatal hypoxic insult. Molecular processes regulating the serotonergic receptors play an important role in the control of respiration under hypoxic insult. The present study focused on the serotonergic regulation of neonatal hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were done to evaluate the changes in 5HT2A receptors and its transporter in the corpus striatum of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen and epinephrine. Total 5HT and 5HT2A receptor number was increased in hypoxic neonates along with an up regulation of 5HT2A receptor and 5HT transporter gene. The enhanced striatal 5HT2A receptors modulate the ventilatory response to hypoxia. Immediate glucose resuscitation was found to ameliorate the receptor and transporter alterations. Hypoxia induced ATP depletion mediated reduction in blood glucose levels can be encountered by glucose administration and oxygenation helps in overcoming the anaerobic condition. The adverse effect of immediate oxygenation and epinephrine supplementation was also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia. [Copyright &y& Elsevier]

Purpose: This study was undertaken to assess the relationship between the degree of meconium staining of the extraplacental membranes at birth, meconium aspiration, and pulmonary changes in neonates and stillbirth. Methods: The lungs, extraplacental membranes and placenta from 20 stillborn with meconium-stained membranes and 13 lungs of perinatal deaths were collected and microscopically examined for meconium, intra-alveolar presence of aspiration and inflammation. Results: Microscopically, 32% and 40% of the lungs had evidence of meconium for the stained and nonstained groups, respectively. The microscopic grade of meconium aspiration and inflammatory cells was not different between nonstained and meconium-stained membranes. Aspiration of meconium induced a granulomatous response in the lungs. Conclusion: It was concluded that the grade of meconium staining is a good indicator of fetal hypoxia, but not a good predictor for meconium aspiration and MAS in newborn. [ABSTRACT FROM AUTHOR]

Background-:Hypoxia during the first week of life can induce neuronal death in vulnerable brain regions usuallyassociated with an impairment of cognitive function that can be detected later in life. The neurobiological changesmediated through neurotransmitters and other signaling molecules associated with neonatal hypoxia are animportant aspect in establishing a proper neonatal care.Methods-:The present study evaluated total GABA, GABAB receptor alterations, gene expression changes in GABAB receptor and glutamate decarboxylase in the cerebellum and brain stem of hypoxic neonatal rats and theresuscitation groups with glucose, oxygen and epinephrine. Radiolabelled GABA and baclofen were used forreceptor studies of GABA and GABABreceptors respectively and Real Time PCR analysis using specific probes forGABAB receptor and GAD mRNA was done for gene expression studies.Results-:The adaptive response of the body to hypoxic stress resulted in a reduction in total GABA and GABAB receptors along with decreased Breceptor and GAD gene expression in the cerebellum and brain stem.Hypoxic rats supplemented with glucose alone and with oxygen showed a reversal of the receptor alterations and changes in GAD. Resuscitation with oxygen alone and epinephrine was less effective in reversing the receptoralterations.Conclusions-:Being a source of immediate energy, glucose can reduce the ATP-depletion-induced changes inGABA and oxygenation, which helps in encountering hypoxia. The present study suggests that reduction in theGABABreceptors functional regulation during hypoxia plays an important role in central nervous system damage.Resuscitation with glucose alone and glucose and oxygen to hypoxic neonatal rats helps in protecting the brainfrom severe hypoxic damage. [ABSTRACT FROM AUTHOR]

Although recent studies have documented compensatory generation of neurons in adult brains in response to various insults, a noninjurious short episode of hypoxia in rat neonates has been shown to trigger neurogenesis within the ensuing weeks, without apparent brain lesions. Very little is known of the long-term consequences. We therefore investigated the effects of such a conditioning-like hypoxia (100% N2, 5 min) on the brain and the cognitive outcomes of rats at 40 to 100 days of age. Control and posthypoxic rats developed similar learning capacities over postnatal days 14 to 18, but hypoxia was associated with enhanced scores in a test used to evaluate memory retrieval between 40 and 100 days. A striking sexual dimorphism was observed, with an earlier functional gain observed in female (40 days) compared with male (100 days) rats; gains were associated with matching structural changes in areas involved in cognition, including the hippocampus and frontal cortex. Therefore, it is proposed that brief neonatal hypoxia may exert long-term beneficial effects through neurogenesis stimulation. [Copyright &y& Elsevier]

