Neonatal Insult Research Articles

The Temporal Relationship between Blood-Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia.

Blood-brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia-ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). At 6, 12, 24, and 72 h (h) post-HI, brains were collected to assess neuropathology and BBB dysfunction. A significant breakdown of the BBB was observed in the HI injury group compared to the sham group from 6 h in the cortex and hippocampus (p < 0.001), including a significant increase in albumin extravasation (p < 0.0033) and decrease in basal lamina integrity and tight-junction proteins. There was a decrease in resting microglia (p < 0.0001) transitioning to an intermediate state from as early as 6 h post-HI, with the intermediate microglia peaking at 12 h (p < 0.0001), which significantly correlated to the peak of microbleeds. Neonatal HI insult leads to significant brain injury over the first 72 h that is mediated by BBB disruption within 6 h and a transitioning state of the resident microglia. Key BBB events coincide with the appearance of the intermediate microglial state and this relationship warrants further research and may be a key target for therapeutic intervention.

The Clinical, Etiological, and Demographic Profile of Children Aged 1 to 14 Years with Seizures Attending a Tertiary Care Hospital in Gwalior District, India: A Cross-Sectional Study

Purpose: The clinical profile of seizures among children exhibits ethnic and geographical variations. The objective of this study was to examine the clinical, etiological, and demographic profiles of childhood seizures.Methods: This was a hospital-based, cross-sectional study. Data were collected on the socio-demographic profile, details of the clinical presentation of seizure episodes, past history of meningitis, and neuroimaging (i.e., computed tomography [CT] scans), as well as the history of risk factors. Numbers, percentages, the chi-square test, and the Fisher exact test statistic were calculated. A P value of &lt;0.05 was considered significant.Results: This study included 102 patients, of whom 82 experienced generalized tonic-clonic seizures (GTCS) and the remaining 20 had focal seizures. The most common age at presentation was between 1 and 4 years (55.9%). Approximately 70.0% of the children experienced postictal confusion and drowsiness, 38.2% had fever or sleep deprivation, and 25.5% suffered from headaches or vomiting. Postictal confusion and drowsiness were significantly more prevalent in children with GTCS (76.8%) compared to those with focal seizures (45.0%). Cerebral edema was the most common abnormality detected on CT scans in children with GTCS (n=6). Conclusion: Younger age, neonatal brain insult, and family history were found to be associated with a higher risk of seizure episodes. Postictal confusion and drowsiness were identified as the most common clinical features. Postictal confusion and drowsiness were significantly more prevalent in GTCS compared to focal seizures. Cerebral edema was the most common abnormality observed in GTCS on CT neuroimaging.

Epidemiological Assessment of a Pediatric Palliative Care Clinic at a Brazilian Quaternary Hospital: 20 Years of Experience.

Background: The pediatric palliative care (PPC) sets up an interdisciplinary approach of chronic complex diseases throughout birth to adolescence. It encompasses countless contrasts in development and diagnosis scopes, which make this area a challenge to nonpediatric practitioners. Objective: We sought to assess the most prevalent diseases in follow-up of the PPC team. Methods: We analyzed the medical records of PPC clinic during the years 2001 and 2021 and the diagnosis of outpatients. We established a parallel with the world scientific literature concerning the epidemiology of PPC. Results: The most prevalent diseases were epidermolysis bullosa (36.9%), followed by neurological Inherited Errors of Metabolism (IEM) diseases (19.0%), IEM diseases (14.3%), dysmorphological and chromosomal disorders (8.5%), skeletal disorders mainly osteogenesis imperfecta (6.9%), and liver transplantation conditions (5.5%) (p < 0.001). The less frequent conditions were external causes, such as neonatal insults or traffic accidents (2.8%), cancer (1.7%), congenital cardiopathies (1.4%), congenital infectious diseases (1.1%), gastrointestinal and hepatic conditions (0.8%), and rheumatological conditions (0.3%). The patients were older at diagnosis (6.9 years) and at PPC referral (13.2 years) than patients with epidermolysis bullosa and skeletal disorders and dysmorphological and chromosomal disorders were younger on referral. Conclusion: There are a lot of complex chronic conditions which could benefit from palliative care in pediatric setting. However, epidemiological and symptomatological assessment of the health service is necessary to provide an appropriate care to the country's reality.

Long-term recruitment of peripheral immune cells to brain scars after a neonatal insult.

