The Role of Complement in Stroke Therapy

  • Ricardo J. Komotar
  • Grace H. Kim
  • Marc L. Otten
  • Benjamin Hassid
  • J. Mocco
  • Michael E. Sughrue
  • Robert M. Starke
  • William J. Mack
  • Andrew F. Ducruet
  • Maxwell B. Merkow
  • Matthew C. Garrett
  • E. Sander Connolly
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 632)


Cerebral ischemia and reperfusion initiate an inflammatory process which results in secondary neuronal damage. Immunomodulatory agents represent a promising means of salavaging viable tissue following stroke. The complement cascade is a potent mediator of inflammation which is activated following cerebral ischemia. Complement is deposited on apoptotic neurons which likely leads to injury in adjacent viable cells. Studies suggest that blocking the complement cascade during the early phases of infarct evolution may result in decreased penumbral tissue infarction and limit the extent of brain injury. Additionally, other elements of the complement cascade may play a critical role in cell survival. In this paper, we review the role of the complement cascade in neuronal damage following ischemic injury and emphasize possible therapeutic targets.


Complement Cascade Complement Inhibition Acute Stroke Trial Soluble Complement Complement Mediate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Akita N., Nakase H., Kanemoto Y., Kaido T., Nishioka T., Sakaki T. (2001) [The effect of C 1 esterase inhibitor on ischemia: reperfusion injury in the rat brain]. No to Shinkei – Brain and Nerve 53:641–644PubMedGoogle Scholar
  2. Atkinson C., Zhu H., Qiao F., Varela J.C., Yu J., Song H., Kindy M.S., Tomlinson S. (2006) Complement-dependent P-selectin expression and injury following ischemic stroke. Journal of Immunology 177:7266–7274Google Scholar
  3. Bednar M.M.,Raymond S., McAuliffe T., Lodge P.A., Gross C.E. (1991) The role of neutrophils and platelets in a rabbit model of thromboembolic stroke. Stroke 22:44–50PubMedCrossRefGoogle Scholar
  4. Bednar M.M., Gross C.E., Howard D.B., Lynn M. (1997) Neutrophil activation in acute human central nervous system injury. Neurological Research 19:588–592PubMedGoogle Scholar
  5. Belayev L.,Busto R., Zhao W., Ginsberg M.D. (1996) Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Research 739:88–96PubMedCrossRefGoogle Scholar
  6. Buerke M., Murohara T., Lefer A.M. (1995) Cardioprotective effects of a C1 esterase inhibitor in myocardial ischemia and reperfusion. Circulation 91:393–402PubMedGoogle Scholar
  7. Chakraborti T.,Mandal A., Mandal M., Das S., Chakraborti S. (2000) Complement activation in heart diseases. Role of oxidants. Cellular Signalling 12:607–617PubMedCrossRefGoogle Scholar
  8. Cowell R.M.,Plane J.M., Silverstein F.S. (2003a) Complement activation contributes to hypoxic-ischemic brain injury in neonatal rats. Journal of Neuroscience 23:9459–9468Google Scholar
  9. Cowell R.M.,Plane J.M., Silverstein F.S. (2003b) Complement activation contributes to hypoxic-ischemic brain injury in neonatal rats. Journal of Neuroscience: 239459–9468Google Scholar
  10. D’Ambrosio A.L.,Pinsky D.J., Connolly E.S. (2001) The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection. Molecular Medicine 7:367–382PubMedGoogle Scholar
  11. Dawson D.A.,Ruetzler C.A., Carlos T.M., Kochanek P.M., Hallenbeck J.M. (1996) Polymorphonuclear leukocytes and microcirculatory perfusion in acute stroke in the SHR. Keio Journal of Medicine 45:248–252; discussion 252–243PubMedCrossRefGoogle Scholar
  12. De Simone R., Ajmone-Cat M.A., Tirassa P.,MinghettiL(2003) Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells. Journal of Neuropathology and Experimental Neurology 62:208–216PubMedGoogle Scholar
  13. De Simoni M.G Storini C., Barba M., Catapano L., Arabia A.M., Rossi E., Bergamaschini L. (2003) Neuroprotection by complement (C1) inhibitor in mouse transient brain ischemia. Journal of Cerebral Blood Flow and Metabolism 23:232–239PubMedGoogle Scholar
