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The Journal of Neuroscience, April 21, 2004, 24(16):4043-4051; doi:10.1523/JNEUROSCI.5343-03.2004

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Neurobiology of Disease
Transient Blockade of the CD11d/CD18 Integrin Reduces Secondary Damage after Spinal Cord Injury, Improving Sensory, Autonomic, and Motor Function

Denis Gris,^1,2 Daniel R. Marsh,¹ Mark A. Oatway,^1,2 Yuhua Chen,¹ Eilis F. Hamilton,¹ Gregory A. Dekaban,^1,2,3 and Lynne C. Weaver^1,2

¹Spinal Cord Injury Team, BioTherapeutics Research Group, Robarts Research Institute, ²Graduate Program in Neuroscience, and ³Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5K8, Canada

The early inflammatory response to spinal cord injury (SCI) causes significant secondary damage. Strategies that nonselectively suppress inflammation have not improved outcomes after SCI, perhaps because inflammation has both adverse and beneficial effects after SCI. We have shown that the selective, time-limited action of a monoclonal antibody (mAb) to the CD11d subunit of the CD11d/CD18 integrin, delivered intravenously during the first 48 hr after SCI in rats, markedly decreases the infiltration of neutrophils and delays the entry of hematogenous monocyte-macrophages into the injured cord. We hypothesized that this targeted strategy would lead to neuroprotection and improved neurological outcomes. In this study the development of chronic pain was detected in rats by assessing mechanical allodynia on the trunk and hindpaws 2 weeks to 3 months after a clinically relevant clip-compression SCI at the twelfth thoracic segment. The anti-CD11d mAb treatment reduced this pain by half. Motor performance also improved as rats were able to plantar-place their hindpaws and use them for weight support instead of sweeping movements only. Improved cardiovascular outcome was shown after SCI at the fourth thoracic segment by significant decreases in autonomic dysreflexia. Locomotor performance was also improved. These functional changes correlated with significantly greater amounts and increased organization of myelin and neurofilament near the lesion. The improved neurological recovery after the specific reduction of early inflammation after SCI demonstrates that this selective strategy increases tissue at the injury site and improves its functional capacity. This early neuroprotective treatment would be an ideal foundation for building later cell-based therapies.

Key words: spinal cord injury; integrin; inflammation; pain; autonomic; locomotor; myelin; neurofilament

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Received Dec 3, 2003; revised March 12, 2004; accepted March 14, 2004.

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