Keeping promises: translating basic research into new spinal cord injury therapies

Centuries of medical wisdom-namely that spinal cord injury (SCI) treatment was limited to caretaking until the patients inevitably succumbed to complications-has given way to tremendous medical and research advancements. The prognosis for survival after SCI improved significantly after World War II, leading to the largest population of people aging with chronic SCI in history. Despite the general lack of optimism for functional recovery after SCI, the spinal cord has proven to be one of the most attractive systems for studying central nervous system plasticity. Predictions of clinical applications derived from basic findings now routinely accompany reports of evidence for spinal axon regeneration. This has led to great debate in the SCI research community about the level and quality of evidence needed to select truly promising candidate therapies. This article reviews the basis for optimism in the new understanding of the processes of degeneration after SCI and the mechanisms of regeneration. The emphasis is on neuroprotective and reparative strategies emerging from the animal literature, and on the steps remaining to be taken to translate these into effective clinical trials of new therapies. Examples of the translational process in related areas of brain injury and stroke are cited, as well as the specific issues relating to the needs of individuals with SCI.     

Keeping Promises: Translating Basic Research Into New Spinal Cord Injury Therapies

Abstract

Summary: Centuries of medical wisdom-namely that spinal cord injury (SCI) treatmentwas limited to caretaking until the patients inevitably succumbed to complications-has given way to tremendous medical and research advancements. The prognosis for survival after SCI improved significantly after World War II, leading to the largest population of people aging with chronic SCI in history. Despite the general Iack of optimism for functional recovery after SCI, the spinal cord has proven to be one of the most attractive systems for studying central nervaus system plasticity. Predictions of clinical applications derived from basic findings now routinely accompany reports of evidence for spinal axon regeneration. This has led to great debate in the SCI research community about the Ievei and quality of evidence needed to select truly promising candidate therapies. This article reviews the basis for optimism in the new understanding of the processes of degeneration after SCI and the mechanisms of regeneration. The emphasis is on neuroprotective and reparative strategies ernerging from the animal literature, and on the steps remaining to be taken to translate these into effective clinical trials of new therapies. Examples of the translational process in related areas of brain injury and strake are cited, as weil as the specific issues relating to the needs of individuals with SCI.     

Pharmacological treatment of acute spinal cord injury: how do we build on past success?

Most acute spinal cord injuries (SCI) do not involve complete transection of the spinal cord; typically, a rim of white matter survives. The potential for neurological recovery depends on optimal preservation of the ascending and descending white matter axons and their normal myelination. Pharmacologic strategies focus on the control of secondary injury processes, primarily lipid peroxidation (LP), and the salvage of as much white matter as possible. The first effective neuroprotective agent was methylprednisolone (MP), a glucocorticosteroid that in high doses improves neurological recovery in animals and humans following acute SCI. Tirilazad is a more targeted non-glucocorticoid LP inhibitor that has been shown to be neuroprotective and has fewer side effects than MP. Future SCI therapy is likely to encompass various neuroprotective agents, including inhibitors of LP, inhibitors of the nitric oxide-derived reactive oxygen species peroxynitrite, inhibitors of calpain (which is responsible for degrading the spinal cord cytoskeleton), and inhibitors of post-traumatic apoptosis of neurons and myelin-forming oligodendroglia. In addition, neuroprotective strategies will eventually be followed by neurorestorative agents that stimulate the plasticity of surviving neural pathways, and will be used in conjunction with other neurorestorative therapies like cell transplantation and gene therapy techniques.     

Special Article Pharmacological Treatment Of Acute Spinal Cord Injury: How Do We Build On Past Success?

Abstract

Most acute spinal cord injuries (SCI) do not involve complete transection of the spinal cord; typically, a rim of white matter survives. The potential for neurological recovery depends on optimal preservation of the ascending and descending white matter axons and their normal myelination. Pharmacologic strategies focus on the control of secondary injury processes, primarily lipid peroxidation (LP), and the salvage of as much white matter as possible. The first effective neuroprotective agent was methylprednisolone (MP), a glucocorticosteroid that in high doses improves neurological recovery in animals and humans following acute SCI. Tirilazad is a more targeted non-glucocorticoid LP inhibitor that has been shown to be neuroprotective and has fewer side effects than MP. Future SCI therapy is likely to encompass various neuroprotective agents, including inhibitors of LP, inhibitors of the nitric oxidederived reactive oxygen species peroxynitrite, inhibitors of calpain (which is responsible for degrading the spinal cord cytoskeleton), and inhibitors of post-traumatic apoptosis of neurons and myelin-forming oligodendroglia. In addition, neuroprotective strategies will eventually be followed by neurorestorative agents that stimulate the plasticity of surviving neural pathways, and will be used in conjunction with other neurorestorative therapies like cell transplantation and gene therapy techniques.

