Optimized Clustering Algorithm for Comparative Analysis of Different Prenatal Corticosteroid Neurological Deficits in Premature Infants through Magnetic Reasoning Imaging (MRI).

Objective: This study aimed to explore the application of different prenatal corticosteroids in the assessment of neurological deficits and prognosis in premature infants through Magnetic Reasoning Imaging (MRI) under optimized cluster algorithm. Methods: 100 pregnant women with threatened preterm labor were retrospectively analyzed, in which 38 pregnant women with lasting threatened preterm labor (group A) were treated with multiple courses of antenatal corticosteroids (dexamethasone treatment) and 62 cases of pregnant women with threatened preterm labor (group B) were treated with single course of dexamethasone treatment. Craniocerebral MRI images based on optimal clustering algorithm were used to examine neonates. Neonatal hypoxic-ischemic encephalopathy (HIE) rate, serum neuron-specific enolase (NSE) concentration, neonatal behavioral neurological score (NBNA), respiratory distress syndrome (RDS) rate, perinatal mortality, neonatal birth weight, and maternal complications rate of two groups were compared. Results: Compared with other traditional image segmentation algorithms, this algorithm had the best segmentation effect, the shortest running time (1.43 s), the least number of iterations (5 times), and the highest segmentation accuracy (97.98%). There was no significant difference in the HIE rate, serum NSE concentration, NBNA score, RDS score, and perinatal mortality in group A and group B (P > 0.05). Compared with group B, neonates' body weight in group A was decreased, while the maternal complication rate in group A was increased (P < 0.05). Conclusion: MRI images based on optimized clustering algorithm can be used in the diagnosis of neonatal hypoxic-ischemic encephalopathy. There is no significant difference in the application of different antenatal corticosteroids affecting premature nerve function defect and prognosis, but multiple courses of antenatal corticosteroids can affect neonatal body mass and increased maternal complications to a certain extent; therefore, before threatened premature delivery treatment, the pros and cons of multiple courses of antenatal corticosteroids should fully be considered and in the treatment, measures should be actively taken to alleviate the side effect.

Morphine consumption during pregnancy exacerbates neonatal hypoxia-ischemia injury in rats.

OBJECTIVE: Hypoxia-Ischemia (HI) is the most common cause of death and disability in human infants. The use of opiate in pregnant women affects their children. The aim of this study was to evaluate the effect of morphine consumption during pregnancy and lactation on vulnerability to neonatal HI in rats. MATERIALS AND METHODS: Female Wistar rats were randomly assigned into two groups: Group 1-Rats that did not receive any treatment during pregnancy and lactation and Group 2-Rats that received morphine during pregnancy and lactation. After delivery, male offspring were divided into four groups including: (a) SHAM, (b) SHAM/Morphine (SHAM/MO), (c) HI, (d) HI/Morphine (HI/MO). Seven days after HI induction, neurobehavioral tests were performed, and then, brain tissue was taken from the skull to measure cerebral edema, infarct volume, inflammatory factors, oxidative stress, and brain-derived neurotrophic factor (BDNF). RESULTS: Total antioxidant capacity (TAC) and BDNF levels in the HI/MO group were significantly lower than HI and SHAM groups. TNF-α, C-reactive protein and total oxidant capacity levels in the HI/MO group were significantly higher than HI and SHAM groups. Cerebral edema and infarct volume in the HI/MO group were significantly higher than the HI group. CONCLUSION: Based on the results, morphine consumption during pregnancy and lactation enhanced the deleterious effects of HI injury in pups.

A Ferret Model of Inflammation-sensitized Late Preterm Hypoxic-ischemic Brain Injury.

