Search Results (222)

Neuroinflammation is the major contributor to the pathology of neonatal hypoxic–ischemic (HI) brain injury. Our previous studies have demonstrated that microRNA210 (miR210) inhibition with antisense locked nucleic acid (LNA) inhibitor mitigates neuroinflammation and provides neuroprotection after neonatal HI insult. However, the underlying mechanisms remain elusive. In the present study, using miR210 knockout (KO) mice and microglial cultures, we tested the hypothesis that miR210 promotes microglial activation and neuroinflammation through suppressing mitochondrial function in microglia after HI. Neonatal HI brain injury was conducted on postnatal day 9 (P9) wild-type (WT) and miR210 knockout (KO) mouse pups. We found that miR210 KO significantly reduced brain infarct size at 48 h and improved long-term locomotor functions assessed by an open field test three weeks after HI. Moreover, miR210 KO mice exhibited reduced IL1β levels, microglia activation and immune cell infiltration after HI. In addition, in vitro studies of microglia exposed to oxygen–glucose deprivation (OGD) revealed that miR210 inhibition with LNA reduced OGD-induced expression of Il1β and rescued OGD-mediated downregulation of mitochondrial iron–sulfur cluster assembly enzyme (ISCU) and mitochondrial oxidative phosphorylation activity. To validate the link between miR210 and microglia activation, isolated primary murine microglia were transfected with miR210 mimic or negative control. The results showed that miR210 mimic downregulated the expression of mitochondrial ISCU protein abundance and induced the expression of proinflammatory cytokines similar to the effect observed with ISCU silencing RNA. In summary, our results suggest that miR210 is a key regulator of microglial proinflammatory activation through reprogramming mitochondrial function in neonatal HI brain injury. Full article

Background: Hypoxic–ischemic encephalopathy (HIE) is a leading cause of severe neurological impairments in childhood. Therapeutic hypothermia (TH) is both safe and effective in neonates born at ≥36 weeks gestation with moderate to severe HIE. We aimed to evaluate short-term outcomes—including brain injury detected on magnetic resonance imaging (MRI)—in infants born at 34–35 weeks of gestation drawing on our clinical experience with neonates under 36 weeks of gestational age (GA). Methods: In this retrospective cohort study, 20 preterm infants with a GA of 34 to 35 weeks and a matched cohort of 80 infants with a GA of ≥36 weeks who were diagnosed with moderate to severe HIE and underwent TH were included. Infants were matched in a 1:4 ratio based on the worst base deficit in blood gas and sex. Maternal and neonatal characteristics, brain MRI findings and short term outcomes were compared. Results: Infants with a GA of 34–35 weeks had a lower birth weight and a higher rate of caesarean delivery (both p < 0.001). Apgar scores, sex, intubation rate in delivery room, blood gas pH, base deficit and lactate were comparable between the groups. Compared to infants born at ≥36 weeks of GA, preterm neonates were more likely to receive inotropes, had a longer time to achieve full enteral feeding, and experienced a longer hospital stay. The mortality rate was 10% in the 34–35 weeks GA group. Neuroimaging revealed injury in 66.7% of infants born at 34–35 weeks of gestation and in 58.8% of those born at ≥36 weeks (p = 0.56). Injury was observed across multiple brain regions, with white matter being the most frequently affected in the 34–35 weeks GA group. Thalamic and cerebellar abnormal signal intensity or diffusion restriction, punctate white matter lesions, and diffusion restriction in the corpus callosum and optic radiations were more frequently detected in infants born at 34–35 weeks of gestation. Conclusions: Our study contributes to the growing body of literature suggesting that TH may be feasible and tolerated in late preterm infants. Larger randomized controlled trials focused on this vulnerable population are necessary to establish clear guidelines regarding the safety and efficacy of TH in late preterm infants. Full article

