Ischemia Complement Component C 3 Mediates Inflammatory Injury Following Focal Cerebral

The complement cascade has been implicated in ischemia/reperfusion injury, and recent studies have shown that complement inhibition is a promising treatment option for acute stroke. The development of clinically useful therapies has been hindered, however, by insufficient understanding of which complement subcomponents contribute to post-ischemic injury. To address this issue, we subjected mice deficient in selected complement proteins (C1q, C3, C5) to transient focal cerebral ischemia. Of the strains investigated, only C3 / mice were protected, as demonstrated by 34% reductions in both infarct volume (P 0.01) and neurological deficit score (P 0.05). C3-deficient mice also manifested decreased granulocyte infiltration (P 0.02) and reduced oxidative stress (P 0.05). Finally, administration of a C3a-receptor antagonist resulted in commensurate neurological improvement and stroke volume reduction (P 0.05). Together, these results establish C3 activation as the key constituent in complement-related inflammatory tissue injury following stroke and suggest a C3a anaphylatoxin-mediated mechanism. (Circ Res. 2006;99:209-217.)

[1]  J. Mocco,et al.  Alterations in Plasma Complement Levels Following Human Ischemic Stroke. , 2006, Neurosurgery.

[2]  Ralph Weissleder,et al.  Identification of the target self-antigens in reperfusion injury , 2006, The Journal of experimental medicine.

[3]  E. Connolly,et al.  C1q-Deficiency Is Neuroprotective Against Hypoxic-Ischemic Brain Injury in Neonatal Mice , 2005, Stroke.

[4]  A. Therien.  Agonist Activity of the Small Molecule C3aR Ligand SB 290157 , 2005, The Journal of Immunology.

[5]  W. Reenstra,et al.  Gastrointestinal Ischemia-Reperfusion Injury Is Lectin Complement Pathway Dependent without Involving C1q 1 , 2005, The Journal of Immunology.

[6]  F. Colotta,et al.  Targeting C5a: recent advances in drug discovery. , 2005, Current medicinal chemistry.

[7]  F. Van de Werf,et al.  Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial. , 2004, JAMA.

[8]  L. Bergamaschini,et al.  The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q. , 2004, The American journal of pathology.

[9]  T. Schallert,et al.  Intracerebral Hemorrhage in Mice: Model Characterization and Application for Genetically Modified Mice , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  P. Riederer,et al.  Complement C1q and C3 mRNA expression in the frontal cortex of Alzheimer's patients , 1995, Journal of Molecular Medicine.

[11]  F. Silverstein,et al.  Complement Activation Contributes to Hypoxic-Ischemic Brain Injury in Neonatal Rats , 2003, The Journal of Neuroscience.

[12]  L. Bergamaschini,et al.  Neuroprotection by Complement (C1) Inhibitor in Mouse Transient Brain Ischemia , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  Dimitrios Morikis,et al.  Compstatin, a peptide inhibitor of complement, exhibits species-specific binding to complement component C3. , 2003, Molecular immunology.

[14]  Dimitrios Morikis,et al.  The Structural Basis of Compstatin Activity Examined by Structure-Function-based Design of Peptide Analogs and NMR* 210 , 2002, The Journal of Biological Chemistry.

[15]  P. Maycox,et al.  Expression of the complement C3a and C5a receptors after permanent focal ischemia: An alternative interpretation , 2002, Glia.

[16]  A. Tenner.  Complement in Alzheimer’s disease: opportunities for modulating protective and pathogenic events , 2001, Neurobiology of Aging.

[17]  H. Nakase,et al.  [The effect of C 1 esterase inhibitor on ischemia: reperfusion injury in the rat brain]. , 2001, No to shinkei = Brain and nerve.

[18]  E. Connolly,et al.  The Role of the Complement Cascade in Ischemia/Reperfusion Injury: Implications for Neuroprotection , 2001, Molecular medicine.

[19]  J. Adams,et al.  Identification of a Selective Nonpeptide Antagonist of the Anaphylatoxin C3a Receptor That Demonstrates Antiinflammatory Activity in Animal Models , 2001, The Journal of Immunology.

[20]  J. Atkinson,et al.  Structure–function relationships of complement receptor type 1 , 2001, Immunological reviews.

[21]  C. Cotman,et al.  Complement Association with Neurons and β-Amyloid Deposition in the Brains of Aged Individuals with Down Syndrome , 2001, Neurobiology of Disease.

[22]  C. Lemere,et al.  Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease. , 2001, The American journal of pathology.