  14. De Simoni M.G.,Rossi E., Storini C., PizzimentiSEchart C., Bergamaschini L. (2004) The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q. American Journal of Pathology 164:1857–1863PubMedCrossRefGoogle Scholar
  15. del Zoppo G.J., Schmid-Schonbein G.W., Mori E., Copeland B.R., Chang C.M. (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276–1283PubMedCrossRefGoogle Scholar
  16. Dirnagl U.,Iadecola C., Moskowitz. M.A (1999) Pathobiology of ischaemic stroke: an integrated view. Trends in Neurosciences 22:391–397PubMedCrossRefGoogle Scholar
  17. Duffield., J.SWare C.F., Ryffel B., Savill J. (2001) Suppression by apoptotic cells defines tumor necrosis factor-mediated induction of glomerular mesangial cell apoptosis by activated macrophages. American Journal of Pathology 159:1397–1404PubMedCrossRefGoogle Scholar
  18. Eikelenboom P., Hack C.E., Rozemuller J.M., Stam F.C. (1989) Complement activation in amyloid plaques in Alzheimer’s dementia. Virchows Archiv. B. Cell Pathology 56:259–262Google Scholar
  19. Elward K., Gasque P. (2003) “Eat me” and “don’t eat me” signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system. Molecular Immunology 40:85–94PubMedCrossRefGoogle Scholar
  20. Fadok V.A.,(1999) Clearance: the last and often forgotten stage of apoptosis. Journal of Mammary Gland Biology & Neoplasia 4:203–211CrossRefGoogle Scholar
  21. Fadok V.A., Chimini.G (2001) The phagocytosis of apoptotic cells. Seminars in Immunology 13:365–372PubMedCrossRefGoogle Scholar
  22. Fadok V.A., Henson P.M. (1998) Apoptosis: getting rid of the bodies. Current Biology 8:R693–R695PubMedCrossRefGoogle Scholar
  23. Fadok V.A., Bratton D.L., Frasch S.C., Warner M.L., Henson P.M.(1998a) The role of phosphatidylserine in recognition of apoptotic cells by phagocytes [see comment]. Cell Death and Differentiation 5:551–562CrossRefGoogle Scholar
  24. Fadok V.A., Warner M.L., Bratton D.L., Henson P.M. (1998b) CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3). Journal of Immunology 161:6250–6257Google Scholar
  25. Figueroa E., Gordon L.E., Feldhoff P.W., Lassiter H.A. (2005) The administration of cobra venom factor reduces post-ischemic cerebral injury in adult and neonatal rats. Neuroscience Letters 380:48–53PubMedCrossRefGoogle Scholar
  26. Fischer B., Schmoll H., Riederer P., Bauer J., Platt D., Popa-Wagner A. (1995) Complement C1q and C3 mRNA expression in the frontal cortex of Alzheimer’s patients. Journal of Molecular Medicine 73:465–471PubMedCrossRefGoogle Scholar
  27. Fishelson Z., Attali G., Mevorach D. (2001)Complement and apoptosis. Molecular Immunology 38:207–219PubMedCrossRefGoogle Scholar
  28. Furuya, K.Takeda H., Azhar S., McCarron R.M., Chen Y., Ruetzler C.A., Wolcott K.M., DeGraba T.J., Rothlein R., Hugli T.E., del Zoppo G.J., Hallenbeck J.M. (2001) Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine anti-human intercellular adhesion molecule-1 antibody: a bedside-to-bench study. Stroke 32:2665–2674PubMedCrossRefGoogle Scholar
  29. Gasque P. Julen N., Ischenko A.M., Picot C., Mauger C., Chauzy C., Ripoche J., Fontaine M. (1992) Expression of complement components of the alternative pathway by glioma cell lines. Journal of Immunology 149:1381–1387Google Scholar
  30. Gasque P., Ischenko A., Legoedec J., Mauger C., Schouft M.T., Fontaine M. (1993) Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells. Journal of Biological Chemistry 268:25068–25074PubMedGoogle Scholar
  31. Gasque P., Thomas A., Fontaine M., Morgan B.P. (1996) Complement activation on human neuroblastoma cell lines in vitro: route of activation and expression of functional complement regulatory proteins. Journal of Neuroimmunology 66:29–40PubMedCrossRefGoogle Scholar