There is an ongoing need for clinically relevant models of perinatal infection and hypoxia-ischemia (HI) in which to test therapeutic interventions for infants with the neurological sequela of prematurity. Ferrets are ideal candidates for modeling the preterm human brain, as they are born lissencephalic and develop gyrencephalic brains postnatally. At birth, ferret brain development is similar to a 13 week human fetus, with postnatal-day (P) 17 kits considered to be equivalent to an infant at 32-36 weeks' gestation. We describe an injury model in the P17 ferret, where lipopolysaccharide administration is followed by bilateral cerebral ischemia, hypoxia, and hyperoxia. This simulates the complex interaction of prolonged inflammation, ischemia, hypoxia, and oxidative stress experienced in a number of neonates who develop brain injury. Injured animals display a range of gross injury severity, with morphological changes in the brain including narrowing of multiple cortical gyri and associated sulci. Injured animals also show slowed reflex development, slower and more variable speed of locomotion in an automated catwalk, and decreased exploration in an open field. This model provides a platform in which to test putative therapies for infants with neonatal encephalopathy associated with inflammation and HI, study mechanisms of injury that affect cortical development, and investigate pathways that provide resilience in unaffected animals.

Abnormal Presentation of Hypoxic Ischemic Encephalopathy Attributed to Polysubstance Exposure.

BACKGROUND With the increasing prevalence of substance use in pregnancy, the rates of neonatal abstinence syndrome (NAS) are dramatically increasing. There is little information on the use of multiple substances in adults, even less so of polysubstance abuse during pregnancy and the consequences for the fetus as well as the mother. CASE REPORT A newborn male born at 35 weeks presented post-delivery with hips bilaterally dislocated and hyperflexed. The patient's legs fully extended and their shoulders were bilaterally mid-flexed with arms fully extended. This neonate was also reported to have bilateral hearing and vision loss as well as NAS symptoms of high-pitched crying and respiratory distress. During pregnancy the mother in this case study admitted to using buprenorphine, benzodiazepines, gabapentin, and heroin. The consequences of using this combination has not been well studied in pregnancy. CONCLUSIONS The presented case had severe complications, likely due to maternal polysubstance use and poor prenatal care in pregnancy. Clonidine was used to control the NAS symptoms, ranitidine was used to treat the gastroesophageal reflux, and glycopyrronium bromide was used for the neonate's excessive secretions. After delivery, the patient was placed on a nasal noninvasive cannula for respiratory distress and was transferred to a different hospital for treatment of the more serious comorbid conditions.

Perinatal nicotine exposure alters Akt/GSK-3ß/mTOR/autophagy signaling, leading to development of hypoxic-ischemic-sensitive phenotype in rat neonatal brain.

Maternal cigarette smoking is a major perinatal insult that contributes to an increased risk of cardiovascular and neurodevelopmental diseases in offspring. Our previous studies revealed that perinatal nicotine exposure reprograms a sensitive phenotype in neonatal hypoxic-ischemic encephalopathy (HIE), yet the underlying molecular mechanisms remain largely elusive. The present study tested the hypothesis that perinatal nicotine exposure impacts autophagy signaling in the developing brain, resulting in enhanced susceptibility to neonatal HIE. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. Neonatal HIE was conducted in 9-day-old male rat pups. Protein kinase B/glycogen synthase kinase-3ß/mammalian target of rapamycin (Akt/GSK-3ß/mTOR) signaling and key autophagy markers were determined by Western blotting analysis. Rapamycin and MK2206 were administered via intracerebroventricular injection. Nicotine exposure significantly inhibited autophagy activities in neonatal brain tissues, characterized by an increased ratio of phosphoylated (p-) to total mTOR protein expression but reduced levels of autophagy-related 5, Beclin 1, and LC3ßI/II. Treatment with mTOR inhibitor rapamycin effectively blocked nicotine-mediated autophagy deficiency and, more importantly, reversed the nicotine-induced increase in HI brain infarction. In addition, nicotine exposure significantly upregulated p-Akt and p-GSK-3ß. Treatment with the Akt selective inhibitor MK2206 reversed the enhanced p-Akt and p-GSK-3ß, restored basal autophagic flux, and abolished nicotine-mediated HI brain injury. These findings suggest that perinatal nicotine-mediated alteration of Akt/GSK-3ß/mTOR signaling plays a key role in downregulation of autophagic flux, which contributes to the development of hypoxia/ischemia-sensitive phenotype in the neonatal brain.

