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Aims: To assess the maturational status of the brainstem auditory pathway in babies with apnoea of prematurity (AOP) at 33-34 weeks of postmenstrual age (PMA), an important time landmark at which AOP is resolved in most cases., Study Design: Compare brainstem auditory maturation between very preterm babies with AOP and those without AOP (non-AOP) at the same PMA 33-34 weeks to define differences., Results: The AOP group showed significantly longer latencies of waves III and V latency than the non-AOP group (p < 0.05 and 0.01). The I-V interval in the AOP group was significantly longer than in the non-AOP group (p < 0.001). The same was true for the I-III and III-V intervals (p < 0.001 and 0.05). Wave III amplitude was significantly smaller (p < 0.05), and wave V amplitude was moderately smaller than in the non-AOP. At PMA 33 weeks, waves III and V latencies and all intervals in the AOP group were significantly longer than in the non-AOP group (p < 0.05-0.001). At PMA 34 weeks, these wave latencies and intervals in the AOP group were still significantly longer than in the non-AOP group (p < 0.05-0.01). Wave III amplitude in the AOP group was significantly smaller at both PMA 33 and 34 weeks (p < 0.05 and 0.05)., Conclusions: Brainstem auditory maturation in AOP babies is delayed at PMA 33 weeks, and remains delayed at PMA 34 weeks. These findings highlight the importance of monitoring and adequate intervention strategies during PMA 33-34 weeks in AOP babies., Competing Interests: Declaration of competing interest We have no financial relationships relevant to this article to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Ambroxol, a commonly used mucolytic agent, has been extensively studied for its clinical effectiveness in managing respiratory conditions in pediatric and adult patients. The existing body of research on ambroxol demonstrates its safety and efficacy. However, its potential role in preventing and treating neonatal diseases still needs to be explored. This scoping review aims to shed light on the unexplored potential of ambroxol, particularly its applications in perinatal and neonatal care. We aim to offer valuable insights for healthcare professionals, researchers, and academics, thus presenting a positive perspective. Key scientific databases such as Google Scholar, PubMed, Cochrane Library, and Europe PMC were meticulously searched for relevant literature on ambroxol in perinatal and neonatal medicine. Gray literature was also surveyed, and the search encompassed all study designs and languages up to June 2024. Furthermore, citations and reference lists of relevant articles were scrutinized to identify additional pertinent literature. Ambroxol has demonstrated promising effects in preventing and managing respiratory distress syndrome (RDS). It can enter the placental circulation and rapidly build up in human lung tissue to a much greater extent than in plasma. It promotes fetal lung maturation, surfactant production, and alveolar expansion. Numerous studies have demonstrated the efficacy of antenatal and postnatal ambroxol in the prevention and treatment of RDS. Ambroxol has the potential to be administered intravenously or through nebulization, offering the hopeful possibility of reducing the high failure rate typically associated with non-invasive ventilation in extremely preterm infants, instilling a sense of hope and optimism about the potential of ambroxol. It also shows potential in treating bronchopulmonary dysplasia, meconium aspiration syndrome, and neonatal infections. Ambroxol has been observed to assist in the closure of patent ductus arteriosus in preterm infants by inhibiting vasodilator agents such as nitric oxide and exerting vasoconstrictive properties. However, these biological actions may raise concerns regarding the potential induction of pulmonary hypertension and an increased risk of necrotizing enterocolitis. The present scoping review also examines the clinical evidence and the potential of ambroxol in reducing the incidence of intraventricular hemorrhage in preterm infants. Ambroxol may have potential analgesic properties in managing neonatal pain, and as it can penetrate the blood-brain barrier, it suggests potential neuroprotective properties. These properties may encompass the modulation of microglial activation and the antagonistic impact on glutamate receptors. Ambroxol's attributes could contribute to a decreased susceptibility to neurological complications and have demonstrated anticonvulsant effects in preclinical studies. While low-to-moderate-quality evidence indicates potential applications of ambroxol in neonatal care, further research is needed to determine the drug's optimal dosing, timing, and safety profiles in this patient population. We need to investigate ambroxol's potential synergistic effects with antenatal steroids. Exploration is required to assess ambroxol's potential in reducing the high failure rate associated with non-invasive respiratory support for RDS. Lastly, comprehensive studies on the long-term neurodevelopmental outcomes of neonates exposed to ambroxol are essential., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Al-Abdi et al.)