Although brain scars in adults have been extensively studied, there is less data available regarding scar formation during the neonatal period, and the involvement of peripheral immune cells in this process remains unexplored in neonates. Using a murine model of neonatal hypoxic-ischemic encephalopathy (HIE) and confocal microscopy, we characterized the scarring process and examined the recruitment of peripheral immune cells to cortical and hippocampal scars for up to 1 year post-insult. Regional differences in scar formation were observed, including the presence of reticular fibrotic networks in the cortex and perivascular fibrosis in the hippocampus. We identified chemokines with chronically elevated levels in both regions and demonstrated, through a parabiosis-based strategy, the recruitment of lymphocytes, neutrophils, and monocyte-derived macrophages to the scars several weeks after the neonatal insult. After 1 year, however, neutrophils and lymphocytes were absent from the scars. Our data indicate that peripheral immune cells are transient components of HIE-induced brain scars, opening up new possibilities for late therapeutic interventions.

Long-term Effects of Cannabidiol and/or Fentanyl Exposure in Rats Submitted to Neonatal Pain

The current study aimed to evaluate anxiety behavior, hippocampal ionized calcium-binding adaptor molecule 1 (Iba1) and cannabinoid receptor 1 (CB1) gene expression, and nociceptive response in adulthood after a combination of fentanyl and cannabidiol (CBD) for nociceptive stimuli induced during the first week of life in rats. Complete Freund’s adjuvant-induced inflammatory nociceptive insult on postnatal day (PN) 1 and PN3. Both fentanyl and CBD were used alone or in combination from PN1 to PN7. Behavioral and nociceptive tests were performed at PN60 and PN62. The expression of the microglial calcium-binding proteins Iba1 and CB1 was detected in the hippocampus using reverse Quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Our results suggest that the anxiety behavior response and immune activation in adult life depend on the CBD dose combined with fentanyl for the nociceptive stimuli induced during the first week of life. Treatment of neonatal nociceptive insult with CBD and opioids showed significant dose-dependent and male-female differences. The increased gene expression in the hippocampus of the analyzed cannabinoid gene supports this data. In addition, treatment with fentanyl led to an increase in CB1 protein expression. Moreover, the expression of Iba1 varied according to the administered dose of CBD and may or may not be associated with the opioid. A lower dose of CBD during the inflammatory period was associated with enhanced anxiety in adult life. PerspectiveThe treatment of nociceptive stimuli with CBD and opioids during the first week of life demonstrated significant sex differences in adult life on anxiety behavior and supraspinal pain sensitivity.

Sex-Dependent Gliovascular Interface Abnormality in the Hippocampus following Postnatal Immune Activation in Mice

The neuro-gliovascular unit is a crucial structure for providing a balanced well-functioning environment for neurons and their synapses. Activation of the immune system during the developmental period is believed to affect the gliovascular unit, which may trigger neurodevelopmental and neurological/neuropsychiatric diseases. In this study, we hypothesized that vulnerability of the male brain to a neonatal insult was conditioned by sex-dependent differences in the impairment of the hippocampal gliovascular unit. Male and female C57BL/6J pups received lipopolysaccharide (LPS) (1 mg/kg) or saline on postnatal day (P) 5. Brains were collected at P12 and morphological quantifications of hippocampal fibrillary glial acid protein (GFAP⁺) astrocytes and ionized calcium-binding adaptor molecule 1 protein (Iba1+) microglia were performed by using 3-D image analysis together with measuring the length of CD31⁺ and aquaporin-4 (AQP4⁺) vessels. We found a significant increase in the length of CD31⁺ capillaries in the male LPS group compared to the saline group; however, coverage of capillaries by astrocytic end-feet (AQP4⁺) was significantly reduced. In contrast, there was a significant increase in AQP4⁺ capillary length in female pups 1 week after LPS injection. GFAP⁺ astrocytes via morphological changes in the hippocampus showed significant enhancement in the activity 1 week following LPS injection in male mice. We propose that neonatal inflammation could induce susceptibility to neurodevelopmental disorders through modification of hippocampal gliovascular interface in a sex-dependent manner.