Neuroprotective Effects of AG490 in Neonatal Hypoxic-Ischemic Brain Injury.

In infants and children, neonatal hypoxic-ischemic (HI) brain injury represents a major cause of chronic neurological morbidity. The transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel that conducts calcium, can mediate neuronal death following HI brain injury. An important endogenous activator of TRPM2 is H2O2, which has previously been reported to be upregulated in the neonatal brain after hypoxic ischemic injury. Here, incorporating both in vitro (H2O2-induced neuronal cell death model) and in vivo (mouse HI brain injury model) approaches, we examined the effects of AG490, which can inhibit the H2O2-induced TRPM2 channel. We found that AG490 elicited neuroprotective effects. We confirmed that AG490 reduced H2O2-induced TRPM2 currents. Specifically, application of AG490 to neurons ameliorated H2O2-induced cell injury in vitro. In addition, AG490 administration reduced brain damage and improved neurobehavioral performance following HI brain injury in vivo. The neuroprotective benefits of AG490 suggest that pharmacological inhibition of H2O2-activated TRPM2 currents can be exploited as a potential therapeutic strategy to treat HI-induced neurological complications.

Local Injection of Endothelin-1 in the Early Neonatal Rat Brain Models Ischemic Damage Associated with Motor Impairment and Diffuse Loss in Brain Volume.

Cerebral palsy is an irreversible movement disorder resulting from cerebral damage sustained during prenatal or neonatal brain development. As survival outcomes for preterm injury improve, there is increasing need to model ischemic injury at earlier neonatal time-points to better understand the subsequent pathological consequences. Here we demonstrate a novel neonatal ischemic model using focal administration of the potent vasoconstrictor peptide, endothelin-1 (ET-1), in newborn rats. The functional and histopathological outcomes compare favourably to those reported following the widely used hypoxic ischemia (HI) model. These include a robust motor deficit sustained into adulthood and recapitulation of hallmark features of preterm human brain injury, including atrophy of subcortical white matter and periventricular fiber bundles. Compared to procedures involving carotid artery manipulation and periods of hypoxia, the ET-1 ischemia model represents a rapid and technically simplified model more amenable to larger cohorts and with the potential to direct the locus of ischemic damage to specific brain areas.

HIF-1 Repression of PTEN Transcription Mediates Protective Effects of BMSCs on Neurons During Hypoxia.

Neonatal hypoxic-ischemic brain damage (HIBD) is a cerebral hypoxic-ischemic disease caused by a variety of insults during the perinatal period, leading to varying degrees of cognitive dysfunction. Mesenchymal stem cells play an important role in functional recovery, but the mechanism is not yet clear. It has been reported that HIF-1 and PTEN are involved in the process of hypoxia-ischemia, but the specific roles that these proteins play remains to be understood. In this study, we performed oxygen glucose deprivation (OGD) or CoCl2 preconditioning on hippocampal neurons to simulate a hypoxic environment in vitro, and then co-cultured them with BMSCs, to observe the effect of BMSCs and the role of HIF-1. In addition, bpV, an inhibitor of PTEN was added to OGD neurons to determine the role of PTEN during hypoxia. We found that the levels of cell damage and apoptosis in OGD neurons decreased significantly after co-culture with BMSCs. Apoptosis was increased when HIF-1 was inhibited, but neurons remained protected when PTEN was suppressed. We further established that HIF-1 was enriched at the PTEN promoter both in BMSCs and hippocampal neurons, with increased enrichment under hypoxic conditions, leading to reduced transcription of PTEN. Our findings support the conclusion that CoCl2 preconditioning of BMSCs can simulate hypoxic conditions and can protect OGD neurons, an effect that is mediated through activation of the HIF-1 system and repression of PTEN transcription.