We tested the hypothesis that neonatal exposure to hypoxia alters acclimatization to chronic hypoxia later in life. Rat pups were exposed to normobaric hypoxia (12% O2; nHx group) in a sealed chamber, or to normoxia (21% O2; nNx group) from the day before birth to postnatal day 10. The animals were then raised in normal conditions until reaching 12 wk of age. At this age, we assessed ventilatory and hematological acclimatization to chronic hypoxia by exposing male and female nHx and nNx rats for 2 wk to 10% O2. Minute ventilation, metabolic rate, hypoxic ventilatory response, hematocrit, and hemoglobin levels were measured both before and after acclimatization. We also quantified right ventricular hypertrophy as an index of pulmonary hypertension both before and after acclimatization. There was a significant effect of neonatal hypoxia that decreases ventilatory response (relative to metabolic rate, VE/VCO2) to acute hypoxia before acclimatization in males but not in females. nHx rats had an impaired acclimatization to chronic hypoxia characterized by altered respiratory pattern and elevated hematocrit and hemoglobin levels after acclimatization, in both males and females. Right ventricular hypertrophy was present before and after acclimatization in nHx rats, indicating that neonatal hypoxia results in pulmonary hypertension in adults. We conclude that neonatal hypoxia impairs acclimatization to chronic hypoxia in adults and may be a factor contributing to the establishment of chronic mountain sickness in humans living at high altitude. [ABSTRACT FROM AUTHOR]

Several independent lines of evidence suggest mitochondrial dysfunction in schizophrenia in brain and periphery, including mitochondrial hypoplasia, dysfunction of the oxidative phosphorylation system, and altered mitochondrial-related gene expression. In an attempt to decipher whether mitochondrial complex I abnormality in schizophrenia is a core pathophysiological process or is attributable to medication, we studied two animal models of schizophrenia related to the neurodevelopmental hypothesis of this disorder. Protein levels of complex I subunits, 24, 51, and 75 kDa, were assessed in neonatal ventral hippocampal lesion rat model and in rats exposed to hypoxia at a neonatal age. In the prefrontal cortex, a major anatomical substrate of schizophrenia, neonatal ventral hippocampal lesion induced a significant prepubertal increase and postpubertal decrease in all three subunits of complex I as compared to sham-treated rats, while no change was observed in the cingulate cortex. Neonatal exposure to hypoxia did not affect protein levels of any of the three subunits in the prefrontal cortex. An age-dependent increase in the expression of complex I subunits was observed, which was distorted in the prefrontal cortex by the neonatal ventral hippocampal lesion. Complex I alterations in schizophrenia-related neurodevelopmental rat models appear to be brain region and animal model dependent. The results of this study support previous findings suggesting abnormal complex I expression as a pathological characteristic of schizophrenia rather than an effect of medication. [ABSTRACT FROM AUTHOR]

Abstract: Gestational deficiency in methyl donors such as folate and vitamin B12 impairs homocysteine metabolism and can alter brain development in the progeny. Since short hypoxia has been shown to be neuroprotective in preconditioning studies, we aimed to investigate the effects of brief, non-lesioning neonatal hypoxia (100% N2 for 5 min) on the developing brain of rats born to dams fed either a standard diet or a diet lacking vitamins B12, B2, folate and choline until offspring''s weaning. While having no influence on brain accumulation of homocysteine and concomitant apoptosis in 21-day-old deficient pups, exposure to hypoxia reduced morphological injury of the hippocampal CA1 layer. It also markedly stimulated the incorporation of bromodeoxyuridine (BrdU) in permissive areas such as the subventricular zone and the hippocampus followed by the migration of new neurons. Scores in a locomotor coordination test (days 19–21) and learning and memory behavior in the eight-arm maze (days 80–84) were found to be significantly improved in rats exposed to hypoxia in addition to the deficient diet. Therefore, by stimulating neurogenesis in rat pups, brief neonatal hypoxia appeared to attenuate the long-term effects of early exposure to a deficiency in nutritional determinants of hyperhomocysteinemia. [Copyright &y& Elsevier]

