The complement cascade as a therapeutic target in intracerebral hemorrhage

Ducruet, Andrew F.; Zacharia, Brad E.; Hickman, Zachary L.; Grobelny, Bartosz T.; Yeh, Mason L.; Sosunov, Sergey A.; Connolly, E. Sander

doi:10.1016/j.expneurol.2009.07.018

Cited by 112 publications

(94 citation statements)

References 66 publications

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“…Very few studies have evaluated adipokines in relation to ICH although C3 has been implicated in ICH pathogenesis [23,13,10]. We did see differences in the %ASP/C3, ASP, and C3 but not adiponectin, as has been shown with ICH and stroke in a previous study [24].…”

Section: Discussionsupporting

confidence: 61%

Myocardial Infarction and Intracerebral Hemorrhage in a Chinese Population: Relationship with Lipoproteins and Adipokines

Smith¹,

Liu²,

Lü³

et al. 2010

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BACKGROUND: Adipokines and inflammatory factors play an important role in disease progression. Two cardiovascular diseases which have important contributions to mortality and morbidity in China are intracerebral hemorrhage (ICH) and myocardial infarction (MI). Acylation stimulating protein has been shown in North American populations to have strong associations with risk factors for MI. Complement C3 (C3) a component of the innate complement immune system is the precursor protein to ASP; C3 has been implicated in the pathogenesis of ICH. OBJECTIVE: In this case-control study we examined the association between BMI, lipoproteins adiponectin, C3 and ASP) in a Chinese population. METHODS AND RESULTS: Three groups of subjects were studied: ICH group (N = 41), MI group (N = 60) and a control group (N = 44). There was no difference in BMI for either ICH or MI compared to controls Chinese men and women with ICH had ASP levels similar to controls yet lower C3 suggesting that C3, and the regulation of C3 conversion to ASP may be important in ICH disease pathology.

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Section: Discussionsupporting

confidence: 61%

Myocardial Infarction and Intracerebral Hemorrhage in a Chinese Population: Relationship with Lipoproteins and Adipokines

Smith¹,

Liu²,

Lü³

et al. 2010

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“…Edema formation that occurs in the peri-hematomal region is likely because of increased BBB damage, which contributes to consequent neuronal loss and delayed brain injury after ICH. 33,34 We found that after 3 days of ICH, mice treated with rADAMTS 13 developed significantly less brain edema and smaller hemorrhagic lesion volume as compared with the control group. These data suggest that the protective effect of rADAMTS 13 on hemorrhagic brain injury is most likely caused by the reduction in inflammation-related BBB dysfunction.…”

Section: Strokementioning

confidence: 79%

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage

Cai

Luo

et al. 2015

Stroke

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S pontaneous intracerebral hemorrhage (ICH) results from rupture of blood vessels in the brain. It represents ≈10% to 20% of all strokes and is a devastating clinical condition with a 30-day mortality rate of 30% to 55%.1 Currently, there is no proven treatment available for improving ICH outcome. Evidence suggest that ICH is associated with activation of local immune cells and release of inflammatory mediators, which result in enhanced disruption of the blood-brain barrier (BBB), causing an increase in peri-hematomal edema formation and consequent neuronal injury. [2][3][4] Cerebral edema is present in most patients with ICH and is an independent predictor of neurological deterioration.1,2 Therefore, strategies aimed at limiting inflammatory response and BBB dysfunction could be potential therapeutic targets for ICH.von Willebrand factor (VWF) is a multimeric adhesive protein that is released from endothelial Weibel-Palade bodies during injury or inflammation. 5 The multimeric size of VWF is modulated by ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13), which processed proteolytically VWF into smaller lessreactive forms. 6 Accumulating data indicate that ADAMTS 13 and VWF play an opposite role in thrombus formation and Background and Purpose-Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH. Methods-ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3. Results-Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions. Conclusions-Our findings reveal the importance of rADAMTS 13 in regulating...

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“…Apart from activating microglia and complement C3, 23 CRP can directly cause blood-brain barrier disruption and brain edema formation. 24 Experimental studies demonstrate that an acute local inflammatory response to the hematoma can occur within 1 hour of onset, 25 and a systemic state of inflammation is triggered.…”

Section: Prediction Of Ehg and Enwmentioning

confidence: 99%

C-Reactive Protein Predicts Hematoma Growth in Intracerebral Hemorrhage

Napoli

Parry‐Jones

Smith

et al. 2014

Stroke

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Inflammation is a major feature of sICH pathology, [3][4][5] and inflammatory markers on admission, such as fever, elevated white blood cell (WBC) count, interleukin-6 (IL-6), and fibrinogen are associated with worse short-term outcomes. 3,5,6 C-reactive protein (CRP), an acute-phase reactant induced by IL-6, is associated with 30-day mortality in ICH patients, 7 but its relationship with EHG is unknown. Our primary goal was to determine the link between CRP and EHG after sICH. As a secondary objective, we also sought to establish the relationship between CRP and early neurological worsening (ENW).Background and Purpose-Early hematoma growth (EHG) occurs in about one third of patients with spontaneous intracerebral hemorrhage. The main aim of this study was to investigate the potential of plasma C-reactive protein (CRP) for predicting EHG after acute spontaneous intracerebral hemorrhage. Methods-Plasma CRP was measured within 6 hours of onset (median, 120 minutes) in 399 patients with primary or vitamin K antagonist-associated spontaneous intracerebral hemorrhage and without recent infection. Computed tomography brain scans were performed at baseline and repeated within 24 hours (median, 22 hours). The primary outcome was EHG, defined as absolute growth >12.5 cm 3 or relative growth >33%. Secondary outcomes included early neurological worsening (ENW) using the Glasgow Coma Scale and 30-day mortality. Multivariable regression analyses were used to evaluate associations of CRP concentration and outcomes. Kaplan-Meier analysis was used for survival. Key Words: C-reactive protein ◼ cerebral hemorrhage ◼ inflammation ◼ prognosis Results-EHG C-Reactive Protein Predicts Hematoma Growth in Intracerebral HemorrhageMario

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The complement cascade as a therapeutic target in intracerebral hemorrhage

Cited by 112 publications

References 66 publications

Myocardial Infarction and Intracerebral Hemorrhage in a Chinese Population: Relationship with Lipoproteins and Adipokines

Myocardial Infarction and Intracerebral Hemorrhage in a Chinese Population: Relationship with Lipoproteins and Adipokines

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage

C-Reactive Protein Predicts Hematoma Growth in Intracerebral Hemorrhage

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