Abstract- Poster

Introduction:Autism is a neurodevelopmental disorder with impairment in social communication and with restricted repetitive behaviours About 1% to 60% of children with hypomelanotic skin disorders have autism.Case summary:A 3 year old female child had low weight and Neonatal ICU stay at birth, delay in fine motor, social cognition and language, and hyperactivity, along with inappropriate behaviors, poor eye contact and solitary play. Ophthalmology consultation showed foveal hypoplasia and was diagnosed to have oculocutaneous albinism. Paediatricians referred the child to Psychiatry for hyperactivity symptoms. On Psychiatric evaluation, objective assessments showed evidence of autism.Discussion:Autism spectrum disorders are one of the most common neurodevelopmental disorders associated with various comorbidities which could make the core diagnosis of autism challenging. Even though albinism with poor eye sight and intellectual disability secondary to neonatal insult can itself cause all the above clinical features, the child scored high in Modified Checklist for Autism in Toddlers (M-CHAT) and Childhood Autism Rating Scale (CARS) and diagnosed as Severe Autism, which could have been easily missed if not evaluated for.Conclusion:Autism is difficult to diagnose without adequate expertise and it is necessary to get Psychiatry liaison in any child with suspected atypical behaviour for early diagnosis and treatment.

A community-Based Epidemiological Study of Epilepsy among Students of Primary and Preparatory School Stages in New Damietta City

Background:Even though Epilepsy is a common neurological disorder globally, developing countries still have insufficient epidemiological data regarding epilepsy. Aim of the Work:We aimed to estimate the prevalence of epilepsy in primary and preparatory school students in New Damietta city, Damietta governorate, Egypt. Patients and Methods:A cross-sectional community-based study that was conducted over a period of six months from February to July 2020. All students from conventional schools were screened using a special validated Arabic translated questionnaire. Students with positive questionnaire findings were subjected to a detailed history, neurological examination, Electroencephalography [EEG], and Magnetic resonance imaging [MRI] whenever possible. Data were coded and analyzed. Result:Lifetime prevalence was 7.5/1000 in conventional schools. Male: Female ratio was 2:1 with statistical significance [95% Confidence Interval= 0.276 to 0.963]. Low socioeconomic class students had a statistically significant higher prevalence of epilepsy. Prenatal and neonatal insults, history of febrile convulsions, and family history of epilepsy were the risk factors with statistical significance. Generalized seizures were more frequent than focal and 62.2% of children were receiving treatment. EEG detected epileptiform discharges in 33.3% of students. Conclusion: The prevalence of overall epilepsy among primary and preparatory school students was similar to that of other Egyptian districts within the same age group. Being male and low socioeconomic status was associated with a high prevalence of epilepsy. The reported prevalence is similar to the prevalence of epilepsy in other Egyptian Governorates and other Arab countries, but lower than the prevalence in Upper Egypt and most developing countries.

Long-Term Mental Health and Quality of Life Outcomes of Neonatal Insults in Kilifi, Kenya

We examined the mental health and quality of life (QoL) outcomes and their correlates of school-aged survivors of neonatal jaundice (NNJ), hypoxic-ischemic encephalopathy (HIE), and a comparison group. The Child Behavior Checklist and the Pediatric Quality of Life Inventory were administered to assess the mental health and QoL of 375 children (134 with NNJ, 107 with HIE, and 134 comparison group) aged 6 to 12 years [Median age 9 (interquartile range 7 to 11)]. The results showed that survivors of NNJ and HIE have mental health problems and QoL similar to the comparison group. Maternal mental health was the predominant covariate of mental health and QoL in survivors of NNJ and HIE. This result could indicate that mothers with mental health problems are more likely to have children with mental health issues, but also that caring for children with these adversities may affect mental health well-being of the caregivers. There is a need for early mental health screening and psychosocial intervention for caregivers and their children to enhance both their mental health and QoL.

Correlation between increased serum malondialdehyde and spectrum of cranial ultrasonography findings in hypoxic ischemic encephalopathy: could it be used as a predictor of disease severity?

BackgroundHypoxic ischemic encephalopathy (HIE) is a major cause of mortality and morbidity in neonates. Malondialdehyde (MDH) is a colorless lipid that can be used as a marker for oxidative stress. Cranial ultrasound sensitivity and specificity in detection of neonatal HIE ought to be further investigated. This study aims to detect whether serum (MDH) can be used as an indicator for HIE severity and to assess the role of cranial ultrasound in diagnosis of HIE neurological disorders, correlating ultrasound findings to MDA levels.ResultsStatistically significant differences were found between the serum MDA levels in patients compared to controls as well as among serum MDA in patients with advancing Sarnat stages (I, II, III) P value < 0.001. Statistically significant levels of serum MDA were found in patients with ischemic US findings compared to those with normal scan; 36.4% of cases with ischemic US findings were diagnosed as Sarnat stage II while 63.6% were diagnosed with stage III with a statistically significant difference (P = 0.016).ConclusionCranial ultrasound can be used for diagnosis of neonatal hypoxic ischemic insults, with lower sensitivity in mild cases and increased sensitivity in severe cases; and when combined with measuring serum MDA levels, it can be used as a diagnostic marker and as a predictor for severity of HIE.

