Neuroprotective effects of the SCR<sub>1–3</sub> functional domain of CR1 on acute cerebral ischemia and reperfusion injury in rats

Yang, Shengchun; Wang, Xiaoyan; Zhang, Xuan; Lu, Yanzhi; Wang, Zhengqing

doi:10.1179/1743132813y.0000000238

Cited by 6 publications

(3 citation statements)

References 25 publications

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“…In a rat model of liver ischemia/reperfusion, intravenous injection of sCR1 24 hours after ischemia reduced complement activity and C3 deposition on endothelial cells and ameliorated the reperfusion injury [384]. In addition, sCR1 was considered a promising anti-inflammatory therapeutic agent to alleviate complement-mediated ischemic brain injury [387]. In a rat model of cerebral ischemia, intravenous administration of the SCR1-3 or the SCR15-18 functional domain of sCR1 1 hour before surgery reduced infarct volume, C3b deposition and neutrophil infiltration in the brain and attenuated motor deficits after 24 hours of ischemia [387, 388].…”

Section: Therapeutic Approaches Against Complement In Ischemic Strokementioning

confidence: 99%

“…In addition, sCR1 was considered a promising anti-inflammatory therapeutic agent to alleviate complement-mediated ischemic brain injury [387]. In a rat model of cerebral ischemia, intravenous administration of the SCR1-3 or the SCR15-18 functional domain of sCR1 1 hour before surgery reduced infarct volume, C3b deposition and neutrophil infiltration in the brain and attenuated motor deficits after 24 hours of ischemia [387, 388]. Furthermore, sCR1-sLex (sLex-glycosylated sCR1 modification) treatment showed better neuroprotective effects than unmodified sCR1 treatment in ischemic stroke [24].…”

Section: Therapeutic Approaches Against Complement In Ischemic Strokementioning

confidence: 99%

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Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Liu

Zhang

et al. 2019

Aging and disease

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The complement system is an essential part of innate immunity, typically conferring protection via eliminating pathogens and accumulating debris. However, the defensive function of the complement system can exacerbate immune, inflammatory, and degenerative responses in various pathological conditions. Cumulative evidence indicates that the complement system plays a critical role in the pathogenesis of ischemic brain injury, as the depletion of certain complement components or the inhibition of complement activation could reduce ischemic brain injury. Although multiple candidates modulating or inhibiting complement activation show massive potential for the treatment of ischemic stroke, the clinical availability of complement inhibitors remains limited. The complement system is also involved in neural plasticity and neurogenesis during cerebral ischemia. Thus, unexpected side effects could be induced if the systemic complement system is inhibited. In this review, we highlighted the recent concepts and discoveries of the roles of different kinds of complement components, such as C3a, C5a, and their receptors, in both normal brain physiology and the pathophysiology of brain ischemia. In addition, we comprehensively reviewed the current development of complement-targeted therapy for ischemic stroke and discussed the challenges of bringing these therapies into the clinic. The design of future experiments was also discussed to better characterize the role of complement in both tissue injury and recovery after cerebral ischemia. More studies are needed to elucidate the molecular and cellular mechanisms of how complement components exert their functions in different stages of ischemic stroke to optimize the intervention of targeting the complement system.

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Section: Therapeutic Approaches Against Complement In Ischemic Strokementioning

confidence: 99%

Section: Therapeutic Approaches Against Complement In Ischemic Strokementioning

confidence: 99%

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Liu

Zhang

et al. 2019

Aging and disease

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“…It has been found that an inhibitor of C3 convertase, the soluble complement receptor 1 (sCR1), significantly decreased myocardial infarct size and improved myocardial function in a rat model of ischemia-reperfusion [80]. More interestingly, the CR1 short consensus repeats has been confirmed to protect against cerebral ischemia-reperfusion injury in rats, decreasing cerebral infarct size and improving neurological function [81]. Additionally, C5 is another important component of complement system, which after cleavage can be converted into C5a and C5b-9, two potent inflammation mediators that increase vascular permeability, leucocyte adhesion and activation, and endothelial activation [82].…”

Section: Potential Therapeutic Strategies Targeting Ischemia-reperfusmentioning

confidence: 99%

Ischemia-reperfusion Injury in the Brain: Mechanisms and Potential Therapeutic Strategies

