Abstract
With no currently available drug treatment for spinal cord injury, there is a need for additional therapeutic candidates. We took the approach of repositioning existing pharmacological agents to serve as acute treatments for spinal cord injury and previously found imatinib to have positive effects on locomotor and bladder function in experimental spinal cord injury when administered immediately after the injury. However, for imatinib to have translational value, it needs to have sustained beneficial effects with delayed initiation of treatment, as well. Here, we show that imatinib improves hind limb locomotion and bladder recovery when initiation of treatment was delayed until 4 h after injury and that bladder function was improved with a delay of up to 24 h. The treatment did not induce hypersensitivity. Instead, imatinib-treated animals were generally less hypersensitive to either thermal or mechanical stimuli, compared with controls. In an effort to provide potential biomarkers, we found serum levels of three cytokines/chemokines—monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-3α, and keratinocyte chemoattractant/growth-regulated oncogene (interleukin 8)—to increase over time with imatinib treatment and to be significantly higher in injured imatinib-treated animals than in controls during the early treatment period. This correlated to macrophage activation and autofluorescence in lymphoid organs. At the site of injury in the spinal cord, macrophage activation was instead reduced by imatinib treatment. Our data strengthen the case for clinical trials of imatinib by showing that initiation of treatment can be delayed and by identifying serum cytokines that may serve as candidate markers of effective imatinib doses.
Highlights
Spinal cord injury affects 12,000 individuals per year in the U.S and there is no drug treatment in use that may improve functional recovery.[1,2] While several experimental drug treatments have had promising effects, few have made it to clinical trials.[3]
We found that treatment with imatinib initiated 4 h after spinal cord injury led to significantly improved hind limb locomotor capability in the openfield test
Analysis of individual cytokine responses over time for each experimental group identified a potential use both directly monocyte/macrophage associated[43,44] and both spleen and bone marrow are the origin of macrophages in spinal cord injury, with the spleen being responsible for the major proportion of infiltrating monocytes at Day 7.45 We found splenic monocytes/macrophages to display increased ED1 immunoreactivity in rats that received imatinib, compared with those that did not ( p < 0.0007; Fig. 5A)
Summary
Spinal cord injury affects 12,000 individuals per year in the U.S and there is no drug treatment in use that may improve functional recovery.[1,2] While several experimental drug treatments have had promising effects, few have made it to clinical trials.[3]. Imatinib, like most of the receptor tyrosine kinase inhibitors, can inhibit several receptor tyrosine kinases, such as platelet-derived growth factor (PDGFR; a and b), c-Kit, and colony stimulating factor 1 receptor.[6] Further, imatinib has been found to have therapeutic potential in several disorders and is today a treatment for such conditions as hypereosinophila and c-Kit–positive gastrointestinal stromal tumors.[7,8] Imatinib has been shown to exert direct effects on the immune system, including mast cells, T-cells, and macrophages, and has experimentally ameliorated such conditions as lung fibrosis, dermal fibrosis, and autoimmune arthritis.[9,10,11,12,13]
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