  32. Gasque P., Dean Y.D., McGreal E.P., VanBeek J., Morgan B.P. (2000) Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 49:171–186PubMedCrossRefGoogle Scholar
  33. Gasque P., Neal J.W., Singhrao S.K., McGreal E.P., Dean Y.D., Van B.J., Morgan B.P. (2002) Roles of the complement system in human neurodegenerative disorders: pro-inflammatory and tissue remodeling activities. Molecular Neurobiology 25:1–17PubMedCrossRefGoogle Scholar
  34. Gladstone D.J., Black S.E., Hakim A.M. (2002) Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33:2123–2136PubMedCrossRefGoogle Scholar
  35. Head E., Azizeh B.Y., Lott I.T., Tenner A.J., Cotman C.W., Cribbs D.H. (2001) Complement association with neurons and beta-amyloid deposition in the brains of aged individuals with Down Syndrome. Neurobiology of Disease 8:252–265PubMedCrossRefGoogle Scholar
  36. Huang J., Kim L.J., Mealey R., Marsh H.C., Jr., Zhang Y., Tenner A.J., Connolly E.S., Jr., Pinsky D.J. (1999) Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. Science 285:595–599PubMedCrossRefGoogle Scholar
  37. Kilgore K.S., Park J.L., Tanhehco E.J., Booth E.A., Marks R.M., Lucchesi B.R. (1998) Attenuation of interleukin-8 expression in C6-deficient rabbits after myocardial ischemia/reperfusion. Journal of Molecular and Cellular Cardiology 30:75–85PubMedCrossRefGoogle Scholar
  38. Knepper-Nicolai B., Savill J., Brown S.B. (1998) Constitutive apoptosis in human neutrophils requires 99synergy between calpains and the proteasome downstream of caspases. Journal of Biological Chemistry 273:30530–30536PubMedCrossRefGoogle Scholar
  39. Lazar H.L., Hamasaki T., Bao Y., Rivers S., Bernard S.A., Shemin R.J. (1998) Soluble complement receptor type I limits damage during revascularization of ischemic myocardium. Annals of Thoracic Surgery 65:973–977PubMedCrossRefGoogle Scholar
  40. Markiewski M.M., Mastellos D., Tudoran R., DeAngelis R.A., Strey C.W., Franchini S., Wetsel R.A., Erdei A., Lambris J.D. (2004) C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury. Journal of Immunology 173:747–754Google Scholar
  41. Matsuo Y., Onodera H., Shiga Y., Nakamura M., Ninomiya M., Kihara T., Kogure K. (1994) Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 25:1469–1475PubMedCrossRefGoogle Scholar
  42. Matsuoka Y., Picciano M., Malester B., LaFrancois J., Zehr C., Daeschner J.M., Olschowka J.A., Fonseca M.I., O’Banion M.K., Tenner A.J., Lemere C.A., Duff K. (2001) Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. American Journal of Pathology 158:1345–1354PubMedCrossRefGoogle Scholar
  43. McGeer P.L. Akiyama H., Itagaki S., McGeer E.G. (1989) Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neuroscience Letters 107:341–346PubMedCrossRefGoogle Scholar
  44. Mevorach D., (1999) The immune response to apoptotic cells. Annals of the New York Academy of Sciences: 887191–198CrossRefGoogle Scholar
  45. Mevorach D.(2000) Opsonization of apoptotic cells. Implications for uptake and autoimmunity. Annals of the New York Academy of Sciences 926:226–235PubMedCrossRefGoogle Scholar
  46. Mevorach D. (2003) Systemic lupus erythematosus and apoptosis: a question of balance. Clinical Reviews in Allergy and Immunology 25:49–60PubMedCrossRefGoogle Scholar
  47. Mevorach D. Mascarenhas J.O., Gershov D., Elkon K.B. (1998). Complement-dependent clearance of apoptotic cells by human macrophages Journal of Experimental Medicine 188:2313–2320PubMedCrossRefGoogle Scholar
  48. Mocco J. Mack W.J., Ducruet A.F., King R.G., Sughrue M.E., Coon A.L., Sosunov S.A., Sciacca R.R., Zhang Y., Marsh H.C., Jr., Pinsky D.J., Connolly E.S., Jr. (2006a) Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke. Journal of Neurosurgery 105:595–601CrossRefGoogle Scholar
  49. Mocco J. Mack W.J., Ducruet A.F., Sosunov S.A., Sughrue M.E., Hassid B.G., Nair M.N., Laufer I., Komotar R.J., Claire M., Holland H., Pinsky D.J., Connolly E.S., Jr. (2006b) Complement component C3 mediates inflammatory injury following focal cerebral ischemia. Circulation Research 99:209–217CrossRefGoogle Scholar