Lin

Wang

2016

Biochem Pharmacol (Los Angel)

136

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Ischemia-reperfusion injury is a common feature of ischemic stroke, which occurs when blood supply is restored after a period of ischemia. Reperfusion can be achieved either by thrombolysis using thrombolytic reagents such as tissue plasminogen activator (tPA), or through mechanical removal of thrombi. Spontaneous reperfusion also occurs after ischemic stroke. However, despite the beneficial effect of restored oxygen supply by reperfusion, it also causes deleterious effect compared with permanent ischemia. With the recent advancement in endovascular therapy including thrombectomy and thrombus disruption, reperfusion-injury has become an increasingly critical challenge in stroke treatment. It is therefore of extreme importance to understand the mechanisms of ischemia-reperfusion injury in the brain in order to develop effective therapeutics. Accumulating experimental evidence have suggested that the mechanisms of ischemia-reperfusion injury include oxidative stress, leukocyte infiltration, platelet adhesion and aggregation, complement activation, mitochondrial mediated mechanisms, and blood-brain-barrier (BBB) disruption, which altogether ultimately lead to edema or hemorrhagic transformation (HT) in the brain. Potential therapeutic strategies against ischemia-reperfusion injury may be developed targeting these mechanisms. In this review, we briefly discuss the pathophysiology and cellular and molecular mechanisms of cerebral ischemia-reperfusion injury, and potential therapeutic strategies.

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C5a/C5aR Pathway Plays a Vital Role in Brain Inflammatory Injury via Initiating Fgl-2 in Intracerebral Hemorrhage

Yuan

Fu²,

Huang³

et al. 2016

Mol Neurobiol

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Intracerebral hemorrhage (ICH) is a serious emergency with high mortality and morbidity. Up to date, a limited understanding of ICH pathogenesis is difficult to implement effective therapeutic strategy. Much evidence demonstrates that the complement cascade is activated after experimental ICH. However, the exact mechanism has not been well studied in ICH. In the current study, C57BL/6J mice were injected with autologous whole blood. C5a/C5aR levels, microglia infiltration, inflammatory cytokine, and fibrinogen-like protein 2 (Fgl-2) expression in the perihematomal region were analyzed following ICH. In addition, brain water content and neurological dysfunction were detected following ICH. Our data demonstrated that ICH induced complement activation, along with an increase of C5a/C5aR levels, microglia infiltration, and inflammatory cytokine levels. However, C5aR mice exhibited significant attenuation of inflammatory reaction, accompanied by a remarkable reduction of Fgl-2, brain water content, and neurological dysfunction. Furthermore, inhibiting extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 efficiently inhibited C5a-mediated Fgl-2 production following ICH. Taken together, these data suggest that C5a/C5aR plays a vital role in the ICH-induced inflammatory damage via Fgl-2, and ERK1/2 and p38 pathways also are involved in the pathogenesis of ICH. Therefore, inhibition of C5a/C5aR activation might enlarge our insights in ICH therapy.

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Neuroprotective effects of the SCR_1–3 functional domain of CR1 on acute cerebral ischemia and reperfusion injury in rats

Abstract: CR1-SCR1-3 protein could possess a neuroprotective effect on acute CI/R injury.

Cited by 6 publications

References 25 publications

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Ischemia-reperfusion Injury in the Brain: Mechanisms and Potential Therapeutic Strategies

C5a/C5aR Pathway Plays a Vital Role in Brain Inflammatory Injury via Initiating Fgl-2 in Intracerebral Hemorrhage

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Neuroprotective effects of the SCR1–3 functional domain of CR1 on acute cerebral ischemia and reperfusion injury in rats

Abstract: CR1-SCR1-3 protein could possess a neuroprotective effect on acute CI/R injury.

Cited by 6 publications

References 25 publications

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Ischemia-reperfusion Injury in the Brain: Mechanisms and Potential Therapeutic Strategies

C5a/C5aR Pathway Plays a Vital Role in Brain Inflammatory Injury via Initiating Fgl-2 in Intracerebral Hemorrhage

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Neuroprotective effects of the SCR_1–3 functional domain of CR1 on acute cerebral ischemia and reperfusion injury in rats