Perinatal Hypoxia-ischemia Research Articles

Distinctive sleep problems in children with perinatal moderate or mild hypoxic-ischemia

Extensive studies focus on the cognitive and motor impairments after perinatal hypoxic-ischemia (HI). Sleep problems, although reported to be associated with cerebral palsy (CP), are often overlooked in non-severe HI patients. Here, by investigating the sleep qualities of children with different degrees of HI, we discovered that sleep initiation and maintenance, sleep-related breathing problems, or circadian rhythmic issues were highly associated with children of moderate or mild HI, respectively. Follow-up MRI studies in 2-year old patients showed that periventricular white matter lesions including periventricular leukomalacia (PVL) were prevalent in moderate, but not mild, HI children. In contrast, the occurrence of pineal cysts had a high risk in children with mild HI. Our study provides novel insights into the mechanisms of distinctive sleep problems associated with children of different degrees of HI, and therefore sheds light on the studies of targeted therapeutic treatments for sleep disorders in children who suffer from HI.

Immediate Remote Ischemic Postconditioning Reduces Brain Nitrotyrosine Formation in a Piglet Asphyxia Model

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention that could be administered as an alternative to cooling in cases of perinatal hypoxia-ischemia (HI). In the current study we hypothesized that RIPostC in the piglet model of birth asphyxia confers protection by reducing nitrosative stress and subsequent nitrotyrosine formation, as well as having an effect on glial immunoreactivity. Postnatal day 1 (P1) piglets underwent HI brain injury and were randomised to HI (control) or HI + RIPostC. Immunohistochemistry assessment 48 hours after HI revealed a significant decrease in brain nitrotyrosine deposits in the RIPostC-treated group (p = 0.02). This was accompanied by a significant increase in eNOS expression (p < 0.0001) and decrease in iNOS (p = 0.010), with no alteration in nNOS activity. Interestingly, RIPostC treatment was associated with a significant increase in GFAP (p = 0.002) and IBA1 (p = 0.006), markers of astroglial and microglial activity, respectively. The current study demonstrates a beneficial effect of RIPostC therapy in the preclinical piglet model of neonatal asphyxia, which appears to be mediated by modulation of nitrosative stress, despite glial activation.

Temporal progression of evoked field potentials in neocortical slices after unilateral hypoxia–ischemia in perinatal rats: Correlation with cortical epileptogenesis

Infarcts of the neonatal cerebral cortex can lead to progressive epilepsy, which is characterized by time-dependent increases in seizure frequency after the infarct and by shifts in seizure-onset zones from focal to multi-focal. Using a rat model of unilateral perinatal hypoxia–ischemia (PHI), where long-term seizure monitoring had previously demonstrated progressive epilepsy, evoked field potentials (EFPs) were recorded in layers II/III of coronal neocortical slices to analyze the underlying time-dependent, network-level alterations ipsilateral vs. contralateral to the infarct. At 3weeks after PHI, EFPs ipsilateral to the infarct were normal in artificial cerebrospinal fluid (ACSF); however, after blocking GABAA receptors with bicuculline methiodide (BMI, 30μM), the slices with an infarct were more hyperexcitable than slices without an infarct. At 3weeks, contralateral PHI slices had responses indistinguishable from controls. Six months after PHI in normal ACSF, both ipsi- and contralateral slices from rats with cortical infarcts showed prolonged afterdischarges, which were only slightly augmented in BMI. These data suggest that the early changes after PHI are localized to the ipsilateral infarcted cortex and masked by GABA-mediated inhibition; however, after 6months, progressive epileptogenesis results in generation of robust bilateral hyperexcitability. Because these afterdischarges were only slightly prolonged by BMI, a time-dependent reduction of GABAergic transmission is hypothesized to contribute to the pronounced hyperexcitability at 6months. These changes in the EFPs coincide with the seizure semiology of the epilepsy and therefore offer an opportunity to study the mechanisms underlying this form of progressive pediatric epilepsy.

Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats.

Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia.

Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain.

Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl- extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and β-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca2+-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia.

Ischemic injury suppresses hypoxia-induced electrographic seizures and the background EEG in a rat model of perinatal hypoxic-ischemic encephalopathy.

