Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein

• Published in: Science (American Association for the Advancement of Science) 1999-07, Vol.285 (5427), p.595-599
• Main Authors: Huang, J, Kim, L J, Mealey, R, Marsh, Jr, H C, Zhang, Y, Tenner, A J, Connolly, Jr, E S, Pinsky, D J
• Format: Article
• Language: English
• Subjects: Animals; Blood Platelets - physiology; Body Weight; Brain; Cell Adhesion; Cerebral Cortex - blood supply; Cerebral Cortex - immunology; Cerebral Cortex - metabolism; Cerebral Infarction - drug therapy; Cerebrovascular Circulation; Cerebrovascular Disorders - drug therapy; Cerebrovascular Disorders - immunology; Cerebrovascular Disorders - physiopathology; Complement Activation; Complement C1q - metabolism; Glycosylation; Humans; Injuries; Ischemic Attack, Transient - drug therapy; Ischemic Attack, Transient - immunology; Ischemic Attack, Transient - physiopathology; Leukocytes - physiology; Mice; Molecular biology; Neurological Impairments; Neurons; Neurons - immunology; Neurons - metabolism; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - adverse effects; Neuroprotective Agents - metabolism; Neuroprotective Agents - therapeutic use; Neutrophils - physiology; Oligosaccharides - administration & dosage; Oligosaccharides - adverse effects; Oligosaccharides - metabolism; Oligosaccharides - therapeutic use; Physical Disabilities; Platelet Adhesiveness; Proteins; Receptors, Complement - administration & dosage; Receptors, Complement - metabolism; Receptors, Complement - therapeutic use; Reperfusion Injury - drug therapy; Reperfusion Injury - immunology; Reperfusion Injury - metabolism; Scientific Concepts; Selectins - metabolism; Statistical Significance; Stroke; Time Factors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.285.5427.595

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.