[23]  M. Montalto,et al.  Inhibition of complement C5 reduces local and remote organ injury after intestinal ischemia/reperfusion in the rat. , 2001, Gastroenterology.

[24]  P. Gasque,et al.  Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. , 2000, The American journal of pathology.

[25]  K. Reid,et al.  C1q: structure, function, and receptors. , 2000, Immunopharmacology.

[26]  K. Abe,et al.  Predominant role for C5b-9 in renal ischemia/reperfusion injury. , 2000, The Journal of clinical investigation.

[27]  Robert B Sim,et al.  Complement C1q Is Dramatically Up-Regulated in Brain Microglia in Response to Transient Global Cerebral Ischemia1 2 , 2000, The Journal of Immunology.

[28]  E. Mackenzie,et al.  Expression of Receptors for Complement Anaphylatoxins C3a and C5a Following Permanent Focal Cerebral Ischemia in the Mouse , 2000, Experimental Neurology.

[29]  J. Lubinski,et al.  In Vivo Role of Complement-Interacting Domains of Herpes Simplex Virus Type 1 Glycoprotein Gc , 1999, The Journal of experimental medicine.

[30]  P. Gasque,et al.  Increased Complement Biosynthesis By Microglia and Complement Activation on Neurons in Huntington's Disease , 1999, Experimental Neurology.

[31]  Yuan Zhang,et al.  Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. , 1999, Science.

[32]  H. Colten,et al.  Genetic disruption of the murine complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA. , 1999, Immunopharmacology.

[33]  E. Nussbaum,et al.  Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. , 1998, Neurosurgery.

[34]  I. Erdelmeier,et al.  Reactions of 1-methyl-2-phenylindole with malondialdehyde and 4-hydroxyalkenals. Analytical applications to a colorimetric assay of lipid peroxidation. , 1998, Chemical research in toxicology.

[35]  Yili,et al.  Neuronal Damage and Plasticity Identified by Microtubule-Associated Protein 2, Growth-Associated Protein 43, and Cyclin D1 Immunoreactivity After Focal Cerebral Ischemia in Rats , 1998 .

[36]  Pier Paolo Pandolfi,et al.  Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies , 1998, Nature Genetics.

[37]  H. Sarau,et al.  Complement Depletion Improves Neurological Function in Cerebral Ischemia , 1998, Brain Research Bulletin.

[38]  L. Klickstein,et al.  Complement receptor type 1 (CR1, CD35) is a receptor for C1q. , 1997, Immunity.

[39]  S. Kuroda,et al.  Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. , 1997, Clinical neuroscience.

[40]  M. Baudry,et al.  Hereditary Deficiencies in Complement C5 Are Associated with Intensified Neurodegenerative Responses That Implicate New Roles for the C-System in Neuronal and Astrocytic Functions , 1996, Neurobiology of Disease.

[41]  P. Gasque,et al.  Complement activation on human neuroblastoma cell lines in vitro: route of activation and expression of functional complement regulatory proteins , 1996, Journal of Neuroimmunology.

[42]  M. Pangburn,et al.  Investigation of mechanism-based inhibitors of complement targeting the activated thioester of human C3. , 1996, Biochemical pharmacology.

[43]  E. Connolly,et al.  Procedural and strain-related variables significantly affect outcome in a murine model of focal cerebral ischemia. , 1996, Neurosurgery.

[44]  E. Connolly,et al.  Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke. , 1996, The Journal of clinical investigation.

[45]  P. Gasque,et al.  Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells. , 1993, The Journal of biological chemistry.

[46]  E. Peerschke,et al.  Platelet activation by C1q results in the induction of alpha IIb/beta 3 integrins (GPIIb-IIIa) and the expression of P-selectin and procoagulant activity , 1993, The Journal of experimental medicine.

[47]  Steven A. Johnson,et al.  Complement mRNA in the mammalian brain: Responses to Alzheimer's disease and experimental brain lesioning , 1992, Neurobiology of Aging.

[48]  P. Ward,et al.  Superoxide responses of endothelial cells to C5a and TNF-alpha: divergent signal transduction pathways. , 1992, The American journal of physiology.

[49]  P. Mcgeer,et al.  Activation of the classical complement pathway in brain tissue of Alzheimer patients , 1989, Neuroscience Letters.

[50]  P. Eikelenboom,et al.  Complement activation in amyloid plaques in Alzheimer’s dementia , 1988, Virchows Archiv. B, Cell pathology including molecular pathology.

[51]  M. Mallat,et al.  Primary cultures of murine astrocytes produce C3 and factor B, two components of the alternative pathway of complement activation. , 1987, Journal of immunology.