| Abstract No.: | 211 |
| Country: | Canada |
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| Title: | Targeting Neuroinflammation as a Neuroprotective Strategy for Spinal Cord Injury |
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| Authors/Affiliations: | Lynne Weaver
Robarts Research Institute, Univerity of Western Ontario, London, ON, Canada |
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| Content: | 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. This influx is a key component of the human spinal cord injury and is highly associated with secondary cord damage. SCI causes a systemic inflammatory response, increasing oxidative activity of circulating leukocytes. The state of these leukocytes while in the circulation will impact on their actions upon entering the injured spinal cord, potentially exacerbating the original injury as well as causing damage to initially unaffected organs. For example, in a clip compression rat model of thoracic SCI, the cord injury was accompanied by an extensive infiltration of neutrophils into the lungs and kidneys, with associated oxidative tissue damage.
To evaluate the human systemic inflammatory response to SCI, we investigated oxidative activity of blood leukocytes from 9 cord-injured subjects and 6 trauma controls (bone fractures without CNS injury) at 6h-2 wk after injury, comparing values to those of 10 uninjured subjects. Neutrophil and monocyte free radical production, evaluated by flow cytometry, increased significantly more in SCI subjects than trauma controls. In leukocyte homogenates or blood smears, the concentration of free radicals, activity of the enzyme myeloperoxidase, expression of the oxidative enzymes, inducible nitric oxide synthetase, cyclooxygenase-2 and the NADPH oxidase subunit gp91phox, and expression of the pro-inflammatory transcription factor NF-κB increased after either injury. Increases were significantly greater after SCI than in trauma controls. Aldehyde products of tissue-damaging lipid peroxidation also increased significantly more in the plasma of SCI subjects. Limiting the intense systemic inflammatory response after SCI should protect the spinal cord and tissues/organs outside the CNS from secondary damage.
The integrins α4β1 and αDβ2, expressed by these leukocytes, are key to their activa¬tion and migration into/within tissue. Therefore, blocking the function of either of these integrins may afford significant neuroprotection. We used an intravenous treatment paradigm in which rats were treated with a blocking monoclonal antibody (mAb) to the α4 subunit of α4β1, or to the αD subunit of αDβ2, at 2 and 24h or 2, 24, and 48 h after thoracic clip-compression SCI, respectively. These anti-integrin mAb treatments significantly decreased neutrophil and monocyte/macrophage influx at 3d and decreased intraspinal neutrophil influx at 7d after SCI. The anti-integrin treatments also significantly reduced oxidative activity (myeloperoxidase activity, iNOS expression, free radical concentration and lipid peroxidation) measured in injured cord homogenates at 3d. 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, the anti-integrin treatment decreased blood pressure responses during autonomic dysreflexia and, at 2-8 weeks, decreased mechanical allodynia elicited from the trunk and hind paw. 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.
This research was supported by grants from the Canadian Institutes of Health Research.
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