Testing the Robustness of âPromisingâ Neuro-Protective Drug Candidates in a Cervical Hemi-Contusion Model of Rats.
ICORD, Vancouver, BC, Canada
Ward Plunet, Ph.D.; Nicole Janzen B.S.c.; Jie Liu. M.D.; Adrienne Behrens, B.Sc.; Elizabeth Raffaele, B.Sc.; Yuan Jiang, B.Sc.; Jason Cheung; Wenchun Wang, MD; Hui Jiang; Behnia Lashkari, M.D.,Ph.D.; Peggy Assinck, Ph.D.; Leanne Ramer, Ph.D.; Lowell McPhail, Ph.D. and Wolfram Tetzlaff, M.D.,Ph.D.
ICORD (International Collaboration on Repair Discoveries), University of British Columbia, Vancouver, Canada; email@example.com
Objective: A significant number of FDA approved drugs have demonstrated efficacy in preclinical spinal cord injury (SCI). These studies predominantly used thoracic models and treated within one hour after injury. However, most human injuries occur at cervical levels (>65%), and such short windows of intervention used in animal studies are difficult to translate in human trials. We therefore created a team of research staff to assess the effects on functional recovery of the most promising FDA approved drugs when these are administered 3 hours after a cervical spinal cord hemi-contusion injury with the goal of finding robust treatments that could be taken forward into clinical trials.
Design: In 5 experiments, we tested 9 different FDA approved drugs (riluzole, valproic acid, fluoxetine, metformin, inosine, rosuvastatin, acetyl-l-carnitine, glibenclamide, tamoxifen) that had been previously reported to improve functional recovery in SCI lab models.
Results: None of the 9 treatments improved recovery compared to control groups in either a distal limb fine motor task (Montoya staircase: retrieval of food pellets from a staircase), or fruit-loop eating score), nor a proximal limb motor task (cylinder rearing task). We also did not observe any sparing of residual spinal cord tissue for the 6 treatments so far analyzed. However mRNA expression changes in injured spinal cord tissue indicate appropriate changes in gene expression early after injury indicating the drugs are biologically active at the injury site. We reduced the injury force by 20% to 120 kdyn and started treatment at 1 hour and 3 hours after cervical hemi-contusion injury. Testing glibenclamide and tamoxifen again, we found a trend for improvement in both the 1 and 3 hour glibenclamide treated groups. Histological assessment of both groups indicated some neuroprotection.
Conclusion: As in previous replication studies, establishing robustness in preclinical models is challenging and possible reasons will be discussed.
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