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Hypoxia-ischemia (HI) is a model of cerebral ischemia used to model neonatal hypoxia and to study brain damage. Interpreting the results of experiments that use HI rests partly on the assumption that only the brain suffers major damage. In this study, we demonstrate that HI also has adverse consequences on the heart. Both infarction scoring and measurements of troponin I indicate cardiac damage subsequent to HI. These results indicate that the effects of HI on the heart may confound the interpretation of experiments that have used HI to study neuroprotection or other aspects of brain damage.

BACKGROUND Hypoxic preconditioning (HPc) protects the neonatal brain in the setting of hypoxia-ischemia (HI). The mechanisms of protection may depend on activation of hypoxia inducible factor (HIF-1α). The present study sought to clarify the role of HIF-1α after HPc and HI. METHODS To induce HPc, HIF-1α knockout and wildtype mice were exposed to hypoxia at postnatal day 6. At day 7, the mice underwent HI. Brain injury was determined by histology. HIF-1α, downstream targets, and markers of cell death were measured by Western blot. RESULTS HPc protected the wildtype brain compared to wildtype without HPc, but did not protect the HIF-1α knockout brain. In wildtype, HIF-1α increased after hypoxia and after HI, but not with HPc. The HIF-1α knockout showed no change in HIF-1α after hypoxia, HI, or HPc/HI. After HI, spectrin 145/150 was higher in HIF-1α knockout, but after HPc/HI, it was higher in wildtype. LAMP2 was higher in wildtype early after HI, but not later. After HPc/HI, LAMP2 was higher in HIF-1α knockout. CONCLUSION These results indicate that HIF-1α is necessary for HPc protection in the neonatal brain, and may affect cell death after HI. Different death and repair mechanisms depend on the timing of HPc.

Despite its poor outcomes, therapeutic hypothermia (TH) is the current standard treatment for neonatal hypoxic-ischaemic encephalopathy (HIE). In this study, due to its antioxidant, anti-inflammatory, and antiapoptotic properties, the effectiveness of molecular hydrogen (H2) combined with TH was evaluated by means of neurological and histological assessments. Piglets were divided into three groups: hypoxic-ischaemic insult with normothermia (NT), insult with hypothermia (TH, 33.5 ± 0.5 °C), and insult with hypothermia with H2 ventilation (TH-H2, 2.1–2.7%). H2 ventilation and TH were administered for 24 h. After ventilator weaning, neurological assessment was performed every 6 h for 5 days. On day 5, the brains of the piglets were harvested for histopathological analysis. Regarding the neurological score, the piglets in the TH-H2 group consistently had the highest score from day 2 to 5 and showed a significantly higher neurological score from day 3 compared with the NT group. Most piglets in the TH-H2 group could walk at day 3 of recovery, whereas walking ability was delayed in the two other groups. The histological results revealed that TH-H2 tended to improve the status of cortical gray matter and subcortical white matter, with a considerable reduction in cell death. In this study, the combination of TH and H2 improved short-term neurological outcomes in neonatal hypoxic-ischaemic piglets.

Purpose To investigate if frequency-dependent contrasts using oscillating gradient diffusion MRI (dMRI) can detect hypoxia–ischemia (HI) -induced neurodegeneration in the neonatal mouse hippocampus. Methods Pulsed- and oscillating-gradient dMR images (at 50, 100, and 150 Hz) were acquired from postmortem fixed brains of mice exposed to neonatal HI using the Rice-Vanucci model. MRI data were acquired at 1, 4, and 8 days following HI, and compared with histological data from the same mice for in situ histological validation of the MRI findings. Results The rate of change of apparent diffusion coefficient with gradient frequency (ΔfADC) revealed unique layer-specific contrasts in the neonatal mouse hippocampus. ΔfADC measurements were found to show a significant decrease in response to neonatal HI injury, in the pyramidal (Py) and granule (GrDG) cell layers compared with contralateral regions. The areas of reduced intensity in the ΔfADC maps corresponded to regional neurodegeneration seen with H&E and Fluoro-Jade C stainings, indicating that alterations in ΔfADC contrasts are sensitive to early microstructural changes due to HI-induced neurodegeneration in the studied regions. Conclusion The findings show that the frequency-dependence of ADC measurements with oscillating-gradient dMRI can provide a sensitive contrast to detect HI-induced neurodegeneration in neuronal layers of the neonatal mouse hippocampus. Magn Reson Med 72:829–840, 2014. © 2013 Wiley Periodicals, Inc.