The relationship among neonatal seizures, abnormalities of the electroencephalogram (EEG), brain injury, and long-term neurological outcome (e.g., epilepsy) remains controversial. The effects of hypoxia alone (Ha) and hypoxia-ischemia (HI) were studied in neonatal rats at postnatal day 7; both models generate EEG seizures during the 2-h hypoxia treatment, but only HI causes an infarct with severe neuronal degeneration. Single-channel, differential recordings of acute EEG seizures and background suppression were recorded with a novel miniature telemetry device during the hypoxia treatment and analyzed quantitatively. The waveforms of electrographic seizures (and their behavioral correlates) appeared virtually identical in both models and were identified as discrete events with high power in the traditional delta (0.1-4 Hz) and/or alpha (8-12 Hz) bands. Although the EEG patterns during seizures were similar in Ha- and HI-treated animals at the beginning of the hypoxic insult, Ha caused a more severe electrographic seizure profile than HI near the end. Analyses of power spectral density and seizure frequency profiles indicated that the electrographic seizures progressively increased during the 2-h Ha treatment, while HI led to a progressive decrease in the seizures with significant suppression of the EEG background. These data show that 1) the hypoxia component of these two models drives the seizures; 2) the seizures during Ha are substantially more robust than those during HI, possibly because ongoing neuronal damage blunts the electrographic activity; and 3) a progressive decrease in background EEG, rather than the presence of electrographic seizures, indicates neuronal degeneration during perinatal HI.

Dysregulation of FMRP/mTOR Signaling Cascade in Hypoxic-Ischemic Injury of Premature Human Brain.

In this study the authors investigated whether dysregulation of the fragile X mental retardation protein and mammalian target of rapamycin signaling cascade can have a role in the pathogenesis of encephalopathy of prematurity following perinatal hypoxia-ischemia. The authors examined the brain tissue of newborns with encephalopathy and compared it to age-matched controls with normal brain development and adults. In normal controls, the fragile X mental retardation protein expression in cortical gray matter spiked 4-fold during 36-39 gestational weeks compared to the adult, with a concomitant suppression of p70S6K and S6. In encephalopathy cases, the developmental spike of fragile X mental retardation protein was not observed, and fragile X mental retardation protein levels remained significantly lower than in normal controls. Importantly, this fragile X mental retardation protein downregulation was followed by a significant overexpression of p70S6K and S6. These novel findings thus suggest that premature hypoxic-ischemic brain injury can affect the fragile X mental retardation protein/mammalian target of rapamycin pathway, as otherwise observed in inherited syndromes of cognitive disability and autism spectrum disorders.

Non-epileptic phenomena in hypoxic-ischemic encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is a clinical syndrome typically described in newborns after a period of intrapartum or perinatal hypoxia-ischemia (HI) [1]. The acute neurological manifestations of HIE have been well described [1,2] and are characterized by clinical evidence of diffuse cerebral dysfunction; impaired brainstem function, autonomic dysregulation, various abnormalities in mental state, epileptic seizures, and, in addition to tone and other motor abnormalities, non-epileptic movements i.e. myoclonus and tremors. The severity of the phenotype is dependent on the degree of cerebral insult, extent of subsequent injury incurred; with some correlation with outcome [1–4]. Because of the wide variety and often changing signs and symptoms post HI, coupled with the numerous co-morbid metabolic and systemic problems and the frequent occurrence of seizures which can be very difficult to differentiate clinically, this article will concentrate solely on describing the hyperkinetic non-epileptic movement disorder observed following transient HI in the term newborn.

Neuronal death after perinatal cerebral hypoxia-ischemia: Focus on autophagy—mediated cell death

Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long-term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia.

