Alpha4beta1 integrin blockade after spinal cord injury decreases damage and improves neurological function.
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.
Fleming
Jennifer C
JC
Spinal Cord Injury Laboratory, BioTherapeutics Research Group, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada N6A 5K8.
Bao
Feng
F
Chen
Yuhua
Y
Hamilton
Eilis F
EF
Relton
Jane K
JK
Weaver
Lynne C
LC
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
D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D018696:Neuroprotective Agents; D012701:Serotonin