Neonatal Hypoxic-ischemic Encephalopathy Research Articles

Risk of uterine rupture among women in a trial of labor after prior cesarean delivery

Uterine rupture during a trial of labor after prior cesarean (TOLAC) delivery is an obstetrical emergency with potentially severe adverse outcomes. The aim of this study was to assess the incidence of uterine rupture and adverse maternal and perinatal outcomes. We conducted a population-based, retrospective cohort analysis with data from all women who gave birth after one prior cesarean delivery at a single tertiary center from 2009 through 2019. Maternal and perinatal outcomes were compared between women who underwent a successful or failed TOLAC and elective repeated cesarean delivery (ERCD) without labor. Out of 95,552 deliveries, TOLAC was attempted by 5,619 (63.35%), while 3,250 (36.64%) women underwent ERCD. The rate of successful TOLAC - vaginal birth after cesarean (VBAC) was 81.92%. Symptomatic uterine rupture occurred in 55 (0.98%) women who underwent TOLAC and asymptomatic rupture in five (0.153%) who underwent ERCD. Compared with women with spontaneous onset of labor, a greater risk, albeit not significant, for uterine rupture was observed among women with induction of labor using prostaglandins (OR 2.44; CI 0.86-6.92), oxytocin (OR 2.16 CI 0.84-5.54), and lower when external amniotic balloon was used (OR 0.52; CI 0.07-3.86). Women who failed in TOLAC needed more blood transfusions (OR 6.06; CI 3.61-10.16, p< 0.011). Neonatal hypoxic–ischemic encephalopathy occurred in a single case of successful TOLAC but in none of the other groups. There were no cases of cesarean hysterectomy, maternal or neonatal death in any group. Our data confirm the relatively small risk of uterine rupture during TOLAC. In a tertiary well-trained center, with close maternal and fetal monitoring, uterine rupture is rare and does not result in severe maternal and neonatal morbidity or mortality.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Retracted: Clinical Efficacy of Subhypothermia in the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy Combined with Myocardial Damage

Retracted: Clinical Efficacy of Subhypothermia in the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy Combined with Myocardial Damage

Retracted: Application Effect Analysis of Clinical Nursing Pathway in the Care of Neonatal Hypoxic-Ischemic Encephalopathy.

[This retracts the article DOI: 10.1155/2022/9379361.].

Correlation analysis of NT-proBNP (N-terminal probrain natriuretic peptide), 25-Hydroxyvitamin D, HMGB1(High-mobility group box 1), ACTA (endogenous activin A), blood glucose level, and electrolyte level with developmental quotient scores in neonates with hypoxic-ischemic encephalopathy