It is believed that neonatal hypoxia–ischemia (HI) brain injury causes neuron loss and brain functional defects. However, the effect of HI brain injury on dendritic development of the remaining pyramidal cells of the hippocampus and the reaction of contralateral hippocampal neurons require further studies. The Morris water maze and Golgi–Cox staining were used to evaluate the learning and memory and dendritic morphology of pyramidal cells. The results of Golgi–Cox staining showed CA1 pyramidal neurons of HI injury models with fewer bifurcations and shorter dendrite length than the naive control group. The density of dendritic spines of hippocampal CA1 pyramidal neurons was significantly lower in the HI brain injury group than in controls. With respect to hippocampal function, the HI brain injury group presented cognitive deficits in the reference memory task and probe trail. In the HI group, the pyramidal cells of left hippocampus that did not experienced ischemia but did experience hypoxia had more complex dendrites and higher density of spine than the HI injury side and control. The functional implementation of injured hippocampus might depend mainly on the hypertrophy of contralateral hippocampus after HI brain injury. Corticosterone can partially prevent the hippocampal pyramidal cells from HI injury and reduce the difference of the bilateral hippocampus pyramidal cells, but there was no improvement in learning and memory. © 2013 Wiley Periodicals, Inc.

Neonatal hypoxia-ischemia (HI) affects 60% of low birth weight infants and up to 40% of preterm births. Cell death and brain injury after HI have been shown to cause long-lasting behavioral deficits. By using a battery of behavioral tests on second generation 3-week-old rodents, we found that neonatal HI is associated with behavioral outcomes in the progeny of HI-affected parents. Our results suggest an epigenetic transfer mechanism of some of the neurological symptoms associated with neonatal HI. Elucidating the transfer of brain injury to the next generation after HI calls attention to the risks associated with HI injury and the need for proper treatment to reverse these effects. Assessing the devastating extent of HI's reach serves as a cautionary tale to the risks associated with neonatal HI, and provides an incentive to create improved therapeutic measures to treat HI.

Background: Neonatal encephalopathy induced by perinatal asphyxia is a serious condition associated with high mortality and morbidity. Inflammation after the insult is thought to contribute to brain injury. This inflammatory response to hypoxia-ischemia (HI) may not only occur in the brain but also in peripheral organs. The aim of the present study was to investigate the effect of neonatal HI on the inflammatory response in the liver in comparison to inflammation in the brain. Methods: HI was induced in P7 Wistar rats by unilateral carotid artery occlusion and hypoxia. Cytokine and chemokine mRNA levels were determined in the brain and liver by quantitative PCR. Polarization of brain macrophages to the M1/M2-like phenotype and infiltration of neutrophils were characterized by immunohistochemistry. Results: 3 h after HI, an upregulation of the proinflammatory cytokines TNF-α and IL-1β and anti-inflammatory IL-10 was observed in the ipsilateral hemisphere of the brain compared to mRNA levels in sham-operated animals. Additionally, cerebral CINC-1 and MCP-1 mRNA expressions were increased. We also observed increased numbers of macrophages/microglia of the M1-like phenotype as well as a small increase in granulocyte influx in the ipsilateral hemisphere. Conversely, in the liver 3 h after HI, a downregulation of TNF-α, IL-1β, and MCP-1 and a trend towards an upregulation of IL-10 were observed compared to mRNA levels of sham-operated animals. However, hepatic CINC-1 expression was increased compared to levels in sham-operated animals. Following systemic hypoxia only, no significant changes in the expression of TNF-α, CINC-1 or MCP-1 were observed in the liver compared to sham-operated littermates, except for an upregulation in hepatic IL-1β expression 3 h after hypoxia. Twenty-four hours after insult, cerebral ipsilateral TNF-α, MCP-1 and CINC-1 mRNA expression was still increased, together with an increase in TGF-β expression. Moreover, an increase in macrophages/microglia of the M1-like phenotype was observed together with the appearance of macrophages/microglia of the M2-like phenotype around the cerebral lesion as well as an increase in granulocyte influx in comparison to 3 h after HI. In the liver, 24 h after HI, cytokine and chemokine responses were similar to mRNA levels in sham-operated animals except for a decrease in IL-10 and MCP-1. Conclusion: We describe for the first time that brain damage following neonatal HI induces an early downregulation of the proinflammatory response in the liver. HI induces an early proinflammatory response in the brain with a concomitant increase in influx of neutrophils and polarization of macrophages/microglia to the M1-like phenotype starting at 3 h and increasing up to 24 h after HI. The inflammatory state of the brain changes after 24 h, with an increase in the anti-inflammatory cytokine TGF-β together with the appearance of macrophages/microglia of the M2-like phenotype. The downregulation of proinflammatory cytokines in the liver is not due to systemic hypoxia only, but is induced by the cerebral damage.

