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Aging and disease    2019, Vol. 10 Issue (2) : 429-462     DOI: 10.14336/AD.2019.0119
Review |
Significance of Complement System in Ischemic Stroke: A Comprehensive Review
Yuanyuan Ma1,2, Yanqun Liu3, Zhijun Zhang2, Guo-Yuan Yang1,2,*
1Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
2Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
3Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China
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Abstract  

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.

Keywords brain      C3a      C5a      complement      ischemic stroke     
Corresponding Authors: Yang Guo-Yuan   
About author:

Currently address: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China

Just Accepted Date: 25 January 2019   Online First Date: 12 February 2019    Issue Date: 05 April 2019
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Yuanyuan Ma
Yanqun Liu
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Guo-Yuan Yang
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Yuanyuan Ma,Yanqun Liu,Zhijun Zhang, et al. Significance of Complement System in Ischemic Stroke: A Comprehensive Review[J]. Aging and disease, 2019, 10(2): 429-462.
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http://www.aginganddisease.org/EN/10.14336/AD.2019.0119     OR     http://www.aginganddisease.org/EN/Y2019/V10/I2/429
AnimalsStroke modelsTime of administrationRoutes of injectionTime point of observationsOutcomesMechanismsRefs
C57BL/6 mice1 h MCAO0.5 h before
or 6 h after MCAO
Intravenous injection with IVIg or alone72 h after MCAOReduced brain infarction size, neurological deficit and mortalityReduced deposition of C3b and downregulated excessive TLR2 and p-JNK1 expression in the brain[400]
C57BL/6 mice
& CD rats
1 h MCAO (mice) & 1.5 h MCAO (rats)1 h or 6 h after MCAOIntravenous injection24 h and 7 days after MCAOReduced infarct volumes and improved clinical scoresReduced blood-brain barrier damage, edema formation, and inflammation[366]
Sprague-Dawley ratspMCAO
or thromboembolic stroke
2 h or 4 h after MCAOIntravenous injection with tPA or alone24 h after MCAOReduced intracranial hemorrhage and neurological scoresNot studied[428]
C57Bl/6 mice0.5 h MCAO or pMCAO0 h, 3 h, 6 h, or 18 h after MCAOIntravenous injection48 h and 7 days after MCAOReduced brain infarct volumes and CD45+ cell infiltration in the brainNot studied[367]
CD1 mice2 h MCAOImmediately after ischemiaIntravenous injection48 h after MCAOAttenuated general and focal neurological deficitsReduced TNF-a, IL-18, ICAM-1 and P-selectin mRNA expression and microglia activation; Enhanced IL-6 and IL-10 mRNA expression[369]
C57BL/60.5 h MCAO15 min after ischemiaIntravenous injection4 days after MCAOReduced general and focal neurological deficit scores and neuronal degenerationReduced CD45+ cell infiltration in the brain[33]
CD1 mice2 h MCAO15 min after MCAOIntravenous injection48 h after MCAOReduced infarct volume and neuronal deathDid not affect astrocyte response[364]
Wistar rats1 h MCAOJust before MCAOIntravenous injection48 h after MCAOReduced infarct volume and leukocyte infiltration in the brainNot studied[429]
Table 1  C1-INH treatment for ischemic stroke
AnimalsStroke modelsTime of administrationRoutes of injectionTime point of observationsOutcomesMechanismsRefs
Adult rats &
7-day-old rats
1.5 h MCAO in adult rats;
Unilateral carotid artery ligation followed by transient hypoxia in neonates
24 h before surgeryIntraperitoneal injection48 h after surgeryReduced brain infarct volume and brain atrophyNot studied[64]
7-day-old ratsCerebral hypoxic-ischemic injury24 h before surgeryIntraperitoneal injection1 day and 5 days after cerebral ischemiaReduced systemic C3 and neuronal C3 deposition in the brain; Reduced brain infarct sizeDid not affect neuronal C9 deposition and microglial C3 deposition in the brain[63]
7-day-old ratsUnilateral carotid artery ligation followed by transient hypoxia24 h before surgeryIntraperitoneal injection24 h after surgeryDid not reduce infarct volumeNot studied[300]
Sprague-Dawley ratsAutologous blood induced intracerebral hemorrhage36 h, 24 h, and 12 h before induction of intracerebral hemorrhageIntraperitoneal injection2 h, 24 h, or 72 h after intracerebral hemorrhageReduced brain water content and MPO activity at 72 hours after intracerebral hemorrhageNot studied[430]