Long-term neurocognitive and educational outcomes of neonatal insults in Kilifi, Kenya

BackgroundThere is little data on the long-term neurocognitive and educational outcomes among school-aged survivors of neonatal jaundice (NNJ) and hypoxic-ischemic encephalopathy (HIE) in Africa.This study investigates the long-term neurocognitive and educational outcomes and the correlates of these outcomes in school-aged survivors of NNJ or HIE in Kilifi, Kenya.MethodsWe conducted a cross-sectional study on neurocognitive and educational outcomes among school-aged survivors (6–12 years) of NNJ (n = 134) and HIE (n = 107) and compared them to a community comparison group (n = 134). We assessed nonverbal intelligence, planning, working memory, attention, syntax, pragmatics, word-finding, memory, perceptual-motor, mathematical, and reading abilities. We also collected information on medical history, caregivers’ mental health, and family environment.ResultsThe survivors of NNJ had lower mean total scores in word-finding [F (1, 250) = 3.89, p = 0.050] and memory [F (1, 248) = 6.74, p = 0.010] than the comparison group. The survivors of HIE had lower mean scores in pragmatics [F (1, 230) = 6.61, p = 0.011] and higher scores higher scores in non-verbal reasoning [F (1, 225) =4.10, p = 0.044] than the comparison group. Stunted growth was associated with almost all the outcomes in HIE.ConclusionSurvivors of NNJ and HIE present with impairment in the multiple domains, which need to be taken into consideration in the planning of educational and rehabilitative services.

Brain-targeted hypoxia-inducible factor stabilization reduces neonatal hypoxic-ischemic brain injury

Hypoxia-inducible factor-1α (HIF1α) is a major regulator of cellular adaptation to hypoxia and oxidative stress, and recent advances of prolyl-4-hydroxylase (P4H) inhibitors have produced powerful tools to stabilize HIF1α for clinical applications. However, whether HIF1α provokes or resists neonatal hypoxic-ischemic (HI) brain injury has not been established in previous studies.We hypothesize that systemic and brain-targeted HIF1α stabilization may have divergent effects.To test this notion, herein we compared the effects of GSK360A, a potent P4H inhibitor, in in-vitro oxygen-glucose deprivation (OGD) and in in-vivo neonatal HI via intracerebroventricular (ICV), intraperitoneal (IP), and intranasal (IN) drug-application routes. We found that GSK360A increased the erythropoietin (EPO), heme oxygenase-1 (HO1) and glucose transporter 1 (Glut1) transcripts, all HIF1α target-genes, and promoted the survival of neurons and oligodendrocytes after OGD. Neonatal HI insult stabilized HIF1α in the ipsilateral hemisphere for up to 24 h, and either ICV or IN delivery of GSK360A after HI increased the HIF1α target-gene transcripts and decreased brain damage. In contrast, IP-injection of GSK360A failed to reduce HI brain damage, but elevated the risk of mortality at high doses, which may relate to an increase of the kidney and plasma EPO, leukocytosis, and abundant vascular endothelial growth factor (VEGF) mRNAs in the brain. These results suggest that brain-targeted HIF1α-stabilization is a potential treatment of neonatal HI brain injury, while systemic P4H-inhibition may provoke unwanted adverse effects.

Pre- and early postnatal enriched environmental experiences prevent neonatal hypoxia-ischemia late neurodegeneration via metabolic and neuroplastic mechanisms.