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"., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

The authors hypothesize that particularly severely compromised and asphyctic term infants in need of resuscitation may benefit from delayed umbilical cord clamping (after several minutes). Although evidence is sparse, the underlying pathophysiological mechanisms support this assumption. For this review the authors have analyzed the available research. Based on these data they conclude that it may be unfavorable to immediately clamp the cord of asphyctic newborns (e.g., after shoulder dystocia) although recommended in current guidelines to provide quick neonatological support. Compression of the umbilical cord or thorax obstructs venous flow to the fetus more than arterial flow to the placenta. The fetus is consequently cut off from a supply of oxygenated, venous blood. This may cause not only hypoxemia and consecutive hypoxia during delivery but possibly also hypovolemia. Immediate cord clamping may aggravate the situation of the already compromised newborn, particularly if the cord is cut before the lungs are ventilated. By contrast, delayed cord clamping leads to fetoplacental transfusion of oxygenated venous blood, which may buffer an existing acidosis. Furthermore, it may enhance blood volume by up to 20%, leading to higher levels of various blood components, such as red and white blood cells, thrombocytes, mesenchymal stem cells, immunoglobulins, and iron. In addition, the resulting increase in pulmonary perfusion may compensate for an existing hypoxemia or hypoxia. Early cord clamping before lung perfusion reduces the preload of the left ventricle and hinders the establishment of sufficient circulation. Animal models and clinical trials support this opinion. The authors raise the question whether it would be better to resuscitate compromised newborns with intact umbilical cords. Obstetric and neonatal teams need to work even closer together to improve neonatal outcomes., Competing Interests: Conflict of Interest/Interessenkonflikt Maul: Expert consultant for PeriZert, expert consultant for insurance companies (Ecclesia, Interschaden) and various medical associations, mediation bodies, and courts; lectures for GE Medical, Milupa, Cook Medical, ITF Pharma, CSL Behring; congress organizer for WfM Ultraschall, Buxtehude, and congress organization for Jörg Eickeler, Düsseldorf; Functions: vice-president and regional chairman for Hamburg, Association of Leading Hospital Clinicians (VLK), Düsseldorf; chairman of the North German Society for Gynecology and Obstetrics. Ott: None. Kyvernitakis: None. Kribs: Speakerʼs fees from Chiesi, Medela, Vygon, Infektopharm. Berger: Milupa. Ehlen: None. Schmidtke: None. Rawnaq-Möllers: None. Patrick Stelzl has a part-time job agreement as consultant and speaker and is member of the Steering Committee in concerns of the LION (“Labour Induction Outcomes Network”) project for Angusta 25 μg tablets from Norgine Pharma GmbH. Rath: Lectures for CSL Behring, Nette, Ferring/ Maul: Fachgutachter für PeriZert, Fachgutachter für Versicherungen (Ecclesia, Interschaden) und verschiedene Ärztekammern, Schlichtungsstellen und Gerichte, Vorträge für GE Medical, Milupa, Cook Medical, ITF Pharma, CSL Behring; Kongressorganisator für WfM Ultraschall, Buxtehude, und Kongressorganisation Jörg Eickeler, Düsseldorf; Ämter: Vizepräsident und Landesvorsitzender Hamburg, Verband Leitender Krankenhausärzte (VLK), Düsseldorf, Vorsitzender der Norddeutschen Gesellschaft für Gynäkologie und Geburtshilfe. Ott: Keine. Kyvernitakis: Keine. Kribs: Vortragshonorare von Chiesi, Medela, Vygon, Infektopharm. Berger: Milupa. Ehlen: Keine. Schmidtke: Keine. Rawnaq-Möllers: Keine. Patrick Stelzl hat einen Teilzeitarbeitsvertrag als Berater und Sprecher und ist Mitglied des Steuerungskomitees für Belange des LION-(„Labour Induction Outcomes Network“-)Projekts im Zusammenhang mit Angusta 25 μg Tablettes von Norgine Pharma GmbH. Rath: Vorträge für CSL Behring, Nette, Ferring., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Objective: More 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 Design: Data 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., Results: In 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)., Conclusion: Infants of obese mothers were significantly more likely to have the diagnosis of HIE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Monaco-Brown, Munshi, Horgan, Gifford and Khalak.)

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.