J Spinal Cord Med. 2001 ;24:142–146     

Designing cell- and gene-based regeneration strategies to repair the injured spinal cord

There is an array of new and promising strategies being developed to improve function after spinal cord injury (SCI). The targeting of a diversity of deleterious processes within the tissue after SCI will necessitate a multi-factorial intervention, such as the combination of cell- and gene-based approaches. To ensure proper development and design of these experiments, many issues need to be addressed. It is the purpose of this review to consider the strategies involved in testing the efficacy of these new combinations to improve axonal regeneration. For cell-based therapy, issues are choosing a SCI model, the time of cell implantation, placement of cells and their subsequent migration, fluid versus solid grafts, use of agents to prevent immune rejection, and tracking of implanted cells. Grafting is also discussed in view of improving function, reducing secondary damage, bridging the injured spinal cord, supporting axonal regrowth, replacing lost neurons, facilitating myelination, and promoting axonal growth from the implant into the cord. The choice of a gene delivery system, gene-based therapies in vivo to provide chemoattractant and guidance cues, altering the intrinsic regenerative capacity of neurons, enhancing endogenous non-neuronal cell functions, and targeting the synthesis of growth inhibitory molecules are also discussed, as well as combining ex vivo gene and cell therapies.     

Activity-based Therapies in Spinal Cord Injury:: Clinical Focus and Empirical Evidence in Three Independent Programs

This article summarizes presentations of a symposium examining the potential impact of activity-based therapies (ABT) in promoting neurological and functional recovery after spinal cord injury (SCI). The symposium addressed 3 key questions concerning activity-based therapy in SCI: (1) What clinical approaches are used? (2) Is there empirical evidence supporting efficacy of ABT in promoting neurological recovery and improving overall function, health, and quality of life? (3) What are the issues related to long-term viability of ABT?     

The health and life priorities of individuals with spinal cord injury: a systematic review

Determining the priorities of individuals with spinal cord injury (SCI) can assist in choosing research priorities that will ultimately improve their quality of life. This systematic review examined studies that directly surveyed people with SCI to ascertain their health priorities and life domains of importance. Twenty-four studies (a combined sample of 5262 subjects) that met the inclusion criteria were identified using electronic databases (Medline, EMBASE, CINAHL, and PsycINFO). The questionnaire methods and domains of importance were reviewed and described. While the questionnaires varied across studies, a consistent set of priorities emerged. Functional recovery priorities were identified for the following areas: motor function (including arm/hand function for individuals with tetraplegia, and mobility for individuals with paraplegia), bowel, bladder, and sexual function. In addition, health, as well as relationships, emerged as important life domains. The information from this study, which identified the priorities and domains of importance for individuals with SCI, may be useful for informing health care and research agenda-setting activities.     

G. Heiner Sell memorial lecture: neuronal plasticity after spinal cord injury: significance for present and future treatments

Recent progress in the understanding of movement control allows us to define more precisely the requirements for successful rehabilitation of patients with neurologic deficits after a spinal cord injury (SCI). Load- and hip joint position-related afferent input seems to be of crucial importance for the generation and success of locomotor training. In addition, there is accumulating evidence from animal experiments that axonal regeneration can be induced after a SCI. Consequently, in the near future, new therapeutic approaches will be developed for the treatment of subjects with SCI. Functional training and regeneration represent complimentary approaches. Regenerating spinal tract fibers needs functional training to make the appropriate connections, and training effects will be enhanced by regenerating fibers. A clinical basis for monitoring the effects of novel interventional therapies is needed. Refined and combined clinical and neurophysiologic measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This is a basic requirement for predicting functional outcome, as well as for recognizing any improvement in the recovery of function caused by a new treatment. To this aim, 14 European spinal cord injury centers involved in the rehabilitation of patients with acute SCI have built a close clinical collaboration using a standardized protocol for the assessment of the outcome after SCI and the extent of recovery achieved by actually applied therapies in a larger population of patients with SCI.     

Spinal cord injury after thoracic endovascular aortic aneurysm repair

Purpose

Thoracic endovascular aortic aneurysm repair (TEVAR) has become a mainstay of therapy for aneurysms and other disorders of the thoracic aorta. The purpose of this narrative review article is to summarize the current literature on the risk factors for and pathophysiology of spinal cord injury (SCI) following TEVAR, and to discuss various intraoperative monitoring and treatment strategies.