Therapeutic hypothermia in term infants with neonatal asphyxial encephalopathy has been shown to have beneficial effects in relation to neurodevelopmental outcome and survival. This paper is a critical appraisal of two studies, which compares and contrasts the methodology and findings, and incorporates a synthesis of findings with reflection on clinical practice.

Cerebro-costo-mandibular syndrome (CCMS) is a rare disorder characterized by multiple rib abnormalities, micrognathia described as Pierre-Robin sequence, and cerebral involvement. Appropriate management of respiratory distress immediately after birth is crucial to rescue these patients. A boy, having a mother with Pierre-Robin sequence and a sister with CCMS, was diagnosed prenatally with CCMS and successfully treated with ex utero intrapartum treatment (EXIT) at 36 weeks 6 days of gestation. EXIT would be an effective option for rescuing patients with prenatally diagnosed CCMS and preventing neonatal hypoxia.

Acute hypoxia at postnatal day (P) 10 is an accepted model of human neonatal hypoxia which results, among other consequences, in increased hippocampal excitability. Hypoxic–ischemic injury, which mimics stroke, has been shown to result in changes in connexins (Cxs), however, changes in Cxs have not been studied in the P10 hypoxia model. The aim of this study was to investigate changes in the hippocampal expression of three different connexins at consecutive developmental stages after acute hypoxia at P10 (10 min and 30 min after reoxygenation, P11, P14, P17, P29, and P45) as compared to sham manipulated pups. After acute hypoxia at P10, Cx30 protein levels were increased at 30 min after reoxygenation, at P11 and at P14, and then returned to control levels. Cx36 protein levels transiently decreased at P11 after acute hypoxia then returned to control levels. Cx43 protein levels did not change at any of the time points. Although changes in mRNA expression were observed during development for Cx30 only, acute hypoxia did not result in changes in mRNA expression of all these Cxs when compared to age matched controls suggesting that acute hypoxia induced posttranslational changes in protein expression.

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% N(2), 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.

Neonatal hypoxic ischemic injury (HII) is a devastating brain disease for which hypothermia is currently the only approved treatment. As new therapeutic interventions emerge there is a significant need for noninvasive objective quantification of the spatiotemporal lesion dynamics combined with precise information about lesion constituents (ischemic core and penumbra). These metrics are important for deciding treatment parameters (type, time, site, and dose) and for monitoring injury-therapy interactions. Such information provided ‘on-line’ in a timely fashion to the clinician could revolutionize clinical management. Like other spatiotemporal biological processes, video bioinformatics can assist objective monitoring of injury–therapy interactions. We have been studying the efficacy of various potential treatments in translational (rodent) HII models using magnetic resonance imaging (MRI). We have developed a novel computational tool, hierarchical region splitting (HRS) to rapidly identify ischemic lesion metrics. HRS detects similar lesion volumes compared to manual detection methods and is fast, robust, and reliable compared to other computational methods. HRS also provides additional information about the location, size, and evolution of the core and penumbra, which are difficult to ascertain with manual methods. This chapter summarizes the ability of HRS to identify lesion dynamics and ischemic core-penumbra evolution following neonatal HII. In addition, we demonstrate that HRS provides information about lesion dynamics following different therapies (e.g., hypothermia, stem cell implantation). Our findings show that computational analysis of MR images using HRS provides novel quantitative approaches that can be applied to clinical and translational stroke research using data mining of standard experimental and clinical MRI data.

Hypoxia is the most common cause of neonatal seizures and can lead to epilepsy, but the epileptogenic mechanisms are not yet understood. We have previously shown that hypoxia-induced seizures in the neonatal rat result in acutely decreased amplitudes and frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in hippocampal CA1 pyramidal neurons. In the current study, we asked whether such changes persist for several days following hypoxia-induced seizures. Similar to the acute findings, we observed decreased frequency and amplitudes of sIPSCs and decreased mIPSC amplitudes in CA1 pyramidal neurons at 3–5 days after hypoxia. However, in contrast to the acute findings, we observed no differences between hypoxia-treated and control groups in mIPSC frequency. Additionally, by 7 days after hypoxia, sIPSC amplitudes in the hypoxia group had recovered to control levels, but sIPSC frequency remained decreased. These data indicate that the persistently decreased sIPSC frequency result from decreased firing of presynaptic inhibitory interneurons, with only transient possible changes in postsynaptic responses to GABA release.

