Journal
EXPERIMENTAL NEUROLOGY
Volume 214, Issue 2, Pages 147-159Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2008.04.024
Keywords
Spinal cord injury; Inflammation; Integrin; Oxidative damage; Neuroprotection; Serotonin; Neutrophil; Macrophage; Mechanical allodynia; Autonomic dysreflexia
Categories
Funding
- Canadian Institutes of Health Research
- Ontario Neurotrauma Foundation
- Lawson Health Research Institute
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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 alpha 4 beta 1, 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 alpha 4 Subunit of alpha 4 beta 1 at 2 and 24 h after thoracic clip-compression SCI. Anti-alpha 4 beta 1 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-alpha 4 beta 1 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-alpha 4 beta 1 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. (C) 2008 Elsevier Inc. All rights reserved.
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