Wolfram Tetzlaff, MD, PhD
Professor, Department of Zoology, Faculty of Science, University of British Columbia; Director, International Collaboration on Repair Discoveries (ICORD)
Neuroprotection after Spinal Cord Injury
Ward Plunet, Jie Liu, Nicole Janzen, Liz Raffaele, Adrienne Behrens, Suhama Kamakari, Yuan Jiang, Davey Li, Peggy Assinck, Anthony Choo, Jason Speidel, Alex Burden, Steve Mattucci, Alex Burden and Thomas Oxland
The clinical translation of neuroprotective treatments for the injured spinal cord as hitherto been challenging. Multiple reasons play into this complex problem. Preclinical studies are often performed with very short injury-to-treatment time windows that can’t be realized in the real world; preclinical drug/compound doses are not realized in humans; preclinical models mostly use thoracic contusion injuries which are rare in people who mostly suffer cervical fracture dislocation or ventral burst injuries or milder insults resulting in “central cord” symptoms.
In our previous work, we focused on clinically used drugs that had been reported to show robust neuroprotection in rodents (mostly after thoracic lesions) and tested them after a C5 cervical hemi-contusion in Sprague Dawley rats with a 3 hour delay to treatment onset: Riluzole, Valproic Acid, Fluoxetine, Metformin, Rosuvastatin, Inosine, Glibenclamide (aka Glyburide) and Tamoxifen. Even with group sizes of n=19-20 rats, we did not observe robust behavioral benefits with any of these treatments when given alone using a pellet reaching test (Montoya) or assessing forelimb usage during rearing in a cylinder (Schallert). There was some tissue sparing after Glibenclamide treatment. Only the combination of 2 or 3 treatments (Glibenclamide, Tamoxifen, Inosine) yielded significant functional and histopathological effects. We subsequently assessed this triple combination in two models that closer mimic the injury mechanism as they occur in humans: cervical mid-line contusions and cervical dislocations. Here we find behavioral and histological benefits after injury by some mechanisms, in particular in the milder but not more severe versions of dislocations. These milder injuries display a histopathology that resembles what is seen in “central cord lesions” in humans after cervical injury at low speeds.
Collectively, these data indicate that 3 hours delayed treatment with a single known neuroprotective drug is not successful in cervical hemi-contusions (at least in rats) and that drug combinations are more likely to yield beneficial results. In addition, the success of a drug combination in more clinically relevant models is modest and so far only seen in milder injuries.
In the absence of any “gold standard” of a drug yielding robust clinical benefits, future trials should take into consideration the importance of a short treatment onset time (“spine is time”), the additive effects of rational drug combinations and the pathology induced by different injury mechanisms requiring a personalized treatment approach.
Address: ICORD, International Collaboration on Repair Discoveries, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC, V5Z1M9, Canada
E-mail address: email@example.com
Supported by: The Rick Hansen Foundation through the Blusson Integrated Cure Partnership; The Department of Defense SC180233
Wolfram Tetzlaff obtained his MD degree in Germany and his PhD in Calgary followed by faculty appointments at the Universities of Calgary, Ottawa and British Columbia, where he holds the John and Penny Ryan BC Leadership Chair in Spinal Cord Injury Research. He serves as the Director of ICORD, International Collaboration on Repair Discoveries, and leads a research program focusing on experimental strategies for neuroprotection and neural repair after spinal cord injury (SCI). In particular, his group found that diets affect the cascades of secondary damage after spinal cord injury and can improve outcomes; and that skin-derived progenitors when differentiated into Schwann cells can be used for neural repair in the chronically injured rodent spinal cord. He also directs a team that assesses clinically used drugs for their potential to be repurposed for the treatment of SCI inflicted by a variety of mechanisms. Dr. Tetzlaff’s work is/was funded by the CIHR, Wings-for-Life, NSERC, Craig H. Neilsen Foundation, International Spinal-Research Trust, the MS Society and the New Frontiers in Research Fund – Transformation (Canada).