An increasing number of therapies for spinal cord injury (SCI) are emerging from the laboratory and seeking translation into human clinical trials. Many of these are administered as soon as possible after injury with the hope of attenuating secondary damage and maximizing the extent of spared neurologic tissue. In this article, we systematically review the available pre-clinical research on such neuroprotective therapies that are administered in a non-invasive manner for acute SCI. Specifically, we review treatments that have a relatively high potential for translation due to the fact that they are already used in human clinical applications, or are available in a form that could be administered to humans. These include: erythropoietin, NSAIDs, anti-CD11d antibodies, minocycline, progesterone, estrogen, magnesium, riluzole, polyethylene glycol, atorvastatin, inosine, and pioglitazone. The literature was systematically reviewed to examine studies in which an in-vivo animal model was utilized to assess the efficacy of the therapy in a traumatic SCI paradigm. Using these criteria, 122 studies were identified and reviewed in detail. Wide variations exist in the animal species, injury models, and experimental designs reported in the pre-clinical literature on the therapies reviewed. The review highlights the extent of investigation that has occurred in these specific therapies, and points out gaps in our knowledge that would be potentially valuable prior to human translation.
Much like our colleagues studying neuroprotection for acute stroke, we in the spinal cord injury (SCI) community have witnessed the preclinical emergence of numerous promising neuroprotective and neuro-regenerative treatments that have then disappointingly failed to demonstrate convincing efficacy in clinical trials. In contrast to the stroke field, the SCI community lacks guidelines to steer the preclinical development of therapies and maximize their chance of success prior to translation into expensive and laborious clinical trials. We conducted a survey of the SCI research community to garner perspectives on the question of what preclinical evidence was required before translating an experimental treatment into clinical trials. The opinions of the 324 respondents about what constitutes necessary preclinical evidence before moving to human SCI trials revealed strong support for the demonstration of efficacy in large-animal models, cervical injury models, and for independent replication of promising results. Marked differences exist between the sentiments of the respondents and the translational experience of our field. A framework for guiding the preclinical development of novel therapies prior to human translation would be helpful for ensuring clinical success. Greater dialogue on this issue is necessary to improve our chances of successfully bringing effective treatments to patients with this devastating injury.
An increasing number of therapies for spinal cord injury (SCI) are emerging from the laboratory and seeking translation into human clinical trials. Many of these are administered as soon as possible after injury with the hope of attenuating secondary damage and maximizing the extent of spared neurologic tissue. In this article, we systematically reviewed the available preclinical research on such neuroprotective therapies that are administered in a non-invasive manner for acute SCI. Specifically, we reviewed treatments that have a relatively high potential for translation due to the fact that they are already used in human clinical applications or are available in a form that could be administered to humans. These included: erythropoietin, NSAIDs, anti-CD11d antibodies, minocycline, progesterone, estrogen, magnesium, riluzole, polyethylene glycol, atorvastatin, inosine, and pioglitazone. The literature was systematically reviewed to examine studies in which an in vivo animal model was utilized to assess the efficacy of the therapy in a traumatic spinal cord injury paradigm. Using these criteria, 122 studies were identified and reviewed in detail. Wide variations exist in the animal species, injury models, and experimental designs reported in the preclinical literature on the therapies reviewed. The review highlights the extent of investigation that has occurred in these specific therapies, and points out gaps in our knowledge that would be potentially valuable prior to human translation.
Previous research has shown that small injuries early in development can alter adult pain reactivity and processing of stimuli presented to the side of injury. However, the mechanisms involved and extent of altered adult spinal function following neonatal injury remain unclear. The present experiments were designed to 1) determine whether the effects of neonatal injury affect processing contralateral to the injury and 2) evaluate the role of cells expressing the NK1 receptor, shown to be involved in central sensitization in adults, in the negative effects of neonatal injury. The present findings indicate that the effects of neonatal injury are primarily isolated to the injured hind limb and do not result in a bilateral alteration in adult spinal function. In addition, the effects of neonatal injury appear to be partially dependent on cells expressing the NK1 receptor as ablating these cells at the time of injury or in adulthood results in attenuation of the neonatal injury-induced spinal learning deficit.
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