Source

The articles considered in this review were identified through PubMed using the following search terms: thoracic aortic aneurysm, TEVAR, paralysis+TEVAR, risk factors+TEVAR, spinal cord ischemia+TEVAR, neuromonitoring+thoracic aortic aneurysm, spinal drain, cerebrospinal fluid drainage, treatment of spinal cord ischemia.

Principal findings

Spinal cord injury continues to be a challenging complication after TEVAR. Its incidence after TEVAR is not significantly reduced when compared with open thoracoabdominal aortic aneurysm repair. Nevertheless, compared with open procedures, delayed paralysis/paresis is the predominant presentation of SCI after TEVAR. The pathophysiology of SCI is complex and not fully understood, though the evolving concept of the importance of the spinal cord’s collateral blood supply network and its imbalance after TEVAR is emerging as a leading factor in the development of SCI. Cerebrospinal fluid drainage, optimal blood pressure management, and newer surgical techniques are important components of the most up-to-date strategies for spinal cord protection.

Conclusion

Further experimental and clinical research is needed to aid in the discovery of novel neuroprotective strategies for the protection and treatment of SCI following TEVAR.

     

Neurological and functional recovery from spinal cord injury. Progress and evaluation standards in paraplegic medicine

Today, there is accumulating evidence from animal experiments that axonal regeneration and an enhanced level of functional repair can be induced after a spinal cord injury (SCI). Consequently, in the near future, new therapeutic approaches will be developed for the treatment of patients with SCI. The aim of the project presented here is to provide the required clinical basis for the implementation of novel interventional therapies. Refined and combined clinical and neurophysiological measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This represents a basic requirement for recognizing any improvement in the recovery of function and to monitor any significant effect of a new treatment. The paper presents objective and refined tools as a basis for monitoring the effects of new treatment strategies.     

Providing the clinical basis for new interventional therapies: refined diagnosis and assessment of recovery after spinal cord injury

Today, there is accumulating evidence from animal experiments that axonal regeneration and an enhanced level of functional repair can be induced after a spinal cord injury (SCI). Consequently, in the near future, new therapeutic approaches will be developed for the treatment of patients with SCI. The aim of the project presented here is to provide the required clinical basis for the implementation of novel interventional therapies. Refined and combined clinical and neurophysiological measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This represents a basic requirement to recognise any improvement in the recovery of function and to monitor any significant effect of a new treatment. To this aim, five European Spinal Cord Injury Centres involved in the rehabilitation of acute SCI patients have built up a close clinical collaboration to develop a standardised protocol for the assessment of the outcome after SCI and the extent of recovery achieved by actually applied therapies in a larger population of SCI patients. The project's aim is to establish objective, refined tools as a basis for monitoring the effects of new treatment strategies.     

Descending vasomotor pathways in humans: correlation between axonal preservation and cardiovascular dysfunction after spinal cord injury

Cardiovascular dysfunction is common after cervical spinal cord injury (SCI) in humans. At least three spinal cord elements involved in cardiovascular control have been identified: descending vasomotor pathways (DVPs), sympathetic preganglionic neurons, and spinal afferents. However, little is known about the localization of the DVPs within the human spinal cord, which limits our understanding of the mechanisms of cardiovascular dysfunction after SCI. This study was undertaken to examine the association of cardiovascular abnormalities after SCI in humans with the severity of degeneration and axonal loss within the DVPs. A detailed chart review and histopathological examination of postmortem spinal cord tissue was conducted in individuals with cervical SCI (n = 7) and control individuals with an intact central nervous system (n = 5). Individuals with SCI were divided into group 1 (severe cardiovascular abnormalities) and group 2 (no/minor cardiovascular disturbances). The area of degeneration and the number of preserved axons within different areas of the spinal cord were quantitated using EMPIX imaging software. Two areas of possible localization of DVPs were investigated: area I, within the dorsal aspects of the lateral funiculus; and area II, within the white matter adjacent to the dorsolateral aspect of the lateral horn. Comparison of the extent of axonal degeneration in both SCI groups demonstrated that individuals in group 1 had more extensive axonal degeneration than those in group 2. The number of intact axons within areas I and II in individuals from group 1 was significantly lower than those from group 2 or control cases (p = 0.029; p = 0.028). The most dramatic axonal loss was observed within area I in individuals with cardiovascular dysfunction. We conclude that loss and degeneration of DVPs, which are localized within the dorsolateral aspects of the human spinal cord, contributes to abnormal cardiovascular control after SCI. This information adds to our knowledge of pathobiology of cardiovascular dysfunction after human SCI and may ultimately suggest novel therapeutic strategies as regenerative and reparative approaches become translated to the clinic.     