Prognostication of neurodevelopmental outcomes for neonates with hypoxic–ischemic encephalopathy (HIE) is primarily reliant on structural assessment using conventional brain magnetic resonance imaging in the clinical setting. Diffuse optical tomography (DOT) can provide complementary information on brain function at the bedside, further enhancing prognostic accuracy. The predictive accuracy and generalizability of DOT-based neuroimaging markers are unknown. This study aims to test the feasibility of prospectively recruiting and retaining neonates for 12 months in a larger study that investigates the prognostic utility of DOT-based biomarkers of HIE. The study will recruit 25 neonates with HIE over one year and follow them beyond NICU discharge at 6 and 12 months of age. Study subjects will undergo resting-state DOT measurement within 7 days of life for a 30–45-min period without sedation. A customized neonatal cap with 10 sources and eight detectors per side will be used to quantify cortical functional connectivity and to generate brain networks using MATLAB-based software (version 24.2). The Ages and Stages Questionnaires—3rd edition will be used for standardized developmental assessments at follow-up. This feasibility study will help refine the design and sample-size calculation for an adequately powered larger study that determines the clinical utility of DOT-based neuroimaging in perinatal brain injury. Full article

Background: Traumatic brain injury (TBI) and hypoxic–ischemic encephalopathy (HIE) are major causes of long-term neurological disability in children, with limited options for effective neuronal recovery. Recent research has highlighted the therapeutic potential of nerve growth factor (NGF) in promoting neural repair through mechanisms such as neuroprotection, neurogenesis, and the modulation of neuroinflammation. This review evaluates the current evidence on NGF as a treatment strategy for pediatric brain injury, emphasizing its mechanisms of action and translational clinical applications. Methods: A comprehensive review was conducted using the PubMed, Scopus, and Cochrane CENTRAL databases to identify studies published between 1 January 1978 and 1 March 2025, investigating NGF in the context of brain injury. The inclusion criteria comprised studies assessing neurological outcomes through clinical scales, biochemical markers, neuroimaging, or electrophysiological examinations. Results: Seventeen studies met the inclusion criteria, encompassing both preclinical and clinical research. Preclinical models consistently demonstrated that NGF administration reduces neuroinflammation, enhances neurogenesis, and supports neuronal survival following TBI and HIE. Clinical studies, including case reports of pediatric patients treated with intranasal NGF, reported improvements in motor and cognitive function, neuroimaging findings, and electrophysiological parameters, with no significant adverse effects observed. Conclusions: NGF demonstrates significant promise as a neuroprotective and neuroregenerative agent in pediatric brain injury, with both experimental and early clinical evidence supporting its safety and efficacy. Large-scale controlled clinical trials are warranted to validate these preliminary findings and to determine the optimal dosage regimens and administration schedules for NGF in the treatment of TBI and HIE. Full article

Physiological oxidative stress plays a pivotal role in supporting proper growth and development. While moderate oxidative stress is essential for activating key metabolic pathways and maintaining normal cellular signaling, excessive production of reactive oxygen species (ROSs) can overwhelm the immature antioxidant systems of newborns, potentially leading to cellular damage and impaired physiological function. This vulnerability is particularly pronounced in the central nervous system, where limited detoxification capacity exacerbates the risk of oxidative damage, following hypoxic–ischemic events. Antioxidants agents—such as melatonin, erythropoietin, allopurinol, N-acetylcisteine, selenium, iminobiotin, taurine, and acetyl-L-carnitine—have demonstrated significant neuroprotective effects in preclinical experimental studies, reducing markers of oxidative injury and improving neurological outcomes. These neuroprotective agents have also been evaluated in clinical trials, demonstrating antioxidant effects. A major issue lies in the complexity of neurological damage, which is not associated with a single pathological pathway. Additionally, the inability of these agents to reach effective concentrations within the central nervous system, along with inconsistencies across clinical trials in terms of dosage and administration methods, hinders the ability to obtain robust results. Future efforts should therefore focus on the development of delivery systems capable of crossing the blood–brain barrier and on establishing standardized clinical trial protocols and study designs. This educational review aims to provide a comprehensive overview of emerging protective strategies, including antioxidant bioactive agents and nutritional interventions. It also explores the underlying mechanisms of oxidative stress and its impact on neonatal brain injury. Full article