Prenatal and early postnatal periods are important for brain development and neural function. Neonatal insults such as hypoxia-ischemia (HI) causes prolonged neural and metabolic dysregulation, affecting central nervous system maturation. There is evidence that brain hypometabolism could increase the risk of adult-onset neurodegenerative diseases. However, the impact of non-pharmacologic strategies to attenuate HI-induced brain glucose dysfunction is still underexplored. This study investigated the long-term effects of early environmental enrichment in metabolic, cell, and functional responses after neonatal HI. Thereby, male Wistar rats were divided according to surgical procedure, sham, and HI (performed at postnatal day 3), and the allocation to standard (SC) or enriched condition (EC) during gestation and lactation periods. In-vivo cerebral metabolism was assessed by means of [18 F]-FDG micro-positron emission tomography, and cognitive, biochemical, and histological analyses were performed in adulthood. Our findings reveal that HI causes a reduction in glucose metabolism and glucose transporter levels as well as hyposynchronicity in metabolic brain networks. However, EC during prenatal or early postnatal period attenuated these metabolic disturbances. A positive correlation was observed between [18 F]-FDG values and volume ratios in adulthood, indicating that preserved tissue by EC is metabolically active. EC promotes better cognitive scores, as well as down-regulation of amyloid precursor protein in the parietal cortex and hippocampus of HI animals. Furthermore, growth-associated protein 43 was up-regulated in the cortex of EC animals. Altogether, results presented support that EC during gestation and lactation period can reduce HI-induced impairments that may contribute to functional decline and progressive late neurodegeneration.

Serum Biomarkers of Cerebral Insult in Neonates with Hypoxic-ischemic Encephalopathy

Background: Neonatal hypoxic-ischemic encephalopathy (NHIE) is one of the most common causes of fatality albeit the effort spent on the management. We aimed to measure the serum biomarkers of cerebral insult in neonates with hypoxic-ischemic encephalopathy and its correlation with treatment by erythropoietin (Epo). Methods: Serum biomarkers for brain injury were collected from neonates with NHIE at day zero and day five after affection. These biomarkers included brain-related proteins which included; ubiquitin carboxy-terminal hydrolase-L1 (UCH- L1), neuron enolase, Tau, and S100B. Furthermore, the study included different cytokines that can be traced in brain injury including; interleukins (ILs) 1b, 6, 8, 10, 12P70, and 13 in addition to tumor necrosis factor-alpha (NF-a), gamma interferon (IFN-g), monocyte chemoattractant protein-1, and brain-derived neurotrophic factor (BDNF). The brain injury was assessed by MRI after one year. Results: Among the included neonates, brain injury was associated with elevated baseline levels of ILs)1b, 6, 8, 10, and 13, IFN-g, TNF-a, Tau, UCH-L1, and S100B. Furthermore, elevated serum levels of Tau at the baseline and decreased level of BDNF at day five were correlated with a bad prognosis in one year. No correlation detected between Epo treatment and these biomarkers. Conclusions: The increased serum levels of the tested biomarkers at day zero were associated with brain insults in newborns with NHIE. Furthermore, BDNF and Tau were associated with worse prognosis, and there was no correlation detected between Epo treatment and these biomarkers.

MRI of the Neonatal Brain: A Review of Methodological Challenges and Neuroscientific Advances.

In recent years, exploration of the developing brain has become a major focus for researchers and clinicians in an attempt to understand what allows children to acquire amazing and unique abilities, as well as the impact of early disruptions (eg, prematurity, neonatal insults) that can lead to a wide range of neurodevelopmental disorders. Noninvasive neuroimaging methods such as MRI are essential to establish links between the brain and behavioral changes in newborns and infants. In this review article, we aim to highlight recent and representative studies using the various techniques available: anatomical MRI, quantitative MRI (relaxometry, diffusion MRI), multiparametric approaches, and functional MRI. Today, protocols use 1.5 or 3T MRI scanners, and specialized methodologies have been put in place for data acquisition and processing to address the methodological challenges specific to this population, such as sensitivity to motion. MR sequences must be adapted to the brains of newborns and infants to obtain relevant good soft‐tissue contrast, given the small size of the cerebral structures and the incomplete maturation of tissues. The use of age‐specific image postprocessing tools is also essential, as signal and contrast differ from the adult brain. Appropriate methodologies then make it possible to explore multiple neurodevelopmental mechanisms in a precise way, and assess changes with age or differences between groups of subjects, particularly through large‐scale projects. Although MRI measurements only indirectly reflect the complex series of dynamic processes observed throughout development at the molecular and cellular levels, this technique can provide information on brain morphology, structural connectivity, microstructural properties of gray and white matter, and on the functional architecture. Finally, MRI measures related to clinical, behavioral, and electrophysiological markers have a key role to play from a diagnostic and prognostic perspective in the implementation of early interventions to avoid long‐term disabilities in children.Evidence Level2Technical Efficacy Stage1

Long-term outcomes of survivors of neonatal insults: A systematic review and meta-analysis.