A participação de marcadores bioquímicos na avaliação de quadros de asfixia neonatal é cada vez mais relevante. A proteína S100B é de particular importância neste campo. O objetivo deste estudo foi procurar destacar a importância da proteína S100B na avaliação de recém-nascidos a termo com quadro de encefalopatia hipóxico-isquêmica, assim como correlacionar com outras substâncias que também participam do processo isquêmico. Foram analisados 21 casos de recém nascidos a termo que desenvolveram encefalopatia hipóxico-isquêmica no período de setembro de 2003 a outubro de 2004. Realizadas coletas no 1º e 4º dia de vida e dosadas, por método imunocitoquímico, a proteína S100B e o lactato. Observouse correlação positiva entre as duas substâncias, assim como quando comparadas entre si nas suas respectivas dosagens, obteve-se significância estatística. Biochemical markers have played an increasingly relevant role in the assessment of neonatal asphyxia. The S100B protein is particularly important in re s e a rch conducted in this field. The purpose of this study was to underline the importance of the S100B protein in the assessment of term newborn infants with hypoxic-ischemic encephalopathy, as well as to relate it to other substances also involved in the ischemic p rocess. An assessment was made from September 2003 to October 2004 of 21 term newborn infants who developed hypoxic-ischemic encephalopathy. Samples were collected on the 1st and 4th day of life and S100B p rotein and lactate concentrations were calculated using the immune cytochemical method. A positive relationship was found between the two substances. Additionally, a comparison between the two substances showed a statistically significant correlation.

OBJETIVOS: analisar os resultados obstétricos e perinatais de 26 casos de síndrome de aspiração de mecônio (SAM) MÉTODOS: realizou-se revisão dos prontuários de 26 recém-nascidos (RN) com diagnóstico de SAM. Os casos foram estudados em função da média de permanência do RN na UTIN e das principais complicações maternas e neonatais, correlacionando-as entre si. RESULTADOS: dezoito conceptos nasceram no HG-FUCS e 8 fora; no período citado, ocorreram 3.976 nascimentos no HG-FUCS, incidência de SAM de 0,45%. Dos 18 casos estudados, 9 nasceram pela via vaginal; o peso ao nascimento foi >2.500 g em dezesseis casos. Mecônio leve ocorreu em 50%, semelhante ao espesso. O Apgar no 1º minuto foi >7 em 3 casos (16,7%), entre 4 e 6, em 7 casos (38,9%), e entre 0 e 3, em 8 casos (44,4%). No 5º minuto, sete RN permaneceram deprimidos. A principal complicação neonatal foi anoxia (36% dos casos). A taxa de óbito neonatal foi de 7,7%. A internação média na UTIN foi de 19,9 dias. CONCLUSÃO: a SAM constitui grave entidade clínica neonatal, relacionando-se com altas taxas de mortalidade neonatal, mecônio espesso em pelo menos a metade dos casos e nascimento de fetos deprimidos na sua maioria.PURPOSE: to analyze obstetrical and perinatal data in 26 cases of meconium aspiration syndrome (MAS). METHODS: a retrospective review was performed in 26 newborn records diagnosed with meconium aspiration syndrome. Patients were studied emphasizing average days in neonatal intensive care unit and main maternal findings and neonatal complications, correlating them with each other. RESULTS: Eighteen babies were delivered at GH-CSUF and eight out of this hospital. At this time 3,976 deliveries occurred at GH-CSUF, with an incidence of MAS of 0.45%. Nine of 18 babies were born by vaginal delivery; weight was >2,500 g in 16 cases. One-minute Apgar score was >7 in three cases (16.7%), between 4 and 6 in seven cases (38.9%), and between 0 and 3, in eight cases (44.4%). At 5 minutes, seven babies remained

Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process.

