The Role of Complement C3 in Intracerebral Hemorrhage-Induced Brain Injury

Yang, Shuxu; Nakamura, Takehiro; Hua, Ya; Keep, Richard F.; Younger, John G.; He, Yonggen; Hoff, Julian T.; Xi, Guohua

doi:10.1038/sj.jcbfm.9600305

Cited by 85 publications

(72 citation statements)

References 34 publications

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“…Application of N-acetylhepain, an inhibitor of complement activation, suppressed edema formation (42). Moreover, C3-deficient mice that underwent autologous blood injection exhibited less brain edema, lower HO-1 levels, less microglia activation, and neutrophil infiltration, concomitantly with alleviated deficits in motor functions, compared to wild-type mice (43). The deleterious role of C3 is also supported by a study using a C3a-receptor antagonist.…”

Section: Complementsupporting

confidence: 48%

Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

Katsuki

2010

J Pharmacol Sci

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Abstract. Intracerebral hemorrhage (ICH) is a devastating neurological disorder with high mortality and poor prognosis, for which virtually no effective drug therapies are available at present. Experimental animal models, based on intrastriatal injection of collagenase or autologous blood, have enabled great advances in elucidation of cellular/molecular events contributing to brain pathogenesis associated with ICH. Many lines of evidence indicate that blood constituents, including hemoglobin-derived products as well as proteases such as thrombin, play important roles in the pathogenic events. Inflammatory reactions involving neutrophils, activated microglia, and production of proinflammatory cytokines also constitute a critical aspect of pathology leading to neurodegeneration and tissue damage. Efforts are continuing to find drugs that potentially alleviate pathologi cal and neurological outcomes of ICH. Various drugs that possess antioxidative, antiinflammatory or neurotrophic/neuroprotective properties have been demonstrated to produce therapeutic effects on ICH animal models. Drugs already in clinical use such as minocycline, statins, and several nuclear receptor ligands are among the list of effective drugs, but whether they also show therapeutic efficacy in human ICH patients remains unproven. Here, current knowledge of ICH pathogenesis and problems arising with respect to exploration of new drug candidates are discussed.

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Section: Complementsupporting

confidence: 48%

Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

Katsuki

2010

J Pharmacol Sci

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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: 59%

“…By contrast, Chen et al found that a BMI below 20 was also a risk for factor ischemic heart disease in the Chinese population [2]. Hypertension, which is prevalent in the Chinese population, is another major risk factor for both ICH and MI [10,8]. Taken together, these risk factors may be responsible for the higher rates of cardiovascular diseases (CVD) and the development of CVD at a young age in Chinese individuals [11].…”

Section: Introductionmentioning

confidence: 99%

“…However, the precursor protein to ASP, C3, is a key component of the complement innate immune system and has been implicated in ICH disease progression. In rodent models, C3 gene expression has been shown to increase immediately after the occurrence of an ICH [13] and mice lacking C3 are protected from further brain damage after ICH [14,10]. In humans who have had an ICH, it was reported that they had elevated C3 concentrations [14].…”

Section: Introductionmentioning

confidence: 99%

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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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“…In contrast, C1q, C3, and other complement components contributed to brain edema and histopathology in models of ischemic and hemorrhagic brain injury (Ten et al, 2005;Yang et al, 2006). In a closed head TBI model, Rancan et al (2003) reported that astrocyte overexpression of soluble complement receptor protein y (sCrry), a mouse-specific C3 convertase inhibitor, reduced posttraumatic bloodbrain barrier damage and improved neurologic severity scores (including motor function, alertness, and physiologic behavior).…”

Section: Discussionmentioning

confidence: 99%

Reduced Tissue Damage and Improved Recovery of Motor Function after Traumatic Brain Injury in Mice Deficient in Complement Component C4

You

Yang

Takahashi

et al. 2007

J Cereb Blood Flow Metab

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Complement component C4 mediates C3-dependent tissue damage after systemic ischemiareperfusion injury. Activation of C3 also contributes to the pathogenesis of experimental and human traumatic brain injury (TBI); however, few data exist regarding the specific pathways (classic, alternative, and lectin) involved. Using complement knockout mice and a controlled cortical impact (CCI) model, we tested the hypothesis that the classic pathway mediates secondary damage after TBI. After CCI, C4c and C3d immunostaining were detected in cortical vascular endothelial cells in wild-type (WT) mice; however, C4c and C3d immunostaining were also detected in C1q À/À mice, and C3d immunostaining was detected in C4 À/À mice. After CCI, WT and C1q À/À mice had similar motor deficits, Morris water maze performance, and brain lesion size. Naive C4 À/À and WT mice did not differ in baseline motor performance, but C4 À/À mice had reduced postinjury motor deficits (days 1 to 7, P < 0.05) and decreased brain tissue damage (days 14 and 35, P < 0.05) versus WT. Reconstitution of C4 À/À mice with human C4 (hC4) reversed their protection against postinjury motor deficits (P < 0.05 versus vehicle), but administration of hC4 did not impair postinjury motor performance (versus vehicle) in WT mice. The protective effects of C4 À/À were functionally distinct from the classic pathway and terminal complement, as C1q À/À and C3 À/À mice had postinjury tissue damage and motor dysfunction similar to WT. Thus, C4 contributes to motor deficits and brain tissue damage after CCI by mechanism(s) fundamentally different from those involved in experimental systemic ischemia-reperfusion injury.Journal of Cerebral Blood Flow & Metabolism (2007) 27, 1954-1964 doi:10.1038/sj.jcbfm.9600497; published online 25 April 2007 Keywords: complement; mice; behavior; traumatic brain injury; inflammation; genetics Introduction Traumatic brain injury induces an acute inflammatory response that contributes to posttraumatic cell death and functional neurologic deficits (Schmidt et al, 2005). Activation of complement amplifies local inflammation and exacerbates tissue damage and organ dysfunction after systemic and central nervous system ischemia-reperfusion injury (Chan et al, 2003;del Zoppo, 1999;Zhou et al, 2000), and studies in humans and in experimental animal models provide convincing evidence that Stahel et al, 2000). Complement signaling in injured brain parenchyma may also be contributed by serum components that enter the brain through a compromised blood-brain barrier.To date, only four published studies have examined a role for complement in traumatic cerebral contusion models. The investigators showed beneficial effects on histopathologic or functional outcome of pharmacologic C3 convertase inhibitors (Kaczorowski et al, 1995;Leinhase et al, 2006b), genetic inhibition of factor B (a component of the alternative pathway) (Leinhase et al, 2006a), or of astrocyte-specific overexpression of an endogenous C3 convertase inhibitor (Rancan et al, 2003). These studies...

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The Role of Complement C3 in Intracerebral Hemorrhage-Induced Brain Injury

Cited by 85 publications

References 34 publications

Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

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

Reduced Tissue Damage and Improved Recovery of Motor Function after Traumatic Brain Injury in Mice Deficient in Complement Component C4

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