21-day-old ratsRight common carotid artery ligation and hypoxia24 h immediately before and 72 h after surgeryIntraperitoneal injection24 h, 48 h after cerebral ischemiaDid not did not reduce the neuronal loss, brain edema or atrophyNot studied[377]
New Zealand white rabbitsThromboembolic stroke48 h before surgeryIntraperitoneal injection7 h after surgeryDid not reduce brain infarct volumeNot studied[431]
Sprague-Dawley ratsReversible incomplete forebrain ischemia24 h before surgeryIntraperitoneal injectionWithin 4 h after cerebral ischemiaHad a tendency to increase focal cerebral blood flow and increased somatosensory evoked potentials in the cortexNot studied[376]
Table 2  CVF administration for ischemic stroke.
AnimalsStroke modelsTime of administrationRoutes of injectionTime point of observationsOutcomesMechanismsRefs
C57BL/6 mice1 h MCAO0.5 h before or 1 h, 3 h and 6 h after surgeryIntravenous injection of IVIg (1 g/kg)72 h after MCAOReduced brain infarct area, mortality, and neurological deficit scoreInhibited C3b deposition and TLR2 expression in the brain[400]
C57BL/6J mice1 h MCAO3 h after surgeryIntravenous injection of IVIg (1 g/kg)6 h, 24 h after MCAOIncreased low-density lipoprotein receptor-related protein 1 (LRP1) tyrosine phosphorylation in the brainInhibited pro-death signaling pathways such as NF-κB, MAPKs, and caspase-3 in cultured neurons under OGD condition[432]
Sprague-Dawley rats2 h MCAOJust after surgeryIntravenous injection of IVIg (400 mg/kg)72 h after MCAOReduced neurological deficit scoreNot studied[433]
C57BL/6 mice1 h MCAO3 h after surgeryIntravenous injection of IVIg (1 g/kg)6 h, 24 h after MCAOReduced TL2, TLR4 and TLR8 expression in the brain; Reduced NF-κB and MAPK activities in the brainInhibited HMGB1 induced activation of NF-κB-p-p65, p-JNK, p38 MAPK and p-c-Jun, and increased Bcl-2 expression in cultured neurons under oxygen and glucose deprivation[403]
C57BL/6 mice1 h MCAO3 h after surgeryIntravenous injection of IVIg (2 g/kg)24 h after MCAOReduced CD45+ leukocyte infiltration in the brainNot studied[401]
C57BL/6J mice1 h MCAO3 h after surgeryIntravenous injection of IVIg (1 g/kg)6 h, 24 h, 72 h after MCAOReduced inflammasome components NLRP1 and NLRP3, and IL-1β and IL-18 expression in the brainNot studied[402]
C57BL/6 mice1 h MCAO0.5 h before or 3 h after surgeryIntravenous injection of IVIg (2 g/kg)24 h after MCAOReduced brain infarct volume and neurological deficit, increased neuronal survivalInhibited phosphorylation of the cell death-associated kinases p38 MAPK, JNK and p65 in cultured neurons under OGD condition[404]
Wistar rats1.5 h MCAO0.5 h before surgeryIntravenous injection of IVIg (1 g/kg)24 h after MCAOReduced brain infarct volume and neurological deficit scoreNot studied[434]
C57BL/6 mice1 h MCAO0.5 h before or 3 h after surgeryIntravenous injection of IVIg (2 g/kg)24 h after MCAOReduced brain infarct volume and neurological deficitInhibited C3 elevation in the brain; Reduced endothelial cell adhesion, lymphocyte infiltration, and microglial activation[269]
Table 3  IVIg treatment for ischemic stroke.
AnimalsStroke modelsTime of administrationRoutes of injectionTime point of observationsOutcomesMechanismsRefs
Sprague-Dawley rats1 h MCAO1 h before surgeryIntravenous injection of sCR11 h, 24 h after surgeryReduced brain infarct volume and neurological motor deficitsReduced neutrophil accumulation and inflammation; Reduced C4b deposition in the cortex[387]
Sprague-Dawley rats2 h MCAO1 h before surgeryIntravenous injection of sCR12 h, 24 h after surgeryReduced brain infarct size and neurological deficit scoresInhibited neutrophil infiltration and C3b deposition in the brain[388]
Adult male baboons1.25 h MCAO45 min before surgeryIntravenous injection of sCR1-sLex2 h, 6 h, 12 h, 72 h and 10 days of post-ischemiaIncreased brain infarct volume;
Did not improve neurological functions
Not studied[390]
Adult male baboons1.25 h MCAO45 min before surgeryIntravenous injection of sCR172 h and 10 days of post-surgeryDid not affect brain infarct volume and neurological scoresNot studied[389]
7-day-old ratsUnilateral carotid artery ligation followed by transient hypoxia24 h before surgeryIntraperitoneal injection of sCR1 or sCR1-sLex24 h after surgeryDid not reduce infarct volumeNot studied[300]
Mice0.75 h MCAOImmediately before MCAOAdministration of sCR1 or sCR1-sLex24 h after strokeReduced brain infarct volume and neurological deficit scoreInhibited neutrophil and platelet accumulation in the brain[24]
Table 4  sCR1 treatment for ischemic stroke.
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