The Millennium Developmental Goals ensured a significant reduction in childhood mortality. However, this reduction simultaneously raised concerns about the long-term outcomes of survivors of early childhood insults. This systematic review focuses on the long-term neurocognitive and mental health outcomes of neonatal insults (NNI) survivors who are six years or older. Two independent reviewers conducted a comprehensive search for empirical literature by combining index and free terms from the inception of the databases until 10th October 2019. We also searched for additional relevant literature from grey literature and using reference tracking. Studies were included if they: were empirical studies conducted in humans; the study participants were followed at six years of age or longer; have an explicit diagnosis of NNI, and explicitly define the outcome and impairment. Medians and interquartile range (IQR) of the proportions of survivors of the different NNI with any impairment were calculated. A random-effect model was used to explore the estimates accounted for by each impairment domain. Fifty-two studies with 94,978 participants who survived NNI were included in this systematic review. The overall prevalence of impairment in the survivors of NNI was 10.0% (95% CI 9.8-10.2). The highest prevalence of impairment was accounted for by congenital rubella (38.8%: 95% CI 18.8-60.9), congenital cytomegalovirus (23.6%: 95% CI 9.5-41.5), and hypoxic-ischemic encephalopathy (23.3%: 95% CI 14.7-33.1) while neonatal jaundice has the lowest proportion (8.6%: 95% CI 2.7-17.3). The most affected domain was the neurodevelopmental domain (16.6%: 95% CI 13.6-19.8). The frequency of impairment was highest for neurodevelopmental impairment [22.0% (IQR = 9.2-24.8)] and least for school problems [0.0% (IQR = 0.0-0.00)] in any of the conditions. The long-term impact of NNI is also experienced in survivors of NNI who are 6 years or older, with impairments mostly experienced in the neurodevelopmental domain. However, there are limited studies on long-term outcomes of NNI in sub-Saharan Africa despite the high burden of NNI in the region. Registration number: CRD42018082119.

Neuroprotective role of lactate in rat neonatal hypoxia-ischemia

Hypoxic-ischemic (HI) encephalopathy remains a major cause of perinatal mortality and chronic disability in newborns worldwide (1–6 for 1000 births). The only current clinical treatment is hypothermia, which is efficient for less than 60% of babies. Mainly considered as a waste product in the past, lactate, in addition to glucose, is increasingly admitted as a supplementary fuel for neurons and, more recently, as a signaling molecule in the brain. Our aim was to investigate the neuroprotective effect of lactate in a neonatal (seven day old) rat model of hypoxia-ischemia. Pups received intra-peritoneal injection(s) of lactate (40 μmol). Size and apparent diffusion coefficients of brain lesions were assessed by magnetic resonance diffusion-weighted imaging. Oxiblot analyses and long-term behavioral studies were also conducted. A single lactate injection induced a 30% reduction in brain lesion volume, indicating a rapid and efficient neuroprotective effect. When oxamate, a lactate dehydrogenase inhibitor, was co-injected with lactate, the neuroprotection was completely abolished, highlighting the role of lactate metabolism in this protection. After three lactate injections (one per day), pups presented the smallest brain lesion volume and a complete recovery of neurological reflexes, sensorimotor capacities and long-term memory, demonstrating that lactate administration is a promising therapy for neonatal HI insult.

Long-term changes in metabolic brain network drive memory impairments in rats following neonatal hypoxia-ischemia.