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Perinatal Asphyxia (PA) is a leading cause of motor and neuropsychiatric disability associated with sustained oxidative stress, neuroinflammation, and cell death, affecting brain development. Based on a rat model of global PA, we investigated the neuroprotective effect of intranasally administered secretome, derived from human adipose mesenchymal stem cells (MSC-S), preconditioned with either deferoxamine (an hypoxia-mimetic) or TNF-α+IFN-γ (pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 °C for 21 min. Thereafter, 16 μL of MSC-S (containing 6 μg of protein derived from 2 × 10 5 preconditioned-MSC), or vehicle, were intranasally administered 2 h after birth to asphyxia-exposed and control rats, evaluated at postnatal day (P) 7. Alternatively, pups received a dose of either preconditioned MSC-S or vehicle, both at 2 h and P7, and were evaluated at P14, P30, and P60. The preconditioned MSC-S treatment (i) reversed asphyxia-induced oxidative stress in the hippocampus (oxidized/reduced glutathione); (ii) increased antioxidative Nuclear Erythroid 2-Related Factor 2 (NRF2) translocation; (iii) increased NQO1 antioxidant protein; (iv) reduced neuroinflammation (decreasing nuclearNF-κB/p65 levels and microglial reactivity); (v) decreased cleaved-caspase-3 cell-death; (vi) improved righting reflex, negative geotaxis, cliff aversion, locomotor activity, anxiety, motor coordination, and recognition memory. Overall, the study demonstrates that intranasal administration of preconditioned MSC-S is a novel therapeutic strategy that prevents the long-term effects of perinatal asphyxia.

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., Competing Interests: Declaration of competing interest All authors listed in this study entitled “Treadmill Running Attenuates Neonatal Hypoxia Induced Adult Depressive Symptoms and Promoted Hippocampal Neural Stem Cell Differentiation via Modulating AMPK-Mediated Mitochondrial Functions” have no conflict interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Hypoxic ischemic encephalopathy (HIE) is a serious condition which results in neonatal morbidity and mortality. Early prediction of HIE especially in the first six hours of birth leads to early treatment with better prognosis., Aim: The aim of this study was to compare the concentrations of leptin, adiponectin, and erythropoietin between normal neonates and those with HIE for the possible use of these markers for assessment of the degree of HIE and as markers for early prediction of HIE., Patients and Methods: This study was carried out on 50 appropriate for gestational age (AGA) neonates with HIE born in Tanta University Hospital during the period from June 2016 to March 2018 (Group I). This study also included 50 appropriate for gestational age (AGA) normal neonates not suffering from any complications and matched with group I in age and sex as a control group (Group II). For all neonates in both groups, the following were done: Complete prenatal, natal, and postnatal history, assessment of APGAR score at 5 and 10 minutes, complete clinical examination with special account on clinical evidence of encephalopathy including hypotonia, abnormal oculomotor or pupillary movements, weak or absent suckling, apnea, hyperpnea, or seizures, measurement of cord blood gases and measurement of serum erythropoietin, leptin and adiponectin levels by ELISA immediately after birth., Results: There were no significant differences between Group I and Group II regarding gestational age, male to female ratio, mode of delivery, and weight while there were significant differences regarding Apgar score at 1 and 5 minutes with significantly lower Apgar score at 1 and 5 minutes in group I compared with Group II. There were significantly lower cord blood PH and adiponectin level and significantly higher cord blood Leptin and erythropoietin in group I compared with group II. There were significant differences between cord blood adiponectin, leptin, erythropoietin, and PH in different degrees of HIE with significantly lower cord blood adiponectin and PH and significantly higher cord blood leptin and erythropoietin in severe degree of hypoxia compared with moderate degree and in moderate degree compared with mild degree of hypoxia. There was a significant positive correlation between cord blood erythropoietin and leptin and a significant negative correlation between cord blood erythropoietin and both adiponectin and PH in studied neonates with hypoxia. ROC curve showed that EPO had the best sensitivity and specificity followed by leptin then adiponectin while the PH had the least sensitivity and specificity as early predictors of hypoxic neonates., Conclusion and Recommendations: Neonates with HIE had lower cord blood PH and adiponectin levels and higher leptin and erythropoietin levels than normal healthy neonates at birth and during the early postnatal period. The significant differences between cord blood erythropoietin, leptin, and adiponectin between neonates with hypoxia compared with normal neonates may arouse our attention about the use of these markers in the cord blood as early predictors of neonatal HIE which can lead early treatment and subsequently better prognosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (Copyright © 2019 ISDN. Published by Elsevier Ltd. All rights reserved.)

The topic of neonatal hypoxia is of paramount importance to anyone who cares during pregnancy and childbirth. Modern medicine associates this pathology with severe problems in the prenatal period. Underlying diseases of the mother during pregnancy, her anamnesis of life are the leading causes of complications in the newborn. Nevertheless, patterns of fetal hypoxia and neonatal hypoxia, as well as mechanisms of hypoxic-ischemic encephalopathy in newborns, remains poorly known and require further research. This study is focused on finding risk factors related to the chronic fetal hypoxia and defining a group of signs for diagnosing neonatal hypoxia. The real data of 186 pregnant women at the gestation age from 12 to 38 weeks were analyzed. A methodology for discovering interesting associations in gestation course data is proposed. Technique for association rules mining and rules selection by the neonatal hypoxia under study is discussed. The rules suggest that a strong relationship exists between the specific sets of attributes and the diagnosis. As a result, we set up a profile of the pregnant woman with a high likelihood of hypoxia of the newborn that would be beneficial to medical professionals.