BackgroundTo investigate the correlation between N-terminal probrain natriuretic peptide (NT-proBNP), 25-hydroxyvitamin D (25-(OH) D), high-mobility group box 1(HMGB1), endogenous activin A (ACTA), blood glucose level, electrolyte levels and developmental quotient (DQ) scores of Hypoxic-ischemic encephalopathy (HIE).MethodsIn this retrospective study, a total of 90 neonates diagnosed with HIE who were admitted to our hospital from January 2018 to June 2021 were retrospectively enrolled, and 40 healthy full-term neonates born in our hospital during the same period were randomly selected. Neonates with HIE and healthy conditions were set as the study group and control group, respectively. Neonates with HIE are divided into three subgroups, mild, moderate, and severe, based on the severity of HIE. The Gesell Developmental Scale (GDS) was used to assess neural development of neonates at 9 to 12 months postnatal. Biomarkers of peripheral venous blood were measured and collected in all neonates, including NT-proBNP, (25-(OH) D), HMGB1, ACTA, electrolyte levels and blood glucose levels. General demographic information and Apgar score were compared between the two groups. The differences between the two groups of biomarkers were compared and the correlation between these biomarkers and DQ scores was evaluated.ResultsThere was no significant difference in gestational age, maternal age, gender, way of birth, birth weight, gestational age and whether the mother was a primipara between the two groups (P>0.05). The 10 min Apgar score of the study group (5.87±0.36) was lower than that of the control group (9.37±0.32) with significant difference (P<0.05). The levels of NT-proBNP, HMGB1, and ACTA in the study group were higher than that in the control group (243.87±21.29 pmol/L vs. 116.98±22.19 pmol/L; 8.92±1.87 μg/L vs. 3.28±1.08 μg/L; 23.78±0.89 ng/ml vs. 2.98±0.38 ng/ml), while the levels of 25-(OH) D and electrolyte levels were lower than that in the control group (24.28±1.87 vs. 31.29±1.93; K+: 4.49±0.23 mmol/L vs. 4.73±0.21 mmol/L; Na+: 118.76±13.02 mmol/L vs. 134.28±12.29 mmol/L; Ca2+: 1.77±0.23 mmol/L vs. 2.35±0.26 mmol/L; Mg2+: 0.61±0.17 mmol/L vs. 0.91±0.17 mmol/L), with statistically significant differences (P<0.001). The levels of NT-probNP, HMGB1, ACTA and the incidence of hypoglycemia were the highest in the severe group, which were significantly higher than those in the moderate group and mild group (P<0.05). The levels of NT-probNP, HMGB1, ACTA and the incidence of hypoglycemia were the lowest in the mild group. The 25-(OH) D level, the incidence of hyperglycemia and electrolyte levels were the lowest in the severe group, which were significantly lower than those in the moderate and mild groups (all P<0.05). Meanwhile, the 25-(OH) D level, the incidence of hyperglycemia and electrolyte levels in the moderate group were lower than those in the mild group, and the differences were statistically significant (all P<0.05).The incidence of hyperglycemia in severe group (16 cases) was the lowest, significantly lower than that in moderate group (17 cases) and mild group (22 cases), and the difference was statistically significant (all P<0.05).The DQ scores of HIE neonates were negatively correlated with NT-proBNP, HMGB1, and ACTA (r=-0.671, -0.421, -0.518, all P< 0.001). The DQ scores was positively correlated with levels of 25-(OH) D and blood glucose level (r =0.621, 0.802, all P< 0.001). The DQ scores was also positively correlated with levels of potassium, sodium, calcium and magnesium (0.367, 0.782, 0.218, 0.678, all P<0.001). ConclusionThe NT-proBNP, HMGB1, ACTA, 25-(OH) D, blood glucose levels and electrolyte levels are correlated with the severity of HIE, and developmental quotient scores in neonates with HIE. These biomarkers are suggestive for assessing the prognosis of neonate with HIE.

Molecular Hydrogen: an Emerging Therapeutic Medical Gas for Brain Disorders.

Oxidative stress and neuroinflammation are the main physiopathological changes involved in the initiation and progression of various neurodegenerative disorders or brain injuries. Since the landmark finding reported in 2007 found that hydrogen reduced the levels of peroxynitrite anions and hydroxyl free radicals in ischemic stroke, molecular hydrogen's antioxidative and anti-inflammatory effects have aroused widespread interest. Due to its excellent antioxidant and anti-inflammatory properties, hydrogen therapy via different routes of administration exhibits great therapeutic potential for a wide range of brain disorders, including Alzheimer's disease, neonatal hypoxic-ischemic encephalopathy, depression, anxiety, traumatic brain injury, ischemic stroke, Parkinson's disease, and multiple sclerosis. This paper reviews the routes for hydrogen administration, the effects of hydrogen on the previously mentioned brain disorders, and the primary mechanism underlying hydrogen's neuroprotection. Finally, we discuss hydrogen therapy's remaining issues and challenges in brain disorders. We conclude that understanding the exact molecular target, finding novel routes, and determining the optimal dosage for hydrogen administration is critical for future studies and applications.

