Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein.
Glycoprotein adhesion receptors such as selectins contribute to tissue injury in stroke. Ischemic neurons strongly expressed C1q, which may target them for complement-mediated attack or C1qRp-mediated clearance. A hybrid molecule was used to simultaneously inhibit both complement activation and selectin-mediated adhesion. The extracellular domain of soluble complement receptor-1 (sCR1) was sialyl Lewis x glycosylated (sCR1sLex) to inhibit complement activation and endothelial-platelet-leukocyte interactions. sCR1 and sCR1sLex colocalized to ischemic cerebral microvessels and C1q-expressing neurons, inhibited neutrophil and platelet accumulation, and reduced cerebral infarct volumes. Additional benefit was conferred by sialyl Lewis x glycosylation of the unmodified parent sCR1 molecule.
Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
J
J
Huang
L J
LJ
Kim
R
R
Mealey
H C
HC
Marsh
Y
Y
Zhang
A J
AJ
Tenner
E S
ES
Connolly
D J
DJ
Pinsky
D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D002448:Cell Adhesion; D002540:Cerebral Cortex / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy; D002560:Cerebrovascular Circulation; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D003167:Complement Activation; D015922:Complement C1q / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D009504:Neutrophils / Q000502:physiology; D009844:Oligosaccharides / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D010973:Platelet Adhesiveness; D011951:Receptors, Complement / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D019087:Selectins / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D013997:Time Factors
D018696:Neuroprotective Agents; D009844:Oligosaccharides; D011951:Receptors, Complement; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; C082885:soluble complement inhibitor 1; D015922:Complement C1q