Hypoxic–Ischemic Encephalopathy (HIE) occurs in patients who experience a decreased flow of blood and oxygen to the brain, with the optimal window for effective treatment being within the first six hours of life. This puts a significant demand on medical professionals to accurately and effectively grade the severity of the HIE present, which is a time-consuming and challenging task. This paper proposes a novel workflow for background EEG grading, implementing a blend of Digital Signal Processing (DSP) and Machine-Learning (ML) techniques. First, the EEG signal is transformed into an amplitude and frequency modulated audio spectrogram, which enhances its relevant signal properties. The difference between EEG Grades 1 and 2 is enhanced. A convolutional neural network is then designed as a regressor to map the input image into an EEG grade, by utilizing an optimized rounding module to leverage the monotonic relationship among the grades. Using a nested cross-validation approach, an accuracy of 89.97% was achieved, in particular improving the AUC of the most challenging grades, Grade 1 and Grade 2, to 0.98 and 0.96. The results of this study show that the proposed representation and workflow increase the potential for background grading of EEG signals, increasing the accuracy of grading background patterns that are most relevant for therapeutic intervention, across large windows of time. Full article

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article

Rapid ascent to high altitudes by unacclimatized individuals significantly increases the risk of brain damage, given the brain’s heightened sensitivity to hypoxic conditions. Investigating hypoxia-tolerant animals can provide insights into adaptive mechanisms and guide prevention and treatment of hypoxic-ischemic brain injury. In this study, we exposed Brandt’s voles to simulated altitudes (100 m, 3000 m, 5000 m, and 7000 m) for 24 h and performed quantitative proteomic and phosphoproteomic analyses of brain tissue. A total of 3990 proteins and 9125 phosphorylation sites (phospho-sites) were quantified. Differentially expressed (DE) analysis revealed that while protein abundance changes were relatively modest, phosphorylation levels exhibited substantial alterations, suggesting that Brandt’s voles rapidly regulate protein structure and function through phosphorylation to maintain cellular homeostasis under acute hypoxia. Clustering analysis showed that most co-expressed proteins exhibited non-monotonic responses with increasing altitude, which were enriched in pathways related to cytokine secretion regulation and glutathione metabolism, contributing to reduced inflammation and oxidative stress. In contrast, most co-expressed phospho-sites showed monotonic changes, with phospho-proteins enriched in glycolysis and vascular smooth muscle contraction regulation. Kinase activity prediction identified nine hypoxia-responsive kinases, four of which belonging to the CAMK family. Immunoblot validated that the changes in CAMK2A activity were consistent with predictions, suggesting that CAMK may play a crucial role in hypoxic response. In conclusion, this work discovered that Brandt’s voles may cope with hypoxia through three key strategies: (1) vascular regulation to enhance cerebral blood flow, (2) glycolytic activation to increase energy production, and (3) activation of neuroprotective mechanisms. Full article

Measurement of circulating lactate is an essential diagnostic tool in pediatric medicine, playing a crucial role in assessing metabolic status and tissue oxygenation. Initially regarded as a byproduct of anaerobic metabolism, recent research has expanded our understanding of lactate’s roles across various physiological systems, from energy metabolism to immune modulation and neurological health. Elevated lactate levels are widely utilized to monitor critical conditions such as sepsis, trauma, and hypoxic–ischemic injury, offering valuable prognostic information in intensive care settings. Notably, lactate dynamics—particularly trends in serial measurements—are more effective than single readings for predicting clinical outcomes, especially in sepsis and trauma. Measurement of circulating lactate in different body fluids (blood, cerebrospinal fluid, and umbilical blood) provides critical insights into neonatal health and central nervous system involvement. However, challenges remain, including the need for non-invasive and rapid point-of-care testing, particularly in neonatal populations. Our aim was to review and synthesize the current literature on the role and particularities of measurement of circulating lactate in pediatric pathology. Emerging technologies, such as machine learning models and small molecule inhibitors, show promise in advancing lactate regulation and predicting hemodynamic instability. As the role of lactate in pediatric pathology continues to evolve, optimizing measurement protocols and exploring new therapeutic strategies will enhance early detection, intervention, and clinical outcomes for critically ill children. Full article

