Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury

Abstract

<jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p>

Minimizing Errors in Acute Traumatic Spinal Cord Injury Trials by Acknowledging the Heterogeneity of Spinal Cord Anatomy and Injury Severity: An Observational Canadian Cohort Analysis

“…eporting that a therapeutic effect exists when it does not (type I, alpha error) has major repercussions in acute traumatic spinal cord injury (tSCI) because of the lack of recognized treatment, 1 the relative desperation of the population, 2 and the substantial public sympathy and media interest that is mobilized around tSCI research. Promising pharmaceutical, medical, surgical, and rehabilitation interventions identified in preclinical studies heighten the expectations for subsequent clinical trials.…”

Delayed Post-Injury Administration of Riluzole Is Neuroprotective in a Preclinical Rodent Model of Cervical Spinal Cord Injury

“…Many therapeutic strategies have shown functional and histological improvements in animal models of SCI with only limited success in human clinical trials. 4 Riluzole, a neuroprotective drug licensed for the treatment of amyotrophic lateral sclerosis (ALS) patients, has also been tested in a rat model of SCI in a number of laboratories, including our own. 5,6 Riluzole acts on multiple molecular targets to improve functional recovery, although its mechanism of action has not been fully delineated.…”

An analysis of ideal and actual time to surgery after traumatic spinal cord injury in Canada

“…Neuroprotective and neuroregenerative initiatives continue to evolve; however, no well-powered clinical trial has demonstrated an improvement in neurologic recovery and, therefore, these therapies have not been implemented in routine clinical practice. [1][2][3][4][5] A growing body of evidence suggests that timely surgical decompression and stabilization may improve neurological recovery by reducing secondary damage. [6][7][8][9][10] When one of the only interventions to potentially improve neurological outcomes in acute tSCI is early treatment, ensuring this knowledge is accepted and then translated into action is known as knowledge translation.…”