Pharmacological and mechanical management of calcium channel blocker toxicity.

Cardiovascular instability associated with calcium channel blocker toxicity comprises a small percentage of overdose presentations, yet they are associated with a high mortality rate. We detail the management of a 64-year-old man who took an intentional overdose of 840 mg nimodipine. We include the treatment he received and highlight the scarcity of evidence behind the use of gastric decontamination, calcium, glucagon, intravenous lipid emulsion, high-dose insulin therapy, sodium bicarbonate, vasopressors and methylene blue in calcium channel blocker toxicity. Additionally, the article explores the use of electrical pacing and venoarterial extracorporeal membrane oxygenation (VA-ECMO). Following successful weaning of VA-ECMO, the patient was successfully extubated but remained neurologically impaired due to hypoxic-ischaemic brain injury, critical care polyneuropathy and renal failure requiring dialysis. He has cerebral performance category 3; he has mild cognitive impairment but able to perform some activities of daily living independently and communicate his thoughts and needs. He requires no respiratory or cardiovascular support.

Inhibition of miRNA-210 reverses nicotine-induced brain hypoxic-ischemic injury in neonatal rats.

Maternal tobacco use in pregnancy increases the risk of neurodevelopmental disorders and neurobehavioral deficits in postnatal life. The present study tested the hypothesis that perinatal nicotine exposure exacerbated brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats through up-regulation of miR-210 expression in the developing brain. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. Experiments of HI brain injury were performed in 10-day-old pups. Perinatal nicotine treatment significantly decreased neonatal body and brain weights, but increased the brain to body weight ratio. Perinatal nicotine exposure caused a significant increase in HI brain infarct size in the neonates. In addition, nicotine enhanced miR-210 expression and significantly attenuated brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase isoform B (TrkB) protein abundance in the brain. Of importance, intracerebroventricular administration of a miR-210 inhibitor (miR-210-LNA) significantly decreased HI-induced brain infarct size and reversed the nicotine-increased vulnerability to brain HI injury in the neonate. Furthermore, miR-210-LNA treatment also reversed nicotine-mediated down-regulation of BDNF and TrkB protein expression in the neonatal brains. These findings provide novel evidence that the increased miR-210 plays a causal role in perinatal nicotine-induced developmental programming of ischemic sensitive phenotype in the brain. It represents a potential novel therapeutic approach for treatment of brain hypoxic-ischemic encephalopathy in the neonate-induced by fetal stress.

Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism.

We have recently shown that increased hydrogen peroxide (H2O2) generation is involved in hypoxia-ischemia (HI)-mediated neonatal brain injury. H2O2 can react with free iron to form the hydroxyl radical, through Fenton Chemistry. Thus, the objective of this study was to determine if there was a role for the hydroxyl radical in neonatal HI brain injury and to elucidate the underlying mechanisms. Our data demonstrate that HI increases the deposition of free iron and hydroxyl radical formation, in both P7 hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD), and the neonatal rat exposed to HI. Both these processes were found to be nitric oxide (NO) dependent. Further analysis demonstrated that the NO-dependent increase in iron deposition was mediated through increased transferrin receptor expression and a decrease in ferritin expression. This was correlated with a reduction in aconitase activity. Both NO inhibition and iron scavenging, using deferoxamine administration, reduced hydroxyl radical levels and neuronal cell death. In conclusion, our results suggest that increased NO generation leads to neuronal cell death during neonatal HI, at least in part, by altering iron homeostasis and hydroxyl radical generation.

