Dataset Information

Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage.

ABSTRACT:

Background

Neonatal germinal matrix hemorrhage/intraventricular hemorrhage is common and often results in hydrocephalus. The pathogenesis of posthemorrhagic hydrocephalus is not fully understood.

Objective

To explore the potential role of hemoglobin and iron released after hemorrhage.

Methods

Artificial cerebrospinal fluid (aCSF), hemoglobin, or iron was injected into the right lateral ventricle of postnatal day-7 Sprague Dawley rats. Ventricle size, heme oxygenase-1 (HO-1) expression, and the presence of iron were evaluated 24 and 72 hours after injection. A subset of animals was treated with an iron chelator (deferoxamine) or vehicle for 24 hours after hemoglobin injection, and ventricle size and cell death were evaluated.

Results

Intraventricular injection of hemoglobin and iron resulted in ventricular enlargement at 24 hours compared with the injection of aCSF. Protoporphyrin IX, the iron-deficient immediate heme precursor, did not result in ventricular enlargement after injection into the ventricle. HO-1, the enzyme that releases iron from heme, was increased in the hippocampus and cortex of hemoglobin-injected animals at 24 hours compared with aCSF-injected controls. Treatment with an iron chelator, deferoxamine, decreased hemoglobin-induced ventricular enlargement and cell death.

Conclusion

Intraventricular injection of hemoglobin and iron can induce hydrocephalus. Treatment with an iron chelator reduced hemoglobin-induced ventricular enlargement. This has implications for the pathogenesis and treatment of posthemorrhagic hydrocephalus.

Abbreviations

aCSF, artificial cerebrospinal fluidDAB, 3,3'-diaminobenzidine-4HClGMH-IVH, germinal matrix hemorrhage/intraventricular hemorrhageHO-1, heme oxygenase-1ICH, intracerebral hemorrhagePBS, phosphate-buffered salineSVZ, subventricular zoneTBST, tris-buffered saline with Tween 20.

SUBMITTER: Strahle JM

PROVIDER: S-EPMC4237659 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage.

Strahle Jennifer M JM Garton Thomas T Bazzi Ahmad A AA Kilaru Harish H Garton Hugh J L HJ Maher Cormac O CO Muraszko Karin M KM Keep Richard F RF Xi Guohua G

Neurosurgery 20141201 6

<h4>Background</h4>Neonatal germinal matrix hemorrhage/intraventricular hemorrhage is common and often results in hydrocephalus. The pathogenesis of posthemorrhagic hydrocephalus is not fully understood.<h4>Objective</h4>To explore the potential role of hemoglobin and iron released after hemorrhage.<h4>Methods</h4>Artificial cerebrospinal fluid (aCSF), hemoglobin, or iron was injected into the right lateral ventricle of postnatal day-7 Sprague Dawley rats. Ventricle size, heme oxygenase-1 (HO-1) ...[more]

PMID: 25121790

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Project description:Background and Purpose- Preterm neonates with intraventricular hemorrhage (IVH) are at risk for posthemorrhagic hydrocephalus and poor neurological outcomes. Iron has been implicated in ventriculomegaly, hippocampal injury, and poor outcomes following IVH. We hypothesized that levels of cerebrospinal fluid blood breakdown products and endogenous iron clearance proteins in neonates with IVH differ from those of neonates with IVH who subsequently develop posthemorrhagic hydrocephalus. Methods- Premature neonates with an estimated gestational age at birth <30 weeks who underwent lumbar puncture for clinical evaluation an average of 2 weeks after birth were evaluated. Groups consisted of controls (n=16), low-grade IVH (grades I-II; n=4), high-grade IVH (grades III-IV; n=6), and posthemorrhagic hydrocephalus (n=9). Control subjects were preterm neonates born at <30 weeks' gestation without brain abnormality or hemorrhage on cranial ultrasound, who underwent lumbar puncture for clinical purposes. Cerebrospinal fluid hemoglobin, total bilirubin, total iron, ferritin, ceruloplasmin, transferrin, haptoglobin, and hemopexin were quantified. Results- Cerebrospinal fluid hemoglobin levels were increased in posthemorrhagic hydrocephalus compared with high-grade IVH (9.45 versus 6.06 µg/mL, P<0.05) and cerebrospinal fluid ferritin levels were increased in posthemorrhagic hydrocephalus compared with controls (511.33 versus 67.08, P<0.01). No significant group differences existed for the other cerebrospinal fluid blood breakdown and iron-handling proteins tested. We observed positive correlations between ventricular enlargement (frontal occipital horn ratio) and ferritin (Pearson r=0.67), hemoglobin (Pearson r=0.68), and total bilirubin (Pearson r=0.69). Conclusions- Neonates with posthemorrhagic hydrocephalus had significantly higher levels of hemoglobin than those with high-grade IVH. Levels of blood breakdown products, hemoglobin, ferritin, and bilirubin correlated with ventricular size. There was no elevation of several iron-scavenging proteins in cerebrospinal fluid in neonates with posthemorrhagic hydrocpehalus, indicative of posthemorrhagic hydrocephalus as a disease state occurring when endogenous iron clearance mechanisms are overwhelmed.