This study aims to explore the protective effects of Hong-bai-lan-shen (HBLS) extract, a traditional Chinese medicine compound, on myocardial injury based on metabolomics. H9C2 cells were cultured with HBLS extract for 12 h, and then the cells were cultured in a CoCl₂-containing medium, a model simulating the ischemic-hypoxic damage in myocardial cells, for an additional 12 h. The cell viability, cytotoxicity, intracellular metabolite and reactive oxygen species (ROS), mitochondrial membrane potential, apoptosis, and adenosine monophosphate-activated protein kinase (AMPK) signal pathway were determined. The results showed that HBLS extract significantly increased cell viability, stabilized cell morphology, reduced lactate dehydrogenase (LDH) release and ROS production, blocked cysteine-aspartic acid protease 3 (caspase-3) and bcl-2-associated X protein (Bax) expression and decreased apoptotic cell numbers. Meanwhile, HBLS increased membrane potential and the expression of B-cell lymphoma-2 (Bcl-2). Additionally, HBLS extract upregulated the expression of AMPK, PI3K, and protein kinase B (AKT) (p < 0.05, p < 0.01). These findings suggest that HBLS extract has a protective effect on myocardial cells by regulating the AMPK signal pathway and may be a promising therapeutic candidate for ischemic heart disease. Full article

Background/Objectives: The chronic metabolic condition of hyperglycemia in type-2 diabetics is known to cause various neurological disorders and compromise recovery from brain insults. Previously, we reported a delayed and reduced glial cell response and a greater neuronal cell death in different brain regions of diabetic, db/db, mice following cerebral hypoxic- ischemic injury. In this study, we explored the changes in baseline activation of astrocytes and microglia and its impact on vascular permeability in different brain regions. Methods: The numbers of activated astrocytes (GFAP-positive) and microglia/macrophage (Iba-1-positive) in the motor cortex, caudate and hippocampal regions of 12-week old, type-2 diabetic db/db and non-diabetic db/+ mice were quantitated. The leakage of serum IgG and loss of occludin, a tight junctional protein observed in the cortex and caudate of db/db mice, indicated a compromised blood brain barrier. Results: Results indicated significant differences in activation of glial cells in the cortex and caudate along with increased vessel permeability in diabetic mice. Conclusions: The study suggests that a constant activation of glial cells in the diabetic brain may be the cause of impaired inflammatory response and/or degenerating cerebral blood vessels which contribute to neuronal cell death upon CNS injury. Full article

Background/Objectives: The Hammersmith Infant Neurological Examination (HINE) is a standardized neurologic exam for infants between 2 and 24 months. Scores can be compared to optimality cutoffs as one component to support an early diagnosis of cerebral palsy (CP). Some prognosis is also possible for infants diagnosed with CP. We aimed to understand the longitudinal trajectories of HINE scores in infants who were ultimately diagnosed with CP. Methods: Clinical records were reviewed for children who were diagnosed with CP in two high-risk infant follow-up clinics with HINE scores from at least two visits between the corrected ages of 3 months and 2 years. Trajectories were calculated individually and by group for infants in four categories—term neonatal hypoxic ischemic encephalopathy (HIE), term perinatal arterial ischemic stroke (PAIS), premature infants with brain injury, and “Other” (term infants with congenital malformations and/or congenital hydrocephalus). The changes in HINE scores between clinic visits were compared using linear mixed-effect models with a random intercept, pulling data by diagnostic group across visits and accounting for within-child correlations of scores over the follow-up time. Results: The changes in HINE scores for sixty children (twenty-five with prematurity, eighteen with HIE, seven with PAIS, and ten in the other category) were assessed. The linear mixed-effect models indicated that the infants with PAIS had an estimated 10.8-point increase in total HINE scores after 9 months of age compared to earlier assessments (95% CI [2.5, 19.2]. There was no statistically significant improvement in the scores among the infants in the other brain injury groups. The infants with PAIS had an estimated 2.9-point increase in HINE asymmetry scores after 9 months of age compared to prior visits (95% CI [0.7, 5.1]). None of the other diagnostic categories had statistically significant increases in asymmetry scores over time. Conclusions: The children with PAIS with resultant hemiplegia showed increasing HINE scores throughout the first two years of life. In contrast, the HINE scores remained stable for those children with term HIE, prematurity-associated brain injury, and congenital malformations and/or congenital hydrocephalus diagnosed with CP. Tracking individual changes (or stability) in HINE scores can aid diagnosis, inform prognosis, and guide the design of clinical trials targeting neurologic injury. Full article