66: Temperature Control During Transport in Infants with Evidence of Perinatal Hypoxia-Ischemia Referred for Possible Cooling: A QI Study

In our tertiary center all infants with evidence of perinatal hypoxia-ischemia are outborn and transported for assessment of level of encephalopathy and need for cooling. Temperature monitoring during transport is a central and challenging component of their management. Given the lack of consensus on whether therapeutic hypothermia should be initiated outside the NICU, the choice of the target temperature is usually made by the neonatologist responsible for the transport. To evaluate the effectiveness of temperature control during transport in infants referred to our tertiary center. From June 2012 to June 2014 medical records of infants with GA ≥36 weeks, birth weight ≥1800 g and <6 h of life at time of referral for possible cooling were reviewed. Data on demographics, severity of fetal acidemia, presence of perinatal events, ages at referral call and NICU admission, assessment on the level of encephalopathy, and temperature at arrival of transport team and admission to our NICU were collected. A total of 131 eligible infants were transported. Temperature monitoring and recording was variable. There was no recorded temperature in 7% of patients at the referring centers and 1.5% at NICU admission. Several different sites were used: axillary, rectal, or esophageal. Normothermia (36–37°C) was recommended in 84% of the cases with recorded temperatures of 36.4±0.9°C at referring center and 36.1±0.9°C at NICU admission. Infants submitted to passive cooling had temperatures of 34.6±1.5°C and 34.2±1.1°C at referring centers and NICU admission, respectively. There were a large proportion of neonates with temperatures outside the desired range (Figure 1). The level of encephalopathy was mostly assessed by the transport nurse (96%), using neurological exam in all cases. At admission 73 infants (56.1%) had either a normal / Sarnat I neurological exam. Five of the 21 infants submitted to passive cooling (24%) had a normal / Sarnat I exam at admission. Two cases of overcooling were observed in the passive cooling (5%) and six cases of overheating (4.5%) in the normal temperature groups. Current temperature monitoring and control of infants with evidence of hypoxia-ischemia transported to our center is sub-optimal and requires the development and implementation of a well defined protocol.

Flaxseed mitigates brain mass loss, improving motor hyperactivity and spatial memory, in a rodent model of neonatal hypoxic-ischemic encephalopathy

Neonatal hypoxic-ischemic (HI) encephalopathy is a major cause of perinatal morbimortality. There is growing evidence that n-3 polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), attenuate brain injury. This study aimed to investigate the possible neuroprotective effect of maternal intake of flaxseed, rich in DHA׳s precursor α-linolenic acid, in the young male offspring subjected to perinatal HI. Wistar rats were divided in six groups, according to maternal diet and offspring treatment at day 7: Control HI (CHI) and Flaxseed HI (FHI); Control Sham and Flaxseed Sham; Control Control and Flaxseed Control. Flaxseed diet increased offspring׳s hippocampal DHA content and lowered depressive behavior. CHI pups presented brain mass loss, motor hyperactivity and poor spatial memory, which were improved in FHI rats. Maternal flaxseed intake may prevent depressive symptoms in the offspring and promote neuroprotective effects, in the context of perinatal HI, improving brain injury and its cognitive and behavioral impairments.

Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia.

Perinatal hypoxia-ischemia is a major cause of striatal injury and may lead to cerebral palsy. This study investigated whether delayed administration of bone marrow-derived mesenchymal stem cells (MSCs), at one week after neonatal rat hypoxia-ischemia, was neurorestorative of striatal medium-spiny projection neurons and improved motor function. The effect of a subcutaneous injection of a high-dose, or a low-dose, of MSCs was investigated in stereological studies. Postnatal day (PN) 7 pups were subjected to hypoxia-ischemia. At PN14, pups received treatment with either MSCs or diluent. A subset of high-dose pups, and their diluent control pups, were also injected intraperitoneally with bromodeoxyuridine (BrdU), every 24h, on PN15, PN16 and PN17. This permitted tracking of the migration and survival of neuroblasts originating from the subventricular zone into the adjacent injured striatum. Pups were euthanized on PN21 and the absolute number of striatal medium-spiny projection neurons was measured after immunostaining for DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32), double immunostaining for BrdU and DARPP-32, and after cresyl violet staining alone. The absolute number of striatal immunostained calretinin interneurons was also measured. There was a statistically significant increase in the absolute number of DARPP-32-positive, BrdU/DARPP-32-positive, and cresyl violet-stained striatal medium-spiny projection neurons, and fewer striatal calretinin interneurons, in the high-dose mesenchymal stem cell (MSC) group compared to their diluent counterparts. A high-dose of MSCs restored the absolute number of these neurons to normal uninjured levels, when compared with previous stereological data on the absolute number of cresyl violet-stained striatal medium-spiny projection neurons in the normal uninjured brain. For the low-dose experiment, in which cresyl violet-stained striatal medium-spiny neurons alone were measured, there was a lower statistically significant increase in their absolute number in the MSC group compared to their diluent controls. Investigation of behavior in another cohort of animals showed that delayed administration of a high-dose of bone marrow-derived MSCs, at one week after neonatal rat hypoxia-ischemia, improved motor function on the cylinder test. Thus, delayed therapy with a high- or low-dose of adult MSCs, at one week after injury, is effective in restoring the loss of striatal medium-spiny projection neurons after neonatal rat hypoxia-ischemia and a high-dose of MSCs improved motor function.

