title: Alpha4beta1 integrin blockade after spinal cord injury decreases damage and improves neurological function.
abstract: The extent of disability caused by spinal cord injury (SCI) relates to secondary tissue destruction arising partly from an intraspinal influx of neutrophils and monocyte/macrophages after the initial injury. The integrin alpha4beta1, expressed by these leukocytes, is a key to their activation and migration into/within tissue. Therefore, blocking this integrin's functions may afford significant neuroprotection. Rats were treated intravenously with a blocking monoclonal antibody (mAb) to the alpha4 subunit of alpha4beta1 at 2 and 24 h after thoracic clip-compression SCI. Anti-alpha4beta1 treatment significantly decreased neutrophil and monocyte/macrophage influx at 3 d by 47% and 53%, respectively, and decreased neutrophil influx by 61% at 7 d after SCI. Anti-alpha4beta1 treatment also significantly reduced oxidative activity in injured cord homogenates at 3 d. For example, myeloperoxidase activity decreased by 38%, inducible nitric oxide by 44%, dichlorofluorescein (marking free radicals) by 33% and lipid peroxidation (malondialdehyde) by 42%. At 2-8 weeks after SCI, motor function improved by up to 2 points on an open-field locomotor scale. Treated rats supported weight with their hind paws instead of sweeping. At 2-4 weeks after SCI, anti-alpha4beta1 treatment decreased blood pressure responses during autonomic dysreflexia by as much as 43% and, at 2-8 weeks, decreased mechanical allodynia elicited from the trunk and hind paw by up to 54% and 40%, respectively. This improved functional recovery correlated with spared myelin-containing white matter and >10-fold more bulbospinal serotonergic axons below the injury than were in controls. The significant neurological improvement offered by this neuroprotective strategy underscores the potential for an anti-integrin treatment for SCI.
authors.affiliation: Spinal Cord Injury Laboratory, BioTherapeutics Research Group, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada N6A 5K8.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Fleming
authors.forename: Feng
authors.initials: F
authors.lastname: Bao
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Chen
authors.forename: Eilis F
authors.initials: EF
authors.lastname: Hamilton
authors.forename: Jane K
authors.initials: JK
authors.lastname: Relton
authors.forename: Lynne C
authors.initials: LC
authors.lastname: Weaver
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001369:Axons / Q000473:pathology / Q000502:physiology; D002452:Cell Count; D002465:Cell Movement / Q000276:immunology; D005260:Female; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009043:Motor Activity; D009437:Neuralgia / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D012701:Serotonin / Q000502:physiology; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D018696:Neuroprotective Agents; D012701:Serotonin