  50. Morgan B.P., Gasque P. (1996) Expression of complement in the brain: role in health and disease. Immunology Today 17:461–466PubMedCrossRefGoogle Scholar
  51. Morgan B.P., Gasque P. (1997) Extrahepatic complement biosynthesis: where, when and why? Clinical and Experimental Immunology 107:1–7PubMedCrossRefGoogle Scholar
  52. Morgan B.P., Gasque P., Singhrao S., Piddlesden S.J. (1997) The role of complement in disorders of the nervous system. Immunopharmacology 38:43–50PubMedCrossRefGoogle Scholar
  53. Mukherjee P., Pasinetti G.M. (2000) The role of complement anaphylatoxin C5a in neurodegeneration: implications in Alzheimer’s disease. Journal of Neuroimmunology 105:124–130PubMedCrossRefGoogle Scholar
  54. Mukherjee P., Pasinetti G.M. (2001) Complement anaphylatoxin C5a neuroprotects through mitogen-activated protein kinase-dependent inhibition of caspase 3. Journal of Neurochemistry 77:43–49PubMedCrossRefGoogle Scholar
  55. Osaka H.Mukherjee P., Aisen P.S., Pasinetti G.M. (1999). Complement-derived anaphylatoxin C5a protects against glutamate-mediated neurotoxicity Journal of Cellular Biochemistry 73:303–311PubMedCrossRefGoogle Scholar
  56. Pasinetti G.M., Tocco G., Sakhi S., Musleh W.D., DeSimoni M.G., Mascarucci P., Schreiber S., Baudry M., Finch C.E. (1996) Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions. Neurobiology of Disease: 3197–204CrossRefGoogle Scholar
  57. Rahpeymai Y., Hietala M.A., Wilhelmsson U., Fotheringham A., Davies I., Nilsson A.K., Zwirner J., Wetsel R.A., Gerard C., Pekny M., Pekna M (2006) Complement: a novel factor in basal and ischemia-induced neurogenesis. Embo Journal 25:1364–1374PubMedCrossRefGoogle Scholar
  58. Rancan M., Morganti-Kossmann M.C., Barnum S.R., Saft S., Schmidt O.I., Ertel W., Stahel P.F. (2003) Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice. Journal of Cerebral Blood Flow and Metabolism 23:1070–1074PubMedGoogle Scholar
  59. Multicentre Acute Stroke Trial – Italy (MAST-I) Group. (1995) Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 346:1509–1514Google Scholar
  60. Ratajczak M.Z. Reca R., Wysoczynski M., Kucia M., Baran J.T., Allendorf D.J., Ratajczak J., Ross G.D. (2004) Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells. Leukemia 18:1482–1490PubMedCrossRefGoogle Scholar
  61. Ren Y., Stuart L., Lindberg F.P., Rosenkranz A.R., Chen Y., Mayadas T.N., Savill J. (2001) Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient phagocytosis independent of beta 2 integrins. Journal of Immunology 166:4743–4750Google Scholar
  62. Rogers C.A., Gasque P., Piddlesden S.J., Okada N., Holers V.M., Morgan B.P. (1996) Expression and function of membrane regulators of complement on rat astrocytes in culture. Immunology 88:153–161PubMedCrossRefGoogle Scholar
  63. Savill J. (1997) Apoptosis in resolution of inflammation. Journal of Leukocyte Biology 61:375–380PubMedGoogle Scholar
  64. Savill J. (2000) Apoptosis in resolution of inflammation. Kidney and Blood Pressure Research 23:173–174PubMedGoogle Scholar
  65. Schafer M.K., Schwaeble W.J., Post C., Salvati P., Calabresi M., Sim R.B., Petry F., Loos M., Weihe E. (2000) Complement C1q is dramatically up-regulated in brain microglia in response to transient global cerebral ischemia. Journal of Immunology 164:5446–5452Google Scholar
  66. Shimakura A., Kamanaka Y., Ikeda Y., Kondo K., Suzuki Y., Umemura K. (2000) Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion. Brain Research 858:55–60PubMedCrossRefGoogle Scholar
  67. Singhrao S.K., Neal J.W., Gasque P., Morgan B.P., Newman G.R. (1996) Role of complement in the aetiology of Pick’s disease? Journal of Neuropathology and Experimental Neurology 55:578–593Google Scholar
