The second National Acute Spinal Cord Injury Study (NASCIS 2) showed that methylprednisolone (MP) improved neurologic recovery in human spinal cord injury (SCI) but the treatment has a strictly limited therapeutic window. To identify better treatments, laboratories must now evaluate different doses, times, and durations of therapy along and combined with MP, and at several injury levels. Investigation of all these variable requires thousands of experiments, beyond the capabilities of any individual laboratory. Many promising treatments now await such pre-clinical investigation. Systematic pre-clinical data allow rational design treatment protocols. Arbitrary treatment protocols have a high risk of false negatives. A Multicenter Animal Spinal Cord Injury Study (MASCIS) is therefore proposed. Eight leading SCI laboratories will participate: New York University, Ohio State University, Washington University, University of Cincinnati, University of California at San Francisco, Medical University of South Carolina, Georgetown University, A. I. duPont Institute. Data analysis will be carried out at Yale University. The centers will use the same SCI model and outcome measures to study 5 neuroprotective agents: MP (glucocorticoid), YM-14673 thyrotropin releasing hormone analog), tirilazad mesylate (a 21-aminosteroid), nalmefene (a kappa- selective opioid receptor blocker), and excitatory amino acid receptor blockers. MASCIS will annually examine acute (24h) and chronic (6w) outcomes of 1600 rats subjected to 3 standardized grades of SCI and treated with 2-3 different doses of the drugs started at 0.5h, 6h, or 12h after injury, continued for 6h or 24h, alone and combined with MP. Plasma and tissue drug levels will be measured at 2-24h. Acute lesion volumes will be measured at 24h. Injury conditions will be carefully monitored and controlled. Acute lesion volumes, behavioral recovery, and different histologic outcome measures will be compared. This work will provide detailed and systematic pre-clinical data for acute SCI treatments, allowing rationale design of treatment protocols. MASCIS is the first proposal of a multicenter pre-clinical trial on this scale and will establish a needed precedent for similar studies in stroke and traumatic brain injury.
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