Hypothermia Does Not Boost the Neuroprotection Promoted by Umbilical Cord Blood Cells in a Neonatal Hypoxia-Ischemia Rat Model

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of death and long-term disability in the perinatal period. Currently, therapeutic hypothermia is the standard of care for this condition with modest efficacy and strict enrollment criteria. Therapy with umbilical cord blood cells (UCBC) has come forward as a strong candidate for the treatment of neonatal HIE, but no preclinical studies have yet compared the action of UCBC combined with hypothermia (HT) with the action of each therapy by itself. Thus, to evaluate the potential of each therapeutic approach, a hypoxic-ischemic brain lesion was induced in postnatal day ten rat pups; two hours later, HT was applied for 4 h; and 24, 48, and 72 h post-injury, UCBC were administered intravenously. The neonatal hypoxic-ischemic injury led to a brain lesion involving about 48% of the left hemisphere that was not improved by HT (36%) or UCBC alone (28%), but only with the combined therapies (25%; p = 0.0294). Moreover, a decrease in glial reactivity and improved functional outcomes were observed in both groups treated with UCBC. Overall, these results support UCBC as a successful therapeutic approach for HIE, even when treatment with therapeutic hypothermia is not possible.

Gallic acid inhibits neuroinflammation and reduces neonatal hypoxic-ischemic brain damages.

Neuroinflammation is a leading cause of secondary neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE). Regulation of neuroinflammation may be beneficial for treatment of HIE and its secondary complications. Gallic acid (GA) has been shown to have anti-inflammatory and antioxidant effects. In this report we found that oxygen-glucose deprivation and/reoxygenation (OGD/R)-induced cell death, and the generation of excessive reactive oxygen species (ROS) and inflammatory cytokines by microglia were inhibited by GA treatment. Furthermore, GA treatment reduced neuroinflammation and neuronal loss, and alleviated motor and cognitive impairments in rats with hypoxic-ischemic brain damage (HIBD). Together, our results reveal that GA is an effective regulator of neuroinflammation and has potential as a pharmaceutical intervention for HIE therapy.

Ketogenic Diet for Neonatal Hypoxic–Ischemic Encephalopathy

The prevalence of neonatal hypoxic-ischemic encephalopathy (HIE), a devastating neurological injury, is increasing; thus, effective treatments and preventions are urgently needed. The underlying pathology of HIE remains unclear; recent research has focused on elucidating key features of the disease. A variety of diseases can be alleviated by consuming a ketogenic diet (KD) despite differences in pathogenesis and features, given the common mechanisms of KD-induced effects. Dietary modification is the most translatable, cost-efficient, and safest approach to treat acute or chronic neurological disorders and reduces reliance on pharmaceutical treatments. Evidence suggests that the KD can exert beneficial effects in animal models and in humans with brain injuries. The efficacy of the KD in preventing neuronal damage, motor alterations, and cognitive decline varies. Moreover, the KD may provide an alternative source of energy, enhance mitochondrial function, and reduce the expression of inflammatory and apoptotic mediators. Thus, this diet has attracted interest as a potential therapy for HIE. This review examined the role of the KD in HIE treatment and described the mechanisms by which ketone bodies (KBs) exert effects under pathological conditions and protect against brain damage; the evidence supports the implementation of dietary interventions as a therapeutic strategy for HIE. Future research should aim to elucidate the underlying mechanisms of the KD in patients with HIE and determine whether the effect of the KD on clinical outcomes can be reproduced in humans.

Machine learning for the early prediction of infants with electrographic seizures in neonatal hypoxic-ischemic encephalopathy.