Hypoxia and cerebral ischemia (HI) events are capable of triggering important changes in brain metabolism, including glucose metabolism abnormalities, which may be related to the severity of the insult. Using positron emission microtomography (microPET) with [18F]fluorodeoxyglucose (18F-FDG), this study proposes to assess abnormalities of brain glucose metabolism in adult rats previously submitted to the neonatal HI model. We hypothesize that cerebral metabolic outcomes will be associated with cognitive deficits and magnitude of brain injury. Seven-day-old rats were subjected to an HI model, induced by permanent occlusion of the right common carotid artery and systemic hypoxia. 18F-FDG-microPET was used to assess regional and whole brain glucose metabolism in rats at 60 postnatal days (PND 60). An interregional cross-correlation matrix was utilized to construct metabolic brain networks (MBN). Rats were also subjected to the Morris Water Maze (MWM) to evaluate spatial memory and their brains were processed for volumetric evaluation. Brain glucose metabolism changes were observed in adult rats after neonatal HI insult, limited to the right brain hemisphere. However, not all HI animals exhibited significant cerebral hypometabolism. Hippocampal glucose metabolism was used to stratify HI animals into HI hypometabolic (HI-h) and HI non-hypometabolic (HI non-h) groups. The HI-h group had drastic MBN disturbance, cognitive deficit, and brain tissue loss, concomitantly. Conversely, HI non-h rats had normal brain glucose metabolism and brain tissue preserved, but also presented MBN changes and spatial memory impairment. Furthermore, data showed that brain glucose metabolism correlated with cognitive deficits and brain volume outcomes. Our findings demonstrated that long-term changes in MBN drive memory impairments in adult rats subjected to neonatal hypoxic ischemia, using in vivo imaging microPET-FDG. The MBN analyses identified glucose metabolism abnormalities in HI non-h animals, which were not detected by conventional 18F-FDG standardized uptake value (SUVr) measurements. These animals exhibited a metabolic brain signature that may explain the cognitive deficit even with no identifiable brain damage.

Potential biomarkers for neuroinflammation and neurodegeneration at short and long term after neonatal hypoxic-ischemic insult in rat

BackgroundHypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates. Therapies in addition to whole-body cooling are under development to treat the neonate at risk for HI encephalopathy, but are not a quickly measured serum inflammatory or neuronal biomarkers to rapidly and accurately identify brain injury in order to follow the efficacy of therapies.MethodsIn order to identify potential biomarkers for early inflammatory and neurodegenerative events after neonatal hypoxia-ischemia, both male and female Wistar rat pups at postnatal day 7 (P7) were used and had their right carotid artery permanently doubly occluded and exposed to 8% oxygen for 90 min. Sensory and cognitive parameters were assessed by open field, rotarod, CatWalk, and Morris water maze (MWM) test. Plasma and CSF biomarkers were investigated on the acute (24 h and 72 h) and chronic phase (4 weeks). Brains were assessed for gene expression analysis by quantitative RT-PCR Array.ResultsWe found a delay of neurological reflex maturation in HI rats. We observed anxiolytic-like baseline behavior in males more than females following HI injury. HI rats held on the rotarod for a shorter time comparing to sham. HI injury impaired spatial learning ability on MWM test. The CatWalk assessment demonstrated a long-term deficit in gait parameters related to the hind paw. Proinflammatory biomarkers such as IL-6 in plasma and CCL2 and TNF-α in CSF showed an upregulation at 24 h after HI while other cytokines, such as IL-17A and CCL5, were upregulated after 72 h in CSF. At 24 h post-injury, we observed an increase of Edn1, Hif1-α, and Mmp9 mRNA levels in the ipsilateral vs the contralateral hemisphere of HI rats. An upregulation of genes involved with clotting and hematopoietic processes was observed 72 h post-injury.ConclusionsOur work showed that, in the immature brain, the HI injury induced an early increased production of several proinflammatory mediators detectable in plasma and CSF, followed by tissue damage in the hypoxic hemisphere and short-term as well as long-lasting neurobehavioral deficits.

Geniposide attenuates neonatal mouse brain injury after hypoxic-ischemia involving the activation of PI3K/Akt signaling pathway

Perinatal hypoxic-ischemia (HI) is a leading cause of acute mortality and neurologic complications in newborns. Geniposide, a natural product extracted from the herb Gardenia jasminoides, has been shown to possess neuroprotective effects in neurologic deficits. This study aims to investigate whether Geniposide has therapeutic potential to HI brain injury and the underlying mechanisms. C57/bl6 mice were subjected to HI insult on postnatal day 10. Geniposide (20 mg/kg b.w.) was administered intragastrically every day after HI insult for 7 successional days. Then mice at P18 were sacrificed and brain tissues were collected for further analysis. Geniposide treatment significantly inhibited cell apoptosis, reduced serum IgG leakage into brain tissue, attenuated astrogliosis and microgliosis, prevented loss of pericytes, loss of tight junction and adherens junction proteins. The PI3K/Akt signaling pathway, which related proteins were downregulated after HI insult, was activated by Geniposide treatment. Geniposide treatment after neonatal HI insult attenuated HI-induced cell apoptosis, IgG leakage, microgliosis, astrogliosis, pericytes loss and junction protein degradation. Geniposide could protect against HI-induced brain injury, which might be through the activation of PI3K/Akt signaling pathway.