  68. Singhrao S.K., Neal J.W., Rushmere N.K., Morgan B.P., Gasque P. (2000) Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. American Journal of Pathology 157:905–918PubMedCrossRefGoogle Scholar
  69. Small D.L., Morley P., Buchan A.M. (1999) Biology of ischemic cerebral cell death. Progress in Cardiovascular Diseases 42:185–207PubMedCrossRefGoogle Scholar
  70. Stahl G.L., Xu Y., Hao L., Miller M., Buras J.A., Fung M., Zhao H. (2003) Role for the alternative complement pathway in ischemia/reperfusion injury [see comment]. American Journal of Pathology 162:449–455PubMedCrossRefGoogle Scholar
  71. Storini C., Rossi E., Marrella V., Distaso M., Veerhuis R., Vergani C., Bergamaschini L., De Simoni M.G. (2005) C1-inhibitor protects against brain ischemia-reperfusion injury via inhibition of cell recruitment and inflammation. Neurobiology of Diseases 19:10–17CrossRefGoogle Scholar
  72. Strey C.W., Markiewski M., Mastellos D., Tudoran R., Spruce L.A., Greenbaum L.E., Lambris J.D. (2003) The proinflammatory mediators C3a and C5a are essential for liver regeneration. Journal of Experimental Medicine 198: 913 –923PubMedCrossRefGoogle Scholar
  73. Sughrue M.E., Connolly E.S., Jr. (2004) Effectively bridging the preclinical/clinical gap: the results of the ASTIN trial. Stroke 01.STR.0000121164.0000129117.0000121144Google Scholar
  74. Vakeva A., Morgan B.P., Tikkanen I., Helin K., Laurila P., Meri S. (1994) Time course of complement activation and inhibitor expression after ischemic injury of rat myocardium. American Journal of Pathology 144:1357–1368PubMedGoogle Scholar
  75. Vakeva A.P., Agah A., Rollins S.A., Matis L.A., Li L., Stahl G.L. (1998) Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy. Circulation 97:2259–2267PubMedGoogle Scholar
  76. van Beek J., Elward K., Gasque P. (2003) Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Annals of the New York Academy of Sciences 992:56–71PubMedCrossRefGoogle Scholar
  77. Vasthare U.S., Barone F.C., Sarau H.M., Rosenwasser R.H., DiMartino M., Young W.F., Tuma R.F. (1998) Complement depletion improves neurological function in cerebral ischemia. Brain Research Bulletin 45:413–419PubMedCrossRefGoogle Scholar
  78. Vuorte J., Lindsberg P.J., Kaste M., Meri S., Jansson S.E., Rothlein R., Repo H. (1999) Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in whole blood. Journal of Immunology 162:2353–2357Google Scholar
  79. Weiser M.R., Williams J.P., Moore F.D., Jr., Kobzik L., Ma M., Hechtman H.B., Carroll M.C. (1996) Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. Journal of Experimental Medicine 183:2343–2348PubMedCrossRefGoogle Scholar
  80. Weisman H.F., Bartow T., Leppo M.K., Marsh H.C., Jr., Carson G.R., Concino M.F., Boyle M.P., Roux K.H., Weisfeldt M.L., Fearon D.T. (1990) Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249:146–151PubMedCrossRefGoogle Scholar
  81. Wyss-Coray T., Yan F., Lin A.H., Lambris J.D., Alexander J.J., Quigg R.J., Masliah E. (2002) Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proceedings of the National Academy of Sciences of the United States of America 99:10837–10842PubMedCrossRefGoogle Scholar
  82. Yano T., Anraku S., Nakayama R., Ushijima K. (2003) Neuroprotective effect of urinary trypsin inhibitor against focal cerebral ischemia-reperfusion injury in rats. Anesthesiology 98:465–473PubMedCrossRefGoogle Scholar
  83. Yasuhara O., Aimi Y., McGeer E.G., McGeer P.L. (1994) Expression of the complement membrane attack complex and its inhibitors in Pick disease brain. Brain Research 652:346-–349PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ricardo J. Komotar
    • 1
  • Grace H. Kim
  • Marc L. Otten
  • Benjamin Hassid
  • J. Mocco
  • Michael E. Sughrue
  • Robert M. Starke
  • William J. Mack
  • Andrew F. Ducruet
  • Maxwell B. Merkow
  • Matthew C. Garrett
  • E. Sander Connolly
  1. 1.Department of Neurological SurgeryColumbia UniversityNew YorkUSA

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