The Neonatal Brain Is Not Protected by Osteopontin Peptide Treatment after Hypoxia-Ischemia

Neonatal encephalopathy due to perinatal hypoxia-ischemia (HI) is a severe condition, and current treatment options are limited. Expression of endogenous osteopontin (OPN), a multifunction glycoprotein, is strongly upregulated in the brain after neonatal HI. Intracerebrally administered OPN has been shown to be neuroprotective following experimental neonatal HI and adult stroke. In the present study, we determined whether intranasal, intraperitoneal or intracerebral treatment with a smaller TAT-OPN peptide is neuroprotective in neonatal mice with HI brain damage. The TAT-OPN peptide exerts bioactivity as it was as potent as full-length OPN in inducing cell adhesion in an in vitro adhesion assay. Intranasal administration of TAT-OPN peptide immediately after HI (T0) or in a repetitive treatment schedule of T0, 3 h, day (D) 1, 2 and 3 after HI did not protect cerebral gray or white matter after HI. Intraperitoneal TAT-OPN treatment at T0 or in two extended treatment schedules (D5, 7, 9, 11, 13, 15 after HI or T0, D1, 3, 5, 7, 9, 11, 13 and 15 after HI) did not result in neuroprotection either. Moreover, no functional improvement (cylinder rearing test and adhesive removal task) was observed following TAT-OPN treatment in any of the intraperitoneal treatment schedules. We validated that the TAT-OPN peptide reached the brain after intranasal or intraperitoneal administration by using an HIV-TAT staining. Finally, also intracerebral administration of the TAT-OPN peptide 1 h after HI did not reduce cerebral damage. Our data show that administration of the TAT-OPN peptide did not exert neuroprotective effects on neonatal HI-induced brain injury or sensorimotor behavioral deficits.

Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets

The severity of perinatal hypoxia-ischemia and the delay in initiating therapeutic hypothermia limit the efficacy of hypothermia. After hypoxia-ischemia in neonatal piglets, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been found to contribute to oxidative stress at 3 h of reoxygenation and to eventual neurodegeneration. We tested whether early administration of a 20-HETE synthesis inhibitor after reoxygenation augments neuroprotection with 3-hour delayed hypothermia. In two hypothermic groups, whole body cooling from 38.5 to 34°C was initiated 3 h after hypoxia-ischemia. Rewarming occurred from 20 to 24 h; then anesthesia was discontinued. One hypothermic group received a 20-HETE inhibitor at 5 min after reoxygenation. A sham-operated group and another hypoxia-ischemia group remained normothermic. At 10 days of recovery, resuscitated piglets with delayed hypothermia alone had significantly greater viable neuronal density in the putamen, caudate nucleus, sensorimotor cortex, CA3 hippocampus, and thalamus than did piglets with normothermic recovery, but the values remained less than those in the sham-operated group. In piglets administered the 20-HETE inhibitor before hypothermia, the density of viable neurons in the putamen, cortex and thalamus was significantly greater than in the group with hypothermia alone. Cytochrome P450 4A, which can synthesize 20-HETE, was expressed in piglet neurons in these regions. We conclude that early treatment with a 20-HETE inhibitor enhances the therapeutic benefit of delayed hypothermia in protecting neurons in brain regions known to be particularly vulnerable to hypoxia-ischemia in term newborns.

