These MMPs are released by local cells as well as by infiltrating leukocytes and Oltipraz result in reduced cell-cell adhesion, disruption of the blood-spinal cord barrier, up-regulation of pro-inflammatory cytokines, and demyelination. Early blockade of MMPs confers neuroprotection after SCI. Short-term administration of the broad-spectrum MMP inhibitor, GM6001, results in sparing of white matter and improves locomotor function when the drug is given over the first 3 days post-injury. Several lines of 1092351-67-1 evidence suggest that one likely target of GM6001 is MMP-9. This protease is not actively expressed in the uninjured spinal cord and is up-regulated over the first 3 days post-injury, corresponding to the time-course for infiltration of neutrophils. While there are local sources of MMP-9, including glia and endothelial cells, neutrophil depletion studies confirm that these leukocytes are the major source of MMP-9 in the acutely injured cord. As this protease is not complexed with tissue inhibitor of MMP-1, degranulation of neutrophils results in release of activated MMP-9, which then may disrupt the barrier and facilitate transmigration of leukocytes into the injured spinal cord. It thus is not surprising that early administration of GM6001 attenuates the trafficking of neutrophils into the injured spinal cord and stabilizes the blood-spinal cord barrier. There are other members of the MMP family that are also determinants of recovery after SCI including MMP-12 and ADAM-8. Thus, broad inhibitors of MMPs may offer greater benefit than specific inhibitors of these proteases. In this study, we have used dimethyl sulfoxide in combination with GM6001. While DMSO is commonly used as a vehicle to increase solubility of a drug, it has been reported to have neuroprotective properties in traumatic brain injury and SCI. The putative neuroprotective activity of DMSO is thought to arise from its ability to block voltage-sensitive sodium channels and calcium influx into cells, and mitigate opening of ionotropic channels that are activated by glutamate. Few studies have considered a pre-clinical platform involving dogs with naturally occurring SCIs resulting from intervertebral disk herniation. This approach mimics pathologic aspects of human