Leucoencefalopatía posthipóxica diferida tras intoxicación por monóxido de carbono: caso clínico / Post-hypoxic leukoencephalopathy after carbon monoxide poisoning: case report

La leucoencefalopatía posthipóxica diferida o retardada fue descrita por primera vez en el año 1976 por Ginsberg. Es un síndrome desmielinizante caracterizado por el comienzo agudo de síntomas neuropsiquiátricos días o semanas después de una aparente recuperación de un coma tras un período prolongado de hipooxigenación cerebral. Se diagnostica, después de excluir otras causas posibles del mismo, con una historia clínica exhaustiva y por pruebas de imagen cerebrales donde se aprecian áreas de afectación difusa en sustancia blanca cerebral. Presentamos el caso de un adulto varón de 52 años quien tras sufrir accidentalmente una intoxicación por monóxido de carbono presenta una cuadro neuropsiquiátrico de rigidez generalizada, apatía, mutismo y afectación pseudobulbar transcurridas varias semanas que requirió de ingreso hospitalario con carácter urgente dado su elevado riesgo vital. Creemos que este caso puede ayudar en el diagnóstico diferencial con otros cuadros extrapiramidales que cursen acompañados de síntomas psiquiátricos y colaborar en el mejor conocimiento del síndrome entre los profesionales sanitarios (AU)

Retarded or delayed post-hypoxic leukoencephalopathy was first described in 1976 by Ginsberg. It is a demyelinating syndrome characterized by the acute onset of neuropsychiatric symptoms days or weeks after apparent recovery from a coma after a prolonged period of cerebral hypo-oxygenation. It is diagnosed after excluding other possible causes of it, with a thorough clinical history and evidence of brain image where areas of diffuse involvement may be seen in cerebral white matter. The case is presented of a 52 year-old adult male who, after suffering an accidental carbon monoxide poisoning, presented with a neuropsychiatric disorder consisting of a generalized rigidity, apathy, mutism and pseudobulbar syndrome for several weeks that required urgent hospital admission due to their high lifetime risk. It is hoped that this case can help in the differential diagnosis with other extrapyramidal syndromes that are accompanied by psychiatric symptoms, and contributes to a better understanding of these disorders among health professionals (AU)

TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain.

BACKGROUND: Hypoxic-ischemia (HI) and inflammation are the two major pathogenic mechanisms of brain injury in very preterm infants. The neurovascular unit is the major target of HI injury in the immature brain. Systemic inflammation may worsen HI by up-regulating neuroinflammation and disrupting the blood-brain barrier (BBB). Since neurons and oligodendrocytes, microvascular endothelial cells, and microglia may closely interact with each other, there may be a common signaling pathway leading to neuroinflammation and neurovascular damage after injury in the immature brain. TNF-α is a key pro-inflammatory cytokine that acts through the TNF receptor (TNFR), and c-Jun N-terminal kinases (JNK) are important stress-responsive kinases. OBJECTIVE: To determine if TNFR1-JNK signaling is a shared pathway underlying neuroinflammation and neurovascular injury after lipopolysaccharide (LPS)-sensitized HI in the immature brain. METHODS: Postpartum (P) day-5 mice received LPS or normal saline (NS) injection before HI. Immunohistochemistry, immunoblotting and TNFR1- and TNFR2-knockout mouse pups were used to determine neuroinflammation, BBB damage, TNF-α expression, JNK activation, and cell apoptosis. The cellular distribution of p-JNK, TNFR1/TNFR2 and cleaved caspase-3 were examined using immunofluorescent staining. RESULTS: The LPS + HI group had significantly greater up-regulation of activated microglia, TNF-α and TNFR1 expression, and increases of BBB disruption and cleaved caspase-3 levels at 24 hours post-insult, and showed more cortical and white matter injury on P17 than the control and NS + HI groups. Cleaved caspase-3 was highly expressed in microvascular endothelial cells, neurons, and oligodendroglial precursor cells. LPS-sensitized HI also induced JNK activation and up-regulation of TNFR1 but not TNFR2 expression in the microglia, endothelial cells, neurons, and oligodendrocyte progenitors, and most of the TNFR1-positive cells co-expressed p-JNK. Etanercept (a TNF-α inhibitor) and AS601245 (a JNK inhibitor) protected against LPS-sensitized HI brain injury. The TNFR1-knockout but not TNFR2-knockout pups had significant reduction in JNK activation, attenuation of microglial activation, BBB breakdown and cleaved caspase-3 expression, and showed markedly less cortical and white matter injury than the wild-type pups after LPS-sensitized HI. CONCLUSION: TNFR1-JNK signaling is the shared pathway leading to neuroinflammation and neurovascular damage after LPS-sensitized HI in the immature brain.