Neurologische und funktionelle Erholung nach Querschnittlähmung

Today, there is accumulating evidence from animal experiments that axonal regeneration and an enhanced level of functional repair can be induced after a spinal cord injury (SCI). Consequently, in the near future, new therapeutic approaches will be developed for the treatment of patients with SCI. The aim of the project presented here is to provide the required clinical basis for the implementation of novel interventional therapies. Refined and combined clinical and neurophysiological measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This represents a basic requirement for recognizing any improvement in the recovery of function and to monitor any significant effect of a new treatment. The paper presents objective and refined tools as a basis for monitoring the effects of new treatment strategies.     

Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury

Prevention of the immediate excitotoxic phase occurring in response to spinal cord injury (SCI) is a major issue to reduce the neuronal damage responsible for any ensuing motor deficits. The present study evaluated the neuroprotective efficacy of three noncompetitive NMDA receptor antagonists: Gacyclidine (GK-11), a new compound, Dizocilpine (MK-801), and Cerestat (CNS-1102) in a rat spinal cord contusion model. To mimic human SCI, a standardized model of rat spinal cord closed contusion in which animals spontaneously and progressively recover from the induced paraplegia was employed. Such model, characterized by a slow recovery of hindlimb locomotor function enables easy quantification of the neuroprotection at both the behavioral and cellular level. The animals were treated intravenously with the respective drugs 10 min after the spinal contusion. The dose range study suggested that 1 mg/kg of Gacyclidine was the most effective dose to promote functional recovery in reducing by half the time needed to reach full locomotor recovery. Racemate and enantiomers of Gacyclidine showed similar neuroprotective effects, but treatment with the enantiomers were not as efficacious in promoting full functional recovery. Similarly, a prolonged treatment with the racemate was not as efficious as a single dose, suggesting that a prolonged blockade of the amino-excitatory neurotransmission may be deleterious. Finally, Dizocilpine and Cerestat treatments induced only a partial and delayed neuroprotective effect compared to Gacyclidine. Neuroprotection characterized by a reduction of the cystic cavity and of the astrogliosis was observed with all treatments. As Gacyclidine is already in clinical trials, the present findings suggest the premise that it is a promising agent for limiting the initial neuronal damage induced by CNS trauma leading to better functional recovery.     

Community-based physical activity and wheelchair mobility programs for individuals with spinal cord injury in Canada: Current reflections and future directions

Rationale: A clear need has been identified to find strategies and opportunities, beyond services provided during rehabilitation, to enhance community-based mobility and leisure-time physical activity (LTPA) participation among members of the spinal cord injury (SCI) population.

Method: This review of existing mobility and LTPA programs that are available for individuals with SCI in Canada reflects the authors’ current knowledge of existing evidence-based and community-based programs. The authors aim to highlight the gaps between existing programs and future needs.

Results: The major gaps identified in this brief clinical report include the need for: community-based mobility training programs, patient reported outcomes, assessment of long-term impact of programs, identifying the best approaches for program delivery, and developing researcher-stakeholder partnerships.

Conclusion: Evidence-based mobility programs and community-based LTPA do exist, and the available research shows their promise. Despite the growing research for LTPA and mobility programs among adults with SCI, many gaps remain. Additional partnerships, community engagement practices, service program funding and health policy changes are needed to address the highlighted gaps to optimize community-based programs and enhance the lives of adults with SCI.     

Pharmacological approaches to repair the injured spinal cord

Acute traumatic spinal cord injury (SCI) results in a devastating loss of neurological function below the level of injury and adversely affects multiple systems within the body. The pathobiology of SCI involves a primary mechanical insult to the spinal cord and activation of a delayed secondary cascade of events, which ultimately causes progressive degeneration of the spinal cord. Whereas cell death from the mechanical injury is predominated by necrosis, secondary injury events trigger a continuum of necrotic and apoptotic cell death mechanisms. These secondary events include vascular abnormalities, ischemia-reperfusion, glutamate excitotoxicity and disturbances in ionic homeostasis, oxidative cell injury, and a robust inflammatory response. No gold standard therapy for SCI has been established, although clinical trials with methylprednisolone (NASCIS II and III) and GM-1 ganglioside (Maryland