To assess if early clinical and electroencephalography (EEG) features predict later seizure development in infants with hypoxic-ischemic encephalopathy (HIE). Clinical and EEG parameters <12 h of birth from infants with HIE across eight European Neonatal Units were used to develop seizure-prediction models. Clinical parameters included intrapartum complications, fetal distress, gestational age, delivery mode, gender, birth weight, Apgar scores, assisted ventilation, cord pH, and blood gases. The earliest EEG hour provided a qualitative analysis (discontinuity, amplitude, asymmetry/asynchrony, sleep-wake cycle [SWC]) and a quantitative analysis (power, discontinuity, spectral distribution, inter-hemispheric connectivity) from full montage and two-channel amplitude-integrated EEG (aEEG). Subgroup analysis, only including infants without anti-seizure medication (ASM) prior to EEG was also performed. Machine-learning (ML) models (random forest and gradient boosting algorithms) were developed to predict infants who would later develop seizures and assessed using Matthews correlation coefficient (MCC) and area under the receiver-operating characteristic curve (AUC). The study included 162 infants with HIE (53 had seizures). Low Apgar, need for ventilation, high lactate, low base excess, absent SWC, low EEG power, and increased EEG discontinuity were associated with seizures. The following predictive models were developed: clinical (MCC 0.368, AUC 0.681), qualitative EEG (MCC 0.467, AUC 0.729), quantitative EEG (MCC 0.473, AUC 0.730), clinical and qualitative EEG (MCC 0.470, AUC 0.721), and clinical and quantitative EEG (MCC 0.513, AUC 0.746). The clinical and qualitative-EEG model significantly outperformed the clinical model alone (MCC 0.470 vs 0.368, p-value .037). The clinical and quantitative-EEG model significantly outperformed the clinical model (MCC 0.513 vs 0.368, p-value .012). The clinical and quantitative-EEG model for infants without ASM (n=131) had MCC 0.588, AUC 0.832. Performance for quantitative aEEG (n=159) was MCC 0.381, AUC 0.696 and clinical and quantitative aEEG was MCC 0.384, AUC 0.720. Early EEG background analysis combined with readily available clinical data helped predict infants who were at highest risk of seizures, hours before they occur. Automated quantitative-EEG analysis was as good as expert analysis for predicting seizures, supporting the use of automated assessment tools for early evaluation of HIE.

Hypothermia for neonatal hypoxic–ischemic encephalopathy: Retrospective descriptive study of features associated with poor outcome

AimTo investigate the clinical, laboratory, electrophysiological, and imaging features associated with death or neurological impairment at 1 year of age in term neonates with hypoxic–ischemic encephalopathy (HIE) treated by therapeutic hypothermia (TH). MethodsThis was a single-center retrospective and descriptive study conducted over a period of 2 years. We included consecutive term newborns with moderate or severe HIE who were treated by TH initiated within the sixth hour after birth and continued for 72 h,. For all patients, brain magnetic resonance imaging (MRI) was performed before the eighth day and a score was established; furthermore, at least two electroencephalograms were recorded. ResultsAmong the 33 patients included, 20 neonates had a favorable outcome and 13 had an unfavorable outcome. Early clinical seizures (15% vs. 53.8%, p = 0.047), the persistence of a poor prognosis according to the electroencephalogram pattern after TH (0% vs. 69.2%, p = 0.0001), and an elevated score on the early brain MRI (2 vs. 11, p < 0.001) combined with a high lactate/N-acetyl-aspartate ratio (0.52 vs. 1.33, p = 0.008) on spectroscopy were associated with death and a poor outcome. ConclusionA combination of tools can help the medical team to establish the most reliable prognosis for these full-term neonates, to guide care, and to inform parents most appropriately and sincerely.

Development of the corpus callosum and cognition after neonatal encephalopathy.

Neonatal imaging studies report corpus callosum abnormalities after neonatal hypoxic-ischaemic encephalopathy (HIE), but corpus callosum development and relation to cognition in childhood are unknown. Using magnetic resonance imaging (MRI), we examined the relationship between corpus callosum size, microstructure and cognitive and motor outcomes at early school-age children cooled for HIE (cases) without cerebral palsy compared to healthy, matched controls. A secondary aim was to examine the impact of HIE-related neonatal brain injury on corpus callosum size, microstructure and growth. Participants aged 6-8 years underwent MRI, the Movement Assessment Battery for Children Second Edition and Wechsler Intelligence Scale for Children Fourth Edition. Cross-sectional area, volume, fractional anisotropy and radial diffusivity of the corpus callosum and five subdivisions were measured. Multivariable regression was used to assess associations between total motor score, full-scale IQ (FSIQ) and imaging metrics. Adjusting for age, sex and intracranial volume, cases (N=40) compared to controls (N=39) demonstrated reduced whole corpus callosum area (β=-26.9, 95% confidence interval [CI]=-53.17, -0.58), volume (β=-138.5, 95% CI=-267.54, -9.56), fractional anisotropy and increased radial diffusivity (P < 0.05) within segments II-V. In cases, segment V area (β=0.18, 95% CI=0.004, 0.35), volume (β=0.04, 95% CI=0.001, 0.079), whole corpus callosum fractional anisotropy (β=13.8 95% CI=0.6, 27.1) and radial diffusivity (β=-11.3, 95% CI=-22.22, -0.42) were associated with FSIQ. Growth of the corpus callosum was restricted in cases with a FSIQ ≤85, and volume was reduced in cases with mild neonatal multifocal injury compared to white matter injury alone. Following neonatal HIE, morphological and microstructural changes in the corpus callosum are associated with reduced cognitive function at early school age.

