Abstract
Study design:
Female Wistar rats (225 g) underwent spinal cord injury (SCI) at the T4 segment and were assigned to one of the three groups treated with: (1) saline; (2) 7.5 mg kg–1 Reparixin; or (3) 15 mg kg–1 Reparixin. Reparixin is a small molecule, allosteric noncompetitive inhibitor of CXCR1 and CXCR2 chemokine receptors involved in inflammation.
Methods:
Spinal cord homogenates at 12 and 72 h post-SCI were assayed for tumor necrosis factor α (TNF-α) and cytokine-induced neutrophil chemoattractant (CINC)-1 using enzyme-linked immunosorbant assay (ELISA). Myeloperoxidase activity and western blots for CD68, Fas and p75 content were used to assess inflammation and death receptor ligands, respectively. Histopathology and neurological outcomes were assessed by immunohistochemistry, locomotion scoring and cardiovascular measurement of autonomic dysreflexia 4 weeks post-SCI.
Results:
Both 7.5 and 15 mg kg–1 doses of Reparixin reduced levels of TNF-α and CINC-1 72 h post-SCI and decreased macrophage (CD68) content in the spinal cord lesion. Only 15 mg kg–1 Reparixin reduced both Fas and p75 levels in the spinal cord compared with untreated SCI. We observed a reduced lesion area and increased neuron number in the gray matter of Reparixin-treated rats. Hindlimb motor scores at 7 and 28 days post-SCI were improved by 15 mg kg–1 Reparixin treatment. Both 7.5 and 15 mg kg–1 Reparixin reduced development of autonomic dysreflexia 4 weeks post-SCI. The change in mean arterial pressure, induced by cutaneous or visceral stimulation, was reduced by 40–50%.
Conclusion:
Acute treatment with 15 mg kg–1 Reparixin reduces acute inflammation and is associated with minor improvements in motor function and a significant reduction in the severity of autonomic dysreflexia.
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Acknowledgements
This research was funded by the Nova Scotia Heart and Stroke Foundation in a grant to DM. In addition, JF was supported by a research fellowship from the Dalhousie Faculty of Medicine and with funding from Dompé Pharma spa., L’Aquila, Italy. We thank Ricardo Bertini at Dompé Pharma spa. for providing Reparixin for the project and valuable information regarding its appropriate in vivo administration. We also thank Ahmed Ghaly for preparing saline and drug treatments and keeping the code private until results were complete
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Marsh, D., Flemming, J. Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury. Spinal Cord 49, 337–344 (2011). https://doi.org/10.1038/sc.2010.127
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DOI: https://doi.org/10.1038/sc.2010.127
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