Project description:BackgroundIron overload plays an important role in hydrocephalus development following intraventricular hemorrhage (IVH). Aquaporin 4 (AQP4) participates in the balance of cerebrospinal fluid secretion and absorption. The current study investigated the role of AQP4 in the formation of hydrocephalus caused by iron overload after IVH.MethodsThere were three parts to this study. First, Sprague-Dawley rats received an intraventricular injection of 100 µl autologous blood or saline control. Second, rats had IVH and were treated with deferoxamine (DFX), an iron chelator, or vehicle. Third, rats had IVH and were treated with 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a specific AQP4 inhibitor, or vehicle. Rats underwent T2-weighted and T2* gradient-echo magnetic resonance imaging to assess lateral ventricular volume and intraventricular iron deposition at 7, 14, and 28 days after intraventricular injection and were then euthanized. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence analyses were conducted on the rat brains to evaluate the expression of AQP4 at different time points. Hematoxylin and eosin-stained brain sections were obtained to assess the ventricular wall damage on day 28.ResultsIntraventricular injection of autologous blood caused a significant ventricular dilatation, iron deposition, and ventricular wall damage. There was increased AQP4 mRNA and protein expression in the periventricular tissue in IVH rats through day 7 to day 28. The DFX treatment group had a lower lateral ventricular volume and less intraventricular iron deposition and ventricular wall damage than the vehicle-treated group after IVH. The expression of AQP4 protein in periventricular tissue was also inhibited by DFX on days 14 and 28 after IVH. The use of TGN-020 attenuated hydrocephalus development after IVH and inhibited the expression of AQP4 protein in the periventricular tissue between day 14 and day 28 without a significant effect on intraventricular iron deposition or ventricular wall damage.ConclusionsAQP4 located in the periventricular area mediated the effect of iron overload on hydrocephalus after IVH.

Project description:BackgroundCerebral intraventricular hemorrhage (IVH) is a major cause of severe neurodevelopmental impairment in preterm infants. To date, no therapy is available that prevents infants from developing serious neurological disability following IVH. Thus, to develop treatment strategies for IVH, it is essential to characterize the initial sequence of molecular events that leads to brain damage. In this study, we investigated extracellular hemoglobin (Hb) as a causal initiator of inflammation in preterm IVH.MethodsUsing a preterm rabbit pup model, we investigated the molecular mechanisms and events following IVH. We also characterized the concentrations of cell-free Hb metabolites and pro-inflammatory mediators in the cerebrospinal fluid (CSF) of preterm human infants and rabbit pups. Finally, Hb metabolites were evaluated as causal initiators of inflammation in primary rabbit astrocyte cell cultures.ResultsFollowing IVH in preterm rabbit pups, the intraventricular CSF concentration of cell-free methemoglobin (metHb) increased from 24 to 72 hours and was strongly correlated with the concentration of TNFα at 72 hours (r2 = 0.896, P <0.001). Also, the mRNA expression of TNFα, IL-1β, and Toll-like receptor-4 and TNFα protein levels were significantly increased in periventricular tissue at 72 hours, which was accompanied by extensive astrocyte activation (that is, glial fibrillary acidic protein (GFAP)staining). Furthermore, exposure of primary rabbit astrocyte cell cultures to metHb caused a dose-dependent increase in TNFα mRNA and protein levels, which was not observed following exposure to oxyhemoglobin (oxyHb) or hemin. Finally, a positive correlation (r2 = 0.237, P <0.03) between metHb and TNFα concentrations was observed in the CSF of preterm human infants following IVH.ConclusionsFollowing preterm IVH, increased metHb formation in the intraventricular space induces expression of pro-inflammatory cytokines. Thus, the formation of metHb might be a crucial initial event in the development of brain damage following preterm IVH. Accordingly, removal, scavenging, or neutralization of Hb could present a therapeutic opportunity and plausible approach to decreasing the damage in the immature brain following preterm IVH.

Project description:BackgroundHydrocephalus is a severe complication of intracerebral hemorrhage with ventricular extension (ICH-IVH) and causes cerebrospinal fluid (CSF) accumulation. The choroid plexus epithelium plays an important role in CSF secretion and constitutes the blood-CSF barrier within the brain-immune system interface. Although the NLRP3 inflammasome, as a key component of the innate immune system, promotes neuroinflammation, its role in the pathogenesis of hydrocephalus after hemorrhage has not been investigated. Therefore, this study aimed to investigate the potential mechanism of NLRP3 in hydrocephalus to discover a potential marker for targeted therapy.MethodsA rat model of hydrocephalus after ICH-IVH was developed through autologous blood infusion in wild-type and Nlrp3-/- rats. By studying the features and processes of the model, we investigated the relationship between the NLRP3 inflammasome and CSF hypersecretion in the choroid plexus.ResultsThe ICH-IVH model rats showed ventricular dilation accompanied by CSF hypersecretion for 3 days. Based on the choroid plexus RNA-seq and proteomics results, we found that an inflammatory response was activated. The NLRP3 inflammasome was investigated, and the expression levels of NLRP3 inflammasome components reached a peak at 3 days after ICH-IVH. Inhibition of NLRP3 by an MCC950 inflammasome inhibitor or Nlrp3 knockout decreased CSF secretion and ventricular dilation and attenuated neurological deficits after ICH-IVH. The mechanism underlying the neuroprotective effects of NLRP3 inhibition involved decreased phosphorylation of NKCC1, which is a major protein that regulates CSF secretion by altering Na+- and K+-coupled water transport, via MCC950 or Nlrp3 knockout. In combination with the in vitro experiments, this experiment confirmed the involvement of the NLRP3/p-NKCC1 pathway and Na+ and K+ flux.ConclusionsThis study demonstrates that NKCC1 phosphorylation in the choroid plexus epithelium promotes NLRP3 inflammasome-mediated CSF hypersecretion and that NLRP3 plays an important role in the pathogenesis of hydrocephalus after hemorrhage. These findings provide a new therapeutic strategy for treating hydrocephalus.

Dataset Information

Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage.

Background

Objective

Methods

Results

Conclusion

Abbreviations

Publications

Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage.

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