MiR-204-5p Inhibits the Proliferation and Differentiation of Fetal Neural Stem Cells by Targeting Wingless-Related MMTV Integration Site 2 to Regulate the Ephrin-A2/EphA7 Pathway

Neonatal hypoxic ischemic encephalopathy (HIE) is mainly resulted from perinatal asphyxia, which can be repaired by NSCs. miR-204-5p is claimed to impact the activity NSCs. Our research will probe the miR-204-5p function in oxygen-glucose deprivation (OGD)-treated NSCs. miR-204-5p level was enhanced and WNT2 level was reduced in HIE rats. Rat NSCs were stimulated with OGD condition under the managing of mimic or inhibitor of miR-204-5p. The declined cell viability, enhanced apoptosis, downregulated Tuj1 and GFAP levels, and shortened total neurite length were observed in OGD-treated NSCs, which were further aggravated by the mimic and rescued by the inhibitor of miR-204-5p. Furthermore, the inactivated WNT2 and Ephrin-A2/EphA7 signaling pathway in OGD-stimulated NSCs was further repressed by the mimic and rescued by the inhibitor of miR-204-5p. In addition, WNT2 was confirmed as the targeting of miR-204-5p. Lastly, the function of miR-204-5p mimic on the proliferation, apoptosis, differentiation, WNT2 and Ephrin-A2/EphA7 signaling pathway in OGD-stimulated NSCs was abolished by HLY78, an activator of Wnt signaling. Collectively, miR-204-5p repressed the growth and differentiation of fetal NSCs by targeting WNT2 to regulate the Ephrin-A2/EphA7 pathway.

Neonatal hypoxic ischemic encephalopathy increases acute kidney injury urinary biomarkers in a rat model.

Hypoxic ischemic encephalopathy (HIE) is associated with acute kidney injury (AKI) in neonates with birth asphyxia. This study aimed to utilize urinary biomarkers to characterize AKI in an established neonatal rat model of HIE. Day 7 Sprague-Dawley rat pups underwent HIE using the Rice-Vannucci model (unilateral carotid ligation followed by 120 mins of 8% oxygen). Controls included no surgery and sham surgery. Weights and urine for biomarkers (NGAL, osteopontin, KIM-1, albumin) were collected the day prior, daily for 3 days post-intervention, and at sacrifice day 14. Kidneys and brains were processed for histology. HIE pups displayed histological evidence of kidney injury including damage to the proximal tubules, consistent with resolving acute tubular necrosis, and had significantly elevated urinary levels of NGAL and albumin compared to sham or controls 1-day post-insult that elevated for 3 days. KIM-1 significantly increased for 2 days post-HIE. HIE did not significantly alter osteopontin levels. Seven days post-start of experiment, controls were 81.2% above starting weight compared to 52.1% in HIE pups. NGAL and albumin levels inversely correlated with body weight following HIE injury. The AKI produced by the Rice-Vannucci HIE model is detectable by urinary biomarkers, which can be used for future studies of treatments to reduce kidney injury.

