title: Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury.
abstract: There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium.   The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria.   In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.
authors.affiliation: Division of Neurosurgery and Spinal Program, Toronto Western Hospital and University of Toronto, Ontario, Canada. charles.tator@uhn.on.ca
authors.forename: Charles H
authors.initials: CH
authors.lastname: Tator
authors.forename: Robin
authors.initials: R
authors.lastname: Hashimoto
authors.forename: Annie
authors.initials: A
authors.lastname: Raich
authors.forename: Daniel
authors.initials: D
authors.lastname: Norvell
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
authors.forename: James S
authors.initials: JS
authors.lastname: Harrop
authors.forename: James
authors.initials: J
authors.lastname: Guest
authors.forename: Bizhan
authors.initials: B
authors.lastname: Aarabi
authors.forename: Robert G
authors.initials: RG
authors.lastname: Grossman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005905:Glyburide / Q000627:therapeutic use; D006801:Humans; D008278:Magnesium Sulfate / Q000627:therapeutic use; D008911:Minocycline / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009553:Nimodipine / Q000627:therapeutic use; D019782:Riluzole / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D057170:Translational Research, Biomedical
chemical_list: D018696:Neuroprotective Agents; D009553:Nimodipine; D008278:Magnesium Sulfate; D019782:Riluzole; D008911:Minocycline; D005905:Glyburide