Levetiracetam increases neonatal hypoxic-ischemic brain injury under normothermic, but not hypothermic conditions.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) resulting from perinatal asphyxia often leads to severe neurologic impairment or even death. There is a need to advance therapy for infants with HIE, for example to combine hypothermia with pharmacological treatment strategies. Levetiracetam (LEV) is approved for clinical administration to infants older than 4 weeks of age and is also used off-label in neonates. Furthermore, LEV was shown to be neuroprotective in adult animal models of brain injury. AIM OF THE STUDY: The aim of this study was to evaluate the neuroprotective potential of LEV in vitro using primary hippocampal neurons, and in vivo using an established model of neonatal hypoxic-ischemic brain injury. RESULTS: LEV treatment per se did not induce neurotoxicity in the developing rodent brain. Following oxygen glucose deprivation, we observed some, although not a significant, increase in cell death after LEV treatment. In vivo, LEV was administered under normothermic and hypothermic conditions following hypoxic-ischemic brain damage. LEV administration significantly increased brain injury under normothermic conditions. Compared to the normothermia-treated group, in the hypothermia group LEV administration did not increase hypoxic-ischemic brain injury. DISCUSSION: This study demonstrates that LEV treatment increases neonatal hypoxic-ischemic brain injury. Administration of LEV in the acute phase of the injury might interfere with the balanced activation and inactivation of excitatory and inhibitory receptors in the developing brain. The neurotoxic effect of LEV in the injured newborn brain might further suggest an agonistic effect of LEV on the GABAergic system. Hypothermia treatment attenuates glutamate release following hypoxic-ischemic brain injury and might therefore limit the potentially deleterious effects of LEV. As a consequence, our findings do not necessarily rule out a potentially beneficial effect, but argue for cautious use of LEV in newborn infants with pre-existing brain injury.

Electrophysiological correlations of morphological restructuring in experimental local ischemia of different severity in the rat sensorimotor cortex.

Local cerebrovascular disorders were modeled by reversible photochemical clotting of hemispheric cortical vessels. Mild ischemia led to reversible edema in the surface layers of the cortex: cytotoxic edema of the neuropile, primarily of the distal dendrites. This status led to an increase in the lower delta rhythm frequency band power. After administration of systemic anesthetic, delta rhythm appeared sooner in the ischemic foci than in intact cortical areas. More severe ischemia led to the appearance of dark and pyknotic neurons and reduction of oscillation power in all EEG spectrum bands. Restructuring of primarily dendrites caused by local moderate ischemia of the surface cortical layers at the early stage of neurodegenerative processes stimulated the inhibitory recovery processes.

Effect of hypoxic-ischemic insults on the composition of fatty acids in the brain of neonatal rats.

BACKGROUND: Long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA; 22:6 n-3), comprise a major component of brain membrane phospholipids. The effect of neonatal hypoxic-ischemic insults on brain fatty acid composition is not completely understood. The aim of this study was to investigate alterations in brain fatty acid composition during development and in response to hypoxic-ischemic insults in neonatal rats. METHODS: Postnatal day 7 pups were randomly assigned to two experimental groups: a control group or a hypoxic-ischemic group in which hypoxia-ischemia was produced by left common carotid artery occlusion and exposure to 8% oxygen for 1.5 h. Various brain fatty acids were measured on postnatal days 8, 10 and 14. RESULTS: On postnatal day 14, the ratio of DHA to total fatty acids increased in the control group, but not in the hypoxic-ischemic group (p < 0.05). We observed no significant differences in arachidonic acid content in the brain between the two groups. CONCLUSIONS: These results suggest that hypoxic-ischemic insults interfere with accumulation of brain DHA in developing rats. DHA supplementation may be beneficial for treating neonatal hypoxic-ischemic encephalopathy.