Erythropoietin Reduces Death and Neurodevelopmental Impairment in Neonatal Hypoxic-Ischemic Encephalopathy

Purpose: Erythropoietin (EPO) is a promising neuroprotective drug. We investigated whether EPO has beneficial effects on neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy (HIE).Methods: We retrospectively reviewed the data of 56 infants with HIE born at or after 35 weeks of gestation who were admitted to Inha University Hospital between 2012 and 2021. Patients were divided into two groups based on EPO use and compared. In the EPO group, patients were administered 1,000 U/kg of EPO on days 1, 2, 3, 5, and 7, starting within 24 hours after birth. The primary outcome was death or neurodevelopmental impairment (NDI) at the age of 12 months.Results: EPO was administered to 38 infants, and 18 did not receive EPO. Only 37.5% of patients with HIE (21/56) and 60% of patients with moderate-to-severe HIE (21/35) received therapeutic hypothermia. Among all patients with HIE, death or NDI (21.1 % vs. 50.0%; odds ratio [OR], 0.09; 95% confidence interval [CI], 0.01 to 0.78; P=0.029) and brain injury on imaging (42.1% vs. 83.3%; OR, 0.16; 95% CI, 0.03 to 0.92; P=0.040) were significantly lower in the EPO group than in the control group. Among patients with moderate-to-severe HIE, brain injury on imaging (54.2% vs. 90.9%; OR, 0.04; 95% CI, 0.002 to 0.700; P=0.027) was significantly lower in the EPO group than in the control group.Conclusion: EPO administration significantly reduced mortality and NDI in infants with HIE. EPO can be considered an adjunctive therapeutic agent for neonatal HIE.

Maternal and neonatal exposure to risk factors for neonates with moderate or severe hypoxic ischemic encephalopathy: a cross-sectional study

BackgroundTo investigate the association between maternal and neonatal exposure to the relevant influencing factors and risk of moderate or severe hypoxic ischemic encephalopathy (HIE), and the possible interactions in the Chinese population.MethodsA cross-sectional study comprising 228 neonates from Henan Children’s Hospital during the five-year period 2015–2020 in China was conducted. All neonatal basic demographic information and clinical records were documented from the neonatal HIE database. Comparisons between mild HIE and moderate or severe HIE were conducted with the t-test or Wilcoxon rank-sum test for continuous variables and the Chi-square test for categorical variables. Unconditional multiple logistic regression models were used to generate the odds ratios(ORs) and 95% confidence intervals(CIs). In addition, we also used an additive model to test for possible biological interactions among the factors.ResultsOf the 228 neonates, the males had a statistically significantly higher frequency compared with the females between the two groups (P = 0.030). Trend analysis results found that with the decreased of the neonatal birth weight, the detection rates of moderate or severe HIE in males and females were gradually increased (Ptrend < 0.05). The detection of moderate or severe HIE in males and females increased with the decreased of neonatal gestational age at birth(Ptrend < 0.05). However, no interaction was detected between neonatal birth weight and gestational age at birth based on the additive model, the Relative Excess Risk of Interaction and 95% CI was 0.821(-0.046,1.687). The adjusted multiple logistic regression model showed that low birth weight(ORadj:1.965, 95%CI:1.086–4.127),premature infant(ORadj:1.557, 95%CI:1.589–4.862),1-min Apgar’s score < 7(ORadj:5.618, 95%CI:3.724–7.353),intrauterine distress(ORadj:4.916, 95%CI:3.431–7.398),amniotic fluid contamination (ORadj:3.965, 95%CI:2.153–5.782) significantly increased the risk of neonatal moderate or severe HIE.ConclusionNeonates with low birth weight, premature infant,1-min Apgar’s score < 7, intrauterine distress, amniotic fluid contamination are risk factors for moderate or severe HIE. Notably, we found no biological interaction between risk factors based on the additive model, these findings may help to inform prevention strategies, as this may effectively reduce the incidence of neonatal moderate or severe HIE.

Suppression of SAMSN1 contributes to neuroprotection in neonatal rats suffering from hypoxic-ischemic encephalopathy injury.