Background: Hypoxic-ischemic brain injury (HIBI) is a feared complication post-cardiac arrest (CA). The timing of brain imaging remains a topic of ongoing debate. Early computed tomography (CT) scans can reveal acute intracranial pathologies but may have limited predictive value due to delayed manifestation of HIBI-related changes. Radiomics analyses present a promising approach to identifying subtle imaging markers, potentially aiding early HIBI detection. Methods: This study retrospectively assessed post-CA patients between 2016 and 2023 who received immediate brain CTs. Patients without acute intracranial pathology on initial scans and who underwent follow-up brain CTs within 14 days post-return of spontaneous circulation (ROSC) were included. Image segmentation involved manual basalganglia segmentation and automated whole-brain segmentation. Radiomics features were calculated using Pyradiomics (v3.0.1) in 3DSlicer (v5.2.2). Feature selection involved reproducibility analysis via ICC and LASSO regression, retaining five features per segmentation method. A logistic regression model for each segmentation method underwent 5-fold cross-validation. Results were summarized with ROC analyses and average sensitivity and specificity. Results: A total of 83 patients (average age: 65 ± 13.3 years, 19 women) with CA and ROSC were included. Follow-up CT scans after 5.2 ± 2.9 days revealed brain edema in 47 patients. The model using manual segmentation achieved an average AUC of 0.76, sensitivity of 0.59, and specificity of 0.78. The automated segmentation model showed an average AUC of 0.66, sensitivity of 0.49, and specificity of 0.68. Conclusions: Radiomics, particularly focused on the basalganglia area in normal-appearing brain CTs after CA and ROSC, may enhance predictive insights for HIBI and the development of brain edema. Full article

SARS-CoV-2 placental infection, also known as placentitis (SP), is an established cause of stillbirth; however, this pathology is rare and its incidence across different viral variants is unknown. We report two new cases of SP-associated stillbirth in the third trimester of pregnancy. The cases were identified by a retrospective review of 84 fetal autopsies performed at our institution from 1 March 2020 to 1 March 2024. In one case, the mother was previously healthy and asymptomatic for COVID-19. In the second case, the mother had a history of multiple sclerosis (MS) and suffered recurrent moderate-to-severe COVID-19. In both cases, the placentas showed SP with massive perivillous fibrin deposition (PVFD), involving more than 90% of placental discs, resulting in placental insufficiency and lethal hypoxic–ischemic injury to the fetuses. Placental tissues were positive for SARS-CoV-2 by in situ hybridization (ISH) and immunohistochemistry (IHC). Sequencing revealed the delta variant in Case 1 and omicron XBB.1.515 in Case 2. The data demonstrate that SP, albeit rare, continues to cause intrauterine fetal demise (IUFD) across viral variants regardless of the clinical severity of the infection. The persistence of rare cases of SP as COVID-19 becomes globally endemic emphasizes the importance of disease prevention in pregnancy. Full article

Background/Objectives: Motor deficits following neonatal brain injury, from cerebral palsy to subtle deficits in motor planning, are common yet underreported. Rodent models of motor deficits in neonatal hypoxia–ischemia (HI) allow improved understanding of the underlying mechanisms and neuroprotective strategies. Our goal was to test motor performance and learning in a mouse model of neonatal HI. Methods: We induced HI in postnatal day (p)10 C57/Bl6 mice through unilateral carotid ligation followed by 60 min of 8% oxygen exposure, or a sham procedure. At p30, we assessed complex motor performance and learning using the accelerating rotarod and complex running wheel tasks. Results: In the rotarod task, HI mice performed worse than sham mice, with shorter latencies to fall (n = 6 sham, 9 HI; day 1, p = 0.033; day 2, p = 0.013; day 3, p = 0.023). Sham mice demonstrated improved performance across days (p = 0.005), and HI mice did not (p = 0.44). During the simple running wheel task, we observed no difference in wheel rotation and speed between groups (n = 5/group; day 1, p = 0.67; day 4, p = 0.53). However, when navigating a wheel with a random pattern of spokes removed (complex task), HI mice took longer than sham mice to reach a plateau in performance (n = 5/group; day 1, p = 0.02; day 4, p = 0.77). Conclusions: Our findings demonstrate that young adult mice exposed to HI exhibit significant deficits and delayed learning in complex motor performance compared to sham mice. HI mice do not show deficits in gross motor performance; however, more subtle impairments are present in complex motor performance and learning. This HI model exhibits subtle motor deficits relevant to findings in humans and may be a useful tool in testing further neuroprotective strategies. Full article