WOS:000346149200005 PubMed: 25491683 Background. Neonatal hypoxic-ischemic (HI) injury has been considered to have acute and long term deleterious effects on many tissues, including the peripheral nerve. Objectives. In this study, the effects of a tumor necrosis factor-alpha (TNF-alpha) inhibitor (etanercept) on peripheral nerve damage and the ultrastructure of the sciatic nerve and gastrocnemius muscle in rats exposed to HI during the neonatal period were examined. Material and Methods. In this study, 45 seven-day-old rats were used and they were divided into three groups. The right carotid arteries of the rats in the saline and etanercept groups were ligated and put in a hypoxia chamber containing 8% oxygen for two hours. Just after hypoxia, the etanercept group was given 10 mg/kg etanercept, but the saline group had only saline intraperitoneally. The sham group rats' carotid arteries were not ligated or put in hypoxia. The amplitude, area and latency of sciatic nerve compound motor action potential (CMAP), which mainly reflects axonopathy and myelinopathy, were measured using standard techniques in the seventeenth week following the HI. Sciatic nerve and gastrocnemius muscle were evaluated with a transmission electron microscope, and grading for myelin sheath damage was done to all groups. Results. Neuropathy was seen in rats after HI. While treatment with etanercept showed a protective effect for the axons of sciatic nerve, demyelination could not be recovered with etanercept. Conclusions. This study is the first in literature to show a partial interruption of the signal through the peripheral nerve fibers caused by axonal and myelin dysfunction continuation in rats exposed to HI after birth, in the 17th week

Unlike in the adult, the perinatal/neonatal pulmonary vascular response to chronic hypoxic exposure is much more rapid and severe and results in the failure of the fetal/neonatal circulation to adapt to a response supporting postnatal life. This, in turn, contributes to the pathogenesis of persistent pulmonary hypertension of the newborn and pulmonary vascular dysfunction later in life. As such, furthering our understanding of the mechanisms and pathology of perinatal/neonatal pulmonary hypertension development leading to adult diseases is important to support more effective therapeutic target identification.

Neonatal hypoxia increases aldosterone production and plasma lipids. Because fatty acids can inhibit aldosterone synthesis, we hypothesized that increases in plasma lipids restrain aldosteronogenesis in the hypoxic neonate. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Plasma was analyzed for lipid content, and steroidogenesis was studied in dispersed whole adrenal glands untreated and treated to wash away lipids. Hypoxia increased plasma cholesterol, triglycerides, and nonesterified fatty acids in the suckling neonatal rat only. Washing away lipids increased aldosterone production in cells from 7-day-old rats exposed to hypoxia, but not in cells from normoxic 7-day-old rats or from normoxic or hypoxic 35-day-old rats. Addition of oleic or linolenic acid to washed cells inhibited both aldosterone and corticosterone production, although cells from hypoxic 7-day-old rats were less sensitive. We conclude that hypoxia induces hyperlipidemia in the suckling neonate and that elevated nonesterified fatty acids inhibit aldosteronogenesis.

Seizures after neonatal hypoxia are difficult to treat. A recent antiepileptic safety and dose-finding study examined phenobarbital plus bumetanide, but was stopped owing to apparent futility and increased risk of hearing loss. However, this decision could have been overcautious: 0.2 mg/kg bumetanide reduced seizure burden, and might not have increased hearing loss.

BACKGROUND The aim of this study is to determine carnitine levels in hypoxic-ischemiac neonates. METHODS Total and free carnitine levels were measured in 20 normal term neonates and 20 term neonates who were diagnosed as hypoxia-ischemia. RESULTS Both total carnitine levels (43.7 +/- 10.0 microg/dl vice 27.8 +/- 11.8 microg/dl, p

BackgroundHypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. Hypothermia is effective but does not provide complete neuroprotection, prompting a search for adjunctive therapies. Erythropoietin (Epo) has been shown to be beneficial in several models of neonatal HI. This study examines combination hypothermia and treatment with erythropoietin in neonatal rat HI.MethodsRats at postnatal day 7 were subjected to HI (Vannucci model) and randomized into four groups: no treatment, hypothermia alone, Epo alone, or hypothermia and Epo. Epo (1,000 U/kg) was administered in three doses: immediately following HI, and 24 h and 1 wk later. Hypothermia consisted of whole-body cooling for 8 h. At 2 and 6 wk following HI, sensorimotor function was assessed via cylinder-rearing test and brain damage by injury scoring. Sham-treated animals not subjected to HI were also studied.ResultsDifferences between experimental groups, except for Epo treatment on histopathological outcome in males, were not statistically significant, and combined therapy had no adverse effects.ConclusionNo significant benefit was observed from treatment with either hypothermia or combination therapy. Future studies may require older animals, a wider range of functional assays, and postinsult assessment of injury severity to identify only moderately damaged animals for targeted therapy.