This article aims to detect the effect of SAM domain, SH3 domain, and nuclear localization signal1 (SAMSN1) in neonatal rats with neurological dysfunction induced by hypoxia and ischemia (HI). The HI model was created using 7-day postnatal rats. Zea-longa score was utilized to validate the neurological injury after HI. Then, the differentially expressed genes (DEGs) were detected by gene sequencing and bioinformatics analysis methods. The oxygen and glucose deprivation (OGD) models were established in the SY5Y cells and fetal human cortical neurons. In addition, SAMSN1-small interfering RNA, methyl thiazolyl tetrazolium assay, and cell growth curve were employed to evaluate the cell viability variation. Obviously, Zea-longa scores increased in rats with HI insult. Subsequently, SAMSN1 was screened out, and it was found that SAMSN1 was strikingly upregulated in SY5Y cells and fetal neurons post-OGD. Interestingly, we found that SAMSN1 silencing could markedly enhance cell viability and cell growth after OGD. These data suggested that downregulation of SAMSN1 may exert a neuroprotective effect on damaged neurons after HI by improving cell viability and cell survival, which provides a potential theoretical basis for clinical trials in the future to treat neonatal hypoxic-ischemic encephalopathy.

Insight into the Neuroprotective Effect of Genistein-3′-Sodium Sulfonate Against Neonatal Hypoxic-Ischaemic Brain Injury in Rats by Bioinformatics

Therapeutic hypothermia (TH) is the only intervention approved for the treatment of neonatal hypoxic-ischaemic encephalopathy (HIE), but its treatment window is narrow (within 6 h after birth), and its efficacy is not ideal. Thus, alternative treatments are urgently needed. Our previous studies showed that genistein-3′-sodium sulfonate (GSS), a derivative of genistein (Gen), has a strong neuroprotective effect in rats with ischaemic stroke, but its role in HIE is unclear. A hypoxia–ischaemia (HI) brain injury model was established in neonatal male Sprague‒Dawley (SD) rats. Twenty-four hours after reperfusion, rats treated with GSS were assessed for cerebral infarction, neurological function, and neuronal damage. RNA-Seq and bioinformatics analysis were used to explore differentially expressed genes (DEGs) and regulated signalling pathways, which were subsequently validated by Western blotting and immunofluorescence. In this study, we found that GSS not only significantly reduced the size of brain infarcts and alleviated nerve damage in rats with HIE but also inhibited neuronal loss and degeneration in neonatal rats with HIE. A total of 2170 DEGs, of which 1102 were upregulated and 1068 were downregulated, were identified in the GSS group compared with the HI group. In an analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) categories, the downregulated DEGs were significantly enriched in the pathways “Phagosome”, “NF-κB signalling”, and “Complement and coagulation cascades”, amongst others. Meanwhile, the upregulated DEGs were significantly enriched in the pathways “Neurodegeneration”, “Glutamatergic synapse”, and “Calcium signalling pathway”, amongst others. These results indicate that GSS intervenes in the process of HIE-induced brain injury by participating in multiple pathways, which suggests potential candidate drugs for the treatment of HIE.Graphical

Application of amide proton transfer imaging for the diagnosis of neonatal hypoxic-ischemic encephalopathy.

This study aimed to evaluate cerebral amide proton transfer signal intensity (SI) among controls, hypoxic-ischemic encephalopathy (HIE) neonates with normal conventional magnetic resonance imaging (HIE/MRI-) findings, and HIE neonates with abnormal conventional MRI (HIE/MRI+) findings. Forty neonates diagnosed with neonatal HIE and sixteen normal neonates were evaluated. All neonates underwent conventional MRI scans and APT imaging. Cerebral APT SIs were compared to identify cerebral regions with significant APT changes among sixteen controls, thirteen HIE/MRI- patients, and twenty-seven HIE/MRI+ patients. Significantly increased APT SIs were observed in the HIE/MRI- group compared with controls, in the left insula, right occipital lobe, left cingulate gyrus (posterior part), and corpus callosum. Significantly increased APT SIs were found in the HIE/MRI+ group compared with controls, in the right anterior temporal lobe (medial part), anterior parts of the right parahippocampal and ambient gyri, left superior temporal gyrus (middle part), left insula, left cingulate gyrus (posterior part), and right lentiform nucleus. No significant APT SI differences were observed in the cerebellum and brainstem among the three groups. Amide proton transfer imaging plays an important role in detecting hypoxic-ischemic encephalopathy regardless of conventional MRI findings. Changes in APT signal intensity may provide important insights into the characterization of the cerebral internal environment. This study suggests that APT imaging could be used as a complement to conventional MRI in the detection of hypoxic-ischemic encephalopathy in clinical practice.