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., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (© 2018 S. Karger AG, Basel.)

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 H 2 O 2 (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 H 2 O 2 challenge led to a concentration-dependent increase in cell death (>fourfold after 0.25 mM of H 2 O 2 ) in CS cultures. In AS cultures, a significant increase in cell death was only observed after 0.5 mM of H 2 O 2 . At higher than 1 mM of H 2 O 2 (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 H 2 O 2 , 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 3 , in substantia nigra and neostriatum. One millimolar of H 2 0 2 increased the number of DAPI/TUNEL cells/mm 3 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 3 was decreased in AS compared to CS cultures, also by 1 mM of H 2 0 2 , both in CS and AS cultures, prevented by nicotinamide. In agreement, the number of MAP-2/TUNEL-positive cells/mm 3 was increased by 1 mM H 2 O 2 , both in CS (twofold) and AS (threefold) cultures, prevented by nicotinamide. The number of MAP-2/TH/TUNEL-positive cells/mm 3 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 H 2 O 2 produced a strong increase in the number of MAP-2/TUNEL-positive cells/mm 3 , both in CS (>2.9-fold) and AS (>fourfold), decreased by nicotinamide. In neocortex, H 2 O 2 increased the number of MAP-2/TUNEL-positive cells/mm 3 , 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 H 2 0 2 , both in CS and AS homogenates. The GSH/GSSG ratio was significantly decreased in AS, compared to CS cultures. One millimolar of H 2 O 2 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.

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.

Background: The relationship between interatrial communication, ductus arteriosus, and pulmonary flow in transposition of the great arteries and intact ventricular septum may help predict postnatal desaturation., Methods: Echocardiographic data of 45 fetuses with transposition of the great arteries and intact ventricular septum and 50 age-matched controls were retrospectively reviewed. Interatrial communication, left and right ventricular output, flow in the ductus arteriosus, as well as effective pulmonary flow were measured. Patients were divided into two groups on the basis of postnatal saturations: group 1 had saturations ⩽50% and group 2 >50%., Results: Of 45 fetuses, 13 (26.7%) were classified into group 1. Compared with fetuses in group 2, they had a smaller interatrial communication (2.9 versus 4.0 mm, p=0.004) and more retrograde diastolic flow in the ductus arteriosus (92 versus 23%, p=0.002). Both groups showed a significant decrease in ductal flow compared with controls. Patients in group 2 had a higher effective pulmonary flow compared with controls. There was a mild correlation between left ventricular output and size of the interatrial communication (Spearman's rank correlation 0.44)., Conclusion: A retrograde diastolic flow is present in most of the fetuses with postnatal desaturation. Fetuses with transposition of the great arteries have a lower flow through the ductus arteriosus compared with controls. Fetuses without restrictive foramen ovale have higher effective pulmonary flow. Peripheral pulmonary vasodilatation due to higher oxygen saturation in pulmonary arteries in the case of transposition of the great arteries could be one possible cause.

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 1 agonist), quinpirole (10 µM, a D 2 agonist) or sulpiride (10 μM, a D 2 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 2 receptors.

Our previous study together with other investigations have reported that neonatal hypoxia or ischemia induces long-term cognitive impairment, at least in part through brain inflammation and hypomyelination. However, the detailed mechanisms are not fully understood. Here, we used a rodent model of neonatal hypoxia by subjecting postnatal day 0 (P0) rat pups to systemic hypoxia (3.5 h). We found that neonatal hypoxia increased the glutamate content and initiated inflammatory responses at 4 h and 1 day after hypoxia, caused hypomyelination in the corpus callosum, and impaired hippocampus-dependent learning and memory when assessed 30-60 days after hypoxia. Interestingly, much of the hypoxia-induced brain damage was ameliorated by treatment with the ATP analogue 2',3'-0-(2,4,6-trinitrophenyl)-adenosine 5'-triphosphate (TNP-ATP; blocks all ionotropic P2X1-7 receptors), whereas treatment with pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; inhibits P2X1-3 and P2X5-7 receptors) was less neuroprotective. Our data indicated that activation of ionotropic ATP receptors might be partially, if not fully, involved in glutamate deregulation, neuroinflammation, hypomyelination, and cognitive dysfunction after neonatal hypoxia.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)