Expression of the Nrf2-system at the blood-CSF barrier is modulated by neonatal inflammation and hypoxia-ischemia.

Transcription factor NF-E2-related factor-2 (Nrf2) is a key regulator of endogenous anti-oxidant systems shown to play a neuroprotective role in the adult by preserving blood-brain barrier function. The choroid plexus, site for the blood-CSF barrier, has been suggested to be particularly important in maintaining brain barrier function in development. We investigated the expression of Nrf2- and detoxification-system genes in choroid plexus following systemic LPS injections, unilateral cerebral hypoxia-ischemia (HI) as well as the combination of LPS and HI (LPS/HI). Plexuses were collected at different time points after LPS, HI and LPS/HI in 9-day old mice. mRNA levels of Nrf2 and many of its target genes were analyzed by quantitative PCR. Cell death was analyzed by caspase-3 immunostaining and TUNEL. LPS caused down-regulation of the Nrf2-system genes while HI increased expression at earlier time points. LPS exposure prior to HI prevented many of the HI-induced gene increases. None of the insults resulted in any apparent cell death to choroidal epithelium. These data imply that the function of the inducible anti-oxidant system in the choroid plexus is down-regulated by inflammation, even if choroid cells are not structurally damaged. Further, LPS prevented the endogenous antioxidant response following HI, suggesting the possibility that the choroid plexus may be at risk if LPS is united with an insult that increases oxidative stress such as hypoxia-ischemia.

Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia.

Intrauterine infection exacerbates neonatal hypoxic-ischemic (HI) brain injury and impairs the development of cerebral cortex. Here we used low-dose lipopolysaccharide (LPS) pre-exposure followed by unilateral cerebral HI insult in 7-day-old rats to study the pathogenic mechanisms. We found that LPS pre-exposure blocked the HI-induced proteolytic activity of tissue-type plasminogen activator (tPA), but significantly enhanced NF-κB signaling, microglia activation, and the production of pro-inflammatory cytokines in newborn brains. Remarkably, these pathogenic responses were all blocked by intracerebroventricular injection of a stable-mutant form of plasminogen activator protein-1 called CPAI. Similarly, LPS pre-exposure amplified, while CPAI therapy mitigated HI-induced blood-brain-barrier damage and the brain tissue loss with a therapeutic window at 4 h after the LPS/HI insult. The CPAI also blocks microglia activation following a brain injection of LPS, which requires the contribution by tPA, but not the urinary-type plasminogen activator (uPA), as shown by experiments in tPA-null and uPA-null mice. These results implicate the nonproteolytic tPA activity in LPS/HI-induced brain damage and microglia activation. Finally, the CPAI treatment protects near-normal motor and white matter development despite neonatal LPS/HI insult. Together, because CPAI blocks both proteolytic and nonproteolytic tPA neurotoxicity, it is a promising therapeutics of neonatal HI injury either with or without infection.

Glucocorticoids and preterm hypoxic-ischemic brain injury: the good and the bad.

Fetuses at risk of premature delivery are now routinely exposed to maternal treatment with synthetic glucocorticoids. In randomized clinical trials, these substantially reduce acute neonatal systemic morbidity, and mortality, after premature birth and reduce intraventricular hemorrhage. However, the overall neurodevelopmental impact is surprisingly unclear; worryingly, postnatal glucocorticoids are consistently associated with impaired brain development. We review the clinical and experimental evidence on how glucocorticoids may affect the developing brain and highlight the need for systematic research.