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.

The NaKCl cotransporter NKCC1 facilitates intraneuronal chloride accumulation in the developing brain. Bumetanide, a clinically available diuretic, inhibits this chloride transporter, and augments the antiepileptic effects of phenobarbital in neonatal rodents. In a neonatal cerebral hypoxia-ischemia (HI) model, elicited by right carotid ligation, followed by 90 min 8% O2 exposure in 7-day-old(P7) rats, phenobarbital(PB) increases the neuroprotective efficacy of hypothermia. We evaluated whether bumetanide influenced the neuroprotective efficacy of combination treatment with PB and hypothermia(HT). P7 rats underwent HI lesioning; 15 min later, all received PB (30 mg/kg). 10 min later, half received bumetanide (10 mg/kg, PB-HT+BUM) and half received saline (PB-HT+SAL). One hour after HI, all were cooled (30°C, 3h). Contralateral forepaw sensorimotor function and brain damage were evaluated 1 to 4 weeks later. Forepaw functional measures were close to normal in the PB-HT+BUM group, while deficits persisted in PB-HT+SAL controls; there were corresponding reductions in right cerebral hemisphere damage (at P35, % damage: PB-HT+BUM, 21±16 versus 38±20 in controls). These results provide evidence that NKCC1 inhibition amplifies phenobarbital bioactivity in the immature brain, and suggest that co-administration of phenobarbital and bumetanide may represent a clinically feasible therapy to augment the neuroprotective efficacy of therapeutic hypothermia in asphyxiated neonates.

Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

Hypoxia-ischemia (HI; concurrent oxygen/blood deficiency) and associated encephalopathy represent a common cause of neurological injury in premature/low-birth-weight infants and term infants with birth complications. Resulting behavioral impairments include cognitive and/or sensory processing deficits, as well as language disabilities, and clinical evidence shows that male infants with HI exhibit more severe cognitive deficits compared to females with equivalent injury. Evidence also demonstrates activation of sex-dependent apoptotic pathways following HI events, with males preferentially activating a caspase-independent cascade of cell death and females preferentially activating a caspase-dependent cascade following neonatal hypoxic and/or ischemic insults. Based on these combined data, the ‘female protection’ following HI injury may reflect the endogenous X-linked inhibitor of apoptosis (XIAP), which effectively binds effector caspases and halts downstream cleavage of effector caspases (thus reducing cell death). To test this theory, the current study utilized neonatal injections of vehicle or embelin (a small molecule inhibitor of XIAP) in male and female rats with or without induced HI injury on postnatal day 7 (P7). Subsequent behavioral testing using a clinically relevant task revealed that the inhibition of XIAP exacerbated HI-induced persistent behavioral deficits in females, with no effect on HI males. These results support sex differences in mechanisms of cell death following early HI injuries, and suggest a potential clinical benefit from the development of sex-specific neuroprotectants for the treatment of HI.

OBJECTIVE. The findings of hypoxia in the term neonate are unique; neonatal brain imaging findings differ from those of older children. Evaluation of neonatal brain images for signs of hypoxic injury requires attention to a specific set of signs.CONCLUSION. Imaging findings in term neonates must be assessed according to different rules from those used in other age groups. Four major signs are proposed as a means of facilitating the diagnosis of hypoxia in the neonate.

Hypoxic-ischemic brain injury is often delayed and involves both apoptotic and immunoregulatory mechanisms. In this study, we used a neonatal model of hypoxia-ischemia to examine the effect of the mixed lineage kinase (MLK) inhibitor CEP-1347 on brain damage, apoptosis and inflammation. The tissue volume loss was reduced by 28% (p = 0.019) in CEP-1347-treated versus vehicle-treated rats and CEP-1347 significantly attenuated microgliosis at 7 days (p = 0.038). CEP-1347 decreased TUNEL-positive staining as well as cleaved caspase 3 immunoreactivity. CEP-1347 did not affect the expression of pro-inflammatory cytokines IL-1β, IL-6 and MCP-1, nor did it affect the expression of OX-42 (CR3) and OX-18 (MHC I) 24 h after the insult. In conclusion, the MLK inhibitor CEP-1347 has protective effects in a neonatal rat model of hypoxia-ischemia, which is mainly related to reduced apoptosis.