Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products

Huang, Felix C.; Xi, Guohua; Keep, Richard F.; Hua, Ya; Nemoianu, Andrei; Hoff, Julian T.

doi:10.3171/jns.2002.96.2.0287

Cited by 406 publications

(338 citation statements)

References 53 publications

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“…The same authors found that subsequently heme‐oxygenase 1, an enzyme, degrading hemoglobin into carbon monoxide, biliverdin, and iron was markedly increased. Intracellular iron overload was shown to result in lipid peroxidation and free radical formation leading to delayed edema and acute brain injury 35, 36, 37, 38, 39. In accordance with these findings, brain tissue damage was reported to be reduced in experimental SAH by the knockout of lipocalin 2, an iron transport protein 40.…”

Section: Discussionmentioning

confidence: 53%

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

Scherfler

Schiefecker

Delazer

et al. 2016

Ann Clin Transl Neurol

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Objective MRI parameters of iron concentration (R2*, transverse relaxation rate), microstructural integrity (mean diffusivity and fractional anisotropy), as well as gray and white matter volumes were analyzed in patients with subarachnoid hemorrhage (SAH) and uncomplicated clinical course to detect the evolution of brain tissue changes 3 weeks and 12 months after ictus.Methods MRI scans of 14 SAH patients (aneurysm of the anterior communicating artery, n = 5; no aneurysm n = 9) were compared with 14 age‐matched healthy control subjects. Statistical parametric mapping (SPM) was applied to objectively identify focal changes of MRI parameters throughout the entire brain and to correlate image parameters with neuropsychological measures.Results SPM localized significant bilateral increases in R2* signal within the white matter compartment of the temporal and parietal lobe and the cingulate gyrus (P < 0.001) which did not change significantly at 12 months. Significant gray matter volume reduction of the left insula and superior temporal gyrus (P < 0.001), as well as decreases in fractional anisotropy of the cingulate gyrus (P < 0.01) were also evident at 12 months. Significant correlations were found between fractional anisotropy signal alterations adjacent to the left middle and superior frontal gyrus and cognitive parameters of executive dysfunction (P < 0.001).InterpretationThe study indicates that iron is trapped predominantly throughout large portions of the white matter compartment in SAH patients at 12 months postbleeding. Increased disintegration of fiber tracts colocalizing with iron overload and correlating with lower executive function performance suggests that the white matter compartment is primarily susceptible toward long‐term damage in patients with good clinical grade SAH.

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Section: Discussionmentioning

confidence: 53%

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

Scherfler

Schiefecker

Delazer

et al. 2016

Ann Clin Transl Neurol

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“…For instance, patients with naturally high levels of macrophage/microglial CD163 may have faster rates of hematoma resorption, and/or less neuroinflammation due to rapid sequestration of toxic hemoglobin. In various experimental models of ICH, augmenting hematoma clearance or neutralizing hemoglobin toxicity generally result in less PHE, reduced tissue injury, and improved functional performance in the animals 4, 5, 25, 26…”

Section: Discussionmentioning

confidence: 99%

“…The initial tissue injury of ICH activates numerous secondary injury pathways, including the release of toxic hemolysis products, enhanced oxidative stress, and robust proinflammatory responses. On a macroscopic level, these processes can result in blood‐brain‐barrier (BBB) disruption, tissue shifts and perihematomal edema (PHE) formation that can result in further neurological deterioration 4, 5, 6. As these secondary injury pathways can evolve over hours to days, they represent attractive targets for medical intervention.…”

Section: Introductionmentioning

confidence: 99%

Soluble CD163 in intracerebral hemorrhage: biomarker for perihematomal edema

Roy-O’Reilly

Zhu

Atadja

et al. 2017

Ann Clin Transl Neurol

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ObjectivePatients with intracerebral hemorrhage (ICH) may elaborate varying degrees of perihematomal edema (PHE), requiring closer monitoring and a higher intensity of treatment. Here, we explore whether the soluble form of CD163, a scavenger receptor responsible for hemoglobin sequestration, can serve as a prognostic biomarker of PHE development and poor outcome after ICH.MethodsOur study cohort was comprised of 51 primary age‐ and sex‐matched ICH patients with moderate‐sized, hypertensive deep hemorrhages. Patients were part of a prospective ICH registry cataloguing admission data along with functional outcomes. We measured sCD163 levels in serial serum and cerebrospinal fluid (CSF) samples obtained at prespecified timepoints. Descriptive statistics, including a generalized estimating equation for longitudinal data, were used to analyze sCD163 in relation to ICH outcomes.ResultsAcute serum sCD163 (<48 h postictus) was significantly elevated in ICH patients compared to both acute neurological event controls (P = <0.001) and healthy controls (P = 0.003). As predicted, acute serum sCD163 levels were significantly associated with both hematoma volume expansion (P = 0.009) and PHE expansion (P = 0.002). Further examination determined that patients with high PHE expansion had poorer modified Rankin Scale scores at discharge (P = 0.024), and circulating sCD163 levels were found to be significantly lower in patients with high‐level PHE expansion.InterpretationAcute sCD163 levels may be a useful biomarker for the acute identification of patients at risk for hematoma expansion, perihematomal edema expansion and poorer short‐term outcomes.

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“…There is overwhelming evidence in young and old animals from several species of the ability of iron chelator desferrioxamine to reduce neurologic injury and improve functional recovery following ICH Hua et al, 2006;Huang et al, 2002;Nakamura et al, 2004a;Okauchi et al, 2009;Song et al, 2007;Wan et al, 2006Wan et al, , 2009Wu et al, 2011b). This remains the most promising putative neuroprotectant, having advanced to clinical trials (Selim, 2009) with a phase II currently underway.…”

Section: Future Directionsmentioning

confidence: 99%

Experimental Intracerebral Hemorrhage: Avoiding Pitfalls in Translational Research

Kirkman

Allan

Parry‐Jones

2011

J Cereb Blood Flow Metab

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Intracerebral hemorrhage (ICH) has the highest mortality of all stroke subtypes, yet treatments are mainly limited to supportive management, and surgery remains controversial. Despite significant advances in our understanding of ICH pathophysiology, we still lack preclinical models that accurately replicate the underlying mechanisms of injury. Current experimental ICH models (including autologous blood and collagenase injection) simulate different aspects of ICH-mediated injury but lack some features of the clinical condition. Newly developed models, notably hypertension-and oral anticoagulant therapy-associated ICH models, offer added benefits but further study is needed to fully validate them. Here, we describe and discuss current approaches to experimental ICH, with suggestions for changes in how this condition is studied in the laboratory. Although advances in imaging over the past few decades have allowed greater insight into clinical ICH, there remains an important role for experimental models in furthering our understanding of the basic pathophysiologic processes underlying ICH, provided limitations of animal models are borne in mind. Owing to differences in existing models and the failed translation of benefits in experimental ICH to clinical practice, putative neuroprotectants should be trialed in multiple models using both histological and functional outcomes until a more accurate model of ICH is developed.

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Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products

Abstract: Hemoglobin causes brain edema, at least in part, through its degradation products. Limiting hemoglobin degradation coupled with the use of iron chelators may be a novel therapeutic approach to limit brain edema after ICH.

Cited by 406 publications

References 53 publications

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

Soluble CD163 in intracerebral hemorrhage: biomarker for perihematomal edema

Experimental Intracerebral Hemorrhage: Avoiding Pitfalls in Translational Research

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