Therapeutic hypothermia achieves neuroprotection via a decrease in acetylcholine with a concurrent increase in carnitine in the neonatal hypoxia-ischemia.

Although therapeutic hypothermia is known to improve neurologic outcomes after perinatal cerebral hypoxia-ischemia, etiology remains unknown. To decipher the mechanisms whereby hypothermia regulates metabolic dynamics in different brain regions, we used a two-step approach: a metabolomics to target metabolic pathways responding to cooling, and a quantitative imaging mass spectrometry to reveal spatial alterations in targeted metabolites in the brain. Seven-day postnatal rats underwent the permanent ligation of the left common carotid artery followed by exposure to 8% O2 for 2.5 hours. The pups were returned to normoxic conditions at either 38°C or 30°C for 3 hours. The brain metabolic states were rapidly fixed using in situ freezing. The profiling of 107 metabolites showed that hypothermia diminishes the carbon biomass related to acetyl moieties, such as pyruvate and acetyl-CoA; conversely, it increases deacetylated metabolites, such as carnitine and choline. Quantitative imaging mass spectrometry demarcated that hypothermia diminishes the acetylcholine contents specifically in hippocampus and amygdala. Such decreases were associated with an inverse increase in carnitine in the same anatomic regions. These findings imply that hypothermia achieves its neuroprotective effects by mediating the cellular acetylation status through a coordinated suppression of acetyl-CoA, which resides in metabolic junctions of glycolysis, amino-acid catabolism, and ketolysis.

Hypothermic neuroprotection is associated with recovery of spectral edge frequency after asphyxia in preterm fetal sheep.

Electroencephalographic recovery is predictive of outcome after perinatal hypoxia-ischemia, but it is unknown whether early changes in electroencephalographic can predict the response to therapeutic hypothermia in the preterm brain. 0.7 gestation fetal sheep received umbilical cord occlusion or sham occlusion for 25 minutes, followed by sham hypothermia or whole-body cooling started either 30 minutes or 5 hours after occlusion and continued for 72 hours. Early but not delayed hypothermia reduced neuronal loss and microglial induction in the striatum, with faster recovery of spectral edge frequency, reduced seizure burden, and less suppression of electroencephalographic amplitude (P<0.05). Recovery of higher electroencephalographic frequencies may be a biomarker of effective hypothermic neuroprotection in the preterm-equivalent brain.

Functional Polymorphism Of The Interleukin-1beta Gene Promoter Is Associated With Increased Risk For Cerebral Palsy In Mexican Children With Perinatal Hypoxia-Ischemia Antecedents

Background: The genetic polymorphism that contributes to the development of infantile cerebral palsy (ICP) after a perinatal hypoxia-ischemia episode remains unknown. Because IL-1? plays a crucial role in the pathogenesis of hypoxic-ischemic encephalopathy, we evaluated whether the interleukin 1, beta (IL-1?) promoter single-nucleotide polymorphisms (SNPs) correlate with the increased risk for ICP following a perinatal hypoxia-ischemia. We assessed -511 C>T and -31 T>C IL-1? SNPs known to be involved in IL-1? expression. Methods: Genomic DNAs were purified from peripheral leukocytes of 48 ICP patients and 57 healthy children, amplified by using polymerase chain reaction (PCR), and then analyzed by using the restriction-fragment-length polymorphism technique. The SNP genotypes were established using real time PCR and validated with the restriction enzymes AvaI for -511C-T and AluI for -31T-C in Restriction fragment length polymorphism (RFLP) analysis. Results: Allelic frequencies of the IL-1? -511 T carrier in patients were significantly higher when compared with those determined in healthy controls. The -511 TT genotype frequency showed a significant difference [odds ratio = 2.4 (95% confidence interval 1.7-3.5), P = 0.0001, and relative risk = 1.5 (95% confidence interval 1.3-1.7)] between patients and controls. The SNP frequencies of -31 genotypes in cerebral palsy patients were not statistically different from the healthy controls. Conclusions: Mexican children with the homozygous TT mutation in the -511 SNP of the IL-1? gene promoter are 2.4 times more susceptible to develop ICP after suffering perinatal asphyxia than healthy children and the presence of a single allele C could be considered as a genetic protective factor.