Mammillary body abnormalities and cognitive outcomes in children cooled for neonatal encephalopathy.

To evaluate mammillary body abnormalities in school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (cases) and matched controls, and associations with cognitive outcome, hippocampal volume, and diffusivity in the mammillothalamic tract (MTT) and fornix. Mammillary body abnormalities were scored from T1-weighted magnetic resonance imaging (MRI) in 32 cases and 35 controls (median age [interquartile range] 7 years [6 years 7 months-7 years 7 months] and 7 years 4 months [6 years 7 months-7 years 7 months] respectively). Cognition was assessed using the Wechsler Intelligence Scale for Children, Fourth Edition. Hippocampal volume (normalized by total brain volume) was measured from T1-weighted MRI. Radial diffusivity and fractional anisotropy were measured in the MTT and fornix, from diffusion-weighted MRI using deterministic tractography. More cases than controls had mammillary body abnormalities (34% vs 0%; p< 0.001). Cases with abnormal mammillary bodies had lower processing speed (p= 0.016) and full-scale IQ (p= 0.028) than cases without abnormal mammillary bodies, and lower scores than controls in all cognitive domains (p< 0.05). Cases with abnormal mammillary bodies had smaller hippocampi (left p= 0.016; right p= 0.004) and increased radial diffusivity in the right MTT (p= 0.004) compared with cases without mammillary body abnormalities. Cooled children with mammillary body abnormalities at school-age have reduced cognitive scores, smaller hippocampi, and altered MTT microstructure compared with those without mammillary body abnormalities, and matched controls. Cooled children are at higher risk of mammillary body abnormalities than controls. Abnormal mammillary bodies are associated with reduced cognitive scores and smaller hippocampi. Abnormal mammillary bodies are associated with altered mammillothalamic tract diffusivity.

Quantitative Evaluation of Brain Echogenicity in Hypoxic-Ischemic Encephalopathy in Term Neonates Compared with Controls.

Purpose Neurosonography evaluation of neonatal hypoxic-ischemic encephalopathy (HIE) is mainly qualitative. We aimed to quantitatively compare the echogenicity of several brain regions in patients with HIE to healthy controls. Materials and Methods 20 term neonates with clinical/MRI evidence of HIE and 20 term healthy neonates were evaluated. Seven brain regions were assessed [frontal, parietal, occipital, and perirolandic white matter (WM), caudate nucleus head, lentiform nucleus, and thalamus]. The echogenicity of the calvarial bones (bone) and the choroid plexus (CP) was used for ratio calculation. Differences in the ratios were determined between neonates with HIE and controls. Results Ratios were significantly higher for HIE neonates in each region (p<0.05). The differences were greatest for the perirolandic WM, with CP and bone ratios being 0.23 and 0.22 greater, respectively, for the HIE compared to the healthy neonates (p<0.001). The perirolandic WM had a high AUC, at 0.980 for both the CP and bone ratios. The intra-observer reliability for all ratios was high, with the caudate to bone ratio being the lowest at 0.832 and the anterior WM to CP ratio being the highest at 0.992. Conclusion When coupled with internal controls, quantitative neurosonography represents a potential tool to identify early neonatal HIE changes. Larger cohort studies could reveal whether a quantitative approach can discern between degrees of severity of HIE. Future neurosonography protocols should be tailored to evaluate the perirolandic region, which requires posterior coronal scanning.