Purpose: To determine if posthypoxia treatment with erythropoietin (EPO) has protective effects against subsequent susceptibility to seizure related neuronal injury in rat pups subjected to acute hypoxia at P10. Methods: Four groups of rats were manipulated at P10, as described below, then all received kainic acid (KA) (10 mg/kg i.p.) at P29: Hypoxia-NS-KA group (n = 11): subjected to acute hypoxia (down to 4% O2), and then immediately received saline i.p. Hypoxia-EPO-KA group (n = 10): subjected to acute hypoxia and then immediately received EPO (1,000 U/Kg i.p.). Normoxia-NS-KA group (n = 11): sham manipulated and injected with saline. Normoxia-EPO-KA group (n = 10): sham manipulated then immediately injected with EPO (1000 U/Kg i.p.). After receiving KA at P29, all rats were monitored using videotape techniques, and were sacrificed at P31. TUNEL and Hoechst stains to assess for apoptosis, and regular histology for hippocampal cell counts were performed. Results: Administration of the single dose of erythropoietin directly after an acute hypoxic event at P10 resulted at P29 in increased latency to forelimb clonus seizures, reduced duration of these seizures, protection against hippocampal cell loss, and decreased hippocampal apoptosis in the Hypoxia-EPO-KA group as compared to the Hypoxia-NS-KA group. Conclusion: These data support the presence of favorable protective effects of erythropoietin against the long-term consequences of acute hypoxia in the developing brain and raise the possibility of its investigation as a potential neuroprotective agent after human neonatal hypoxic encephalopathy. [ABSTRACT FROM AUTHOR]

Chloride (Cl–) efflux induces depolarization and contraction of vascular smooth muscle cells. In the basilar arteries from the New Zealand white rabbits, the role of Cl– flux in serotonin-induced contraction was demonstrated by (i) inhibition of Na+-K+-2Cl– co-transporter (NKCC1) to decreased Cl– influx with bumetanide; (ii) a disabled Cl–/HCO3– exchanger with bicarbonate free HEPES solution; (iii) blockade of Cl– channels using 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and indanyloxyacetic acid 94, R-(+)-methylindazone (R-(+)-IAA-94); and (iv) substitution of extracellular Cl– with methanesulfonate acid (113 mmol/L; Cl–, 10 mmol/L). In addition, the expression of NKCC1 in brain tissues after neonatal hypoxia-ischemia was examined at mRNA and protein levels using RT-PCR and Western blotting techniques. NKCC1 mRNA and protein expressions were increased at 24 and 48 h and returned to normal levels at 72 h after hypoxia insult when compared with the control littermates. In conclusion, Cl– efflux regulates cerebral circulation and the up-regulation of NKCC1 after neonatal hypoxia-ischemia may contribute to brain injury. [ABSTRACT FROM AUTHOR]

1. In the present work we describe the short term effects of mild neonatal hypoxia on the synapse as assessed by the immunoreactivity (IR) of twosynaptic proteins: rab 3A and synaptobrevin (VAMP). 2. Using the sensitive methodology of immunoblotting, we measured rab 3A andVAMP-IR in homogenates from the cerebral cortex, hippocampus, and corpus striatum of control (breathing room air) and hypoxiated (breathing 95.5% N2–6.5% O2 for 70 min) 4-day-old rats at 1, 2, and 6 h after the end of the hypoxia. Immunostaining with examination by light microscopy was performed using the synaptic protein-specific antibodies on fixed brain sections from animals belonging to the same litter and submitted to hypoxia. 3. A transient increase of VAMP-IR was observed in the hippocampus and corpus striatum, and for rab 3A in the striatum, 1 h after initiating reoxygenation.At the following time points the values returned to control levels. This effectwas less clearly observed in the immunostained sections. 4. Mild hypoxia has an effect on sensitive brain regions, eliciting an increase in the IR of at least two proteins involved in the synaptic vesicle cycle. The transient nature of this effect possibly indicates the activation of endogenous neuroprotective mechanisms. [ABSTRACT FROM AUTHOR]