Alteration in rectification of potassium channels in perinatal hypoxia ischemia brain damage.

Oligodendrocyte progenitor cells (OPCs) are susceptible to perinatal hypoxia ischemia brain damage (HIBD), which results in infant cerebral palsy due to the effects on myelination. The origin of OPC vulnerability in HIBD, however, remains controversial. In this study, we defined the HIBD punctate lesions by MRI diffuse excessive high signal intensity (DEHSI) in postnatal 7-day-old rats. The electrophysiological functional properties of OPCs in HIBD were recorded by patch-clamp in acute cerebral cortex slices. The slices were intracellularly injected with Lucifer yellow and immunohistochemically labeled with NG2 antibody to identify local OPCs. Passive membrane properties and K(+) channel functions in OPCs were analyzed to estimate the onset of vulnerability in HIBD. The resting membrane potential, membrane resistance, and membrane capacitance of OPCs were increased in both the gray and white matter of the cerebral cortex. OPCs in both the gray and white matter exhibited voltage-dependent K(+) currents, which consisted of the initiated rectified potassium currents (IA) and the sustained rectified currents (IK). The significant alternation in membrane resistance was influenced by the diversity of potassium channel kinetics. These findings suggest that the rectification of IA and IK channels may play a significant role in OPC vulnerability in HIBD.

PS-157 Moderate To Severe Neonatal Encephalopathy Is Predicted By Rising Serum But Not Csf Biomarkers

Background Term infants with NE of hypoxic-ischaemic origin, have been exposed to generalised oxidative injury which may cause excessive cytokine production and release in serum and CSF. Cytokine levels may correlate with severity of brain injury and aid in outcome prediction. Objective To investigate the relationship between serum and CSF biomarkers and NE in a group of term infants exposed to perinatal hypoxia-ischaemia compared to controls. Design/Methods Levels of serum and CSF biomarkers [VEGF, IL-8, Epo, GM-CSF] were serially measured over day 1–11 in a group of term newborns with NE and controls (serum only). These values were compared to grade of encephalopathy defined by Sarnat score. Results Twelve control and 82 cases had serum samples collected (Grade 0 NE = 6, Grade I NE = 23, Grade II NE = 42, Grade III NE = 11). Thirty-nine infants underwent TH, 4 infants died. Controls had significantly lower serum Epo on day 1–2 compared with cases (p-values Conclusions Term infants exposed to perinatal hypoxia-ischaemia have elevated levels of serum biomarkers compared to controls. Abnormal NE grade is best predicted by day 2 serum Epo and IL-8 while CSF levels were not predictive of outcome. Serum biomarkers may have a role in long term outcome prediction following NE.

MicroRNAs participate in the murine oligodendroglial response to perinatal hypoxia-ischemia.

BackgroundHypoxic-ischemic injury (HI) to preterm brain results in white matter loss. The endogenous oligodendroglial response to perinatal HI is characterized by increased oligodendroglial progenitor cells (OPCs). MicroRNAs (miRs) are important post-transcriptional regulators of gene expression, and a few miRs have been shown to regulate differentiation of OPCs into mature oligodendroglia (OLs). We tested the hypothesis that microRNAs play a role in the increase in OPCs in response to perinatal HI.MethodsWe inducibly deleted the miR-processing enzyme Dicer in OPCs using a tamoxifen-inducible NG2CreERT2 transgene in Dicerfl/fl mice. After HI, mice were analyzed for OPC differentiation using immunofluorescence and for white matter formation by Luxol fast blue (LFB) staining. Functional recovery from injury was investigated using digital gait analysis. We also tested whether HI changed miRs known to regulate OPC differentiation using quantitative RT-PCR.ResultsPerinatal HI induced significant increases in miR-138 and miR-338, two microRNAs known to regulate OPC differentiation. Knockdown of Dicer increased myelin basic protein (MBP) and LFB staining within corpus callosum after HI. In addition, there was significant improvement in motor function 14 and 24 days post lesion.ConclusionChanges in specific mature miRs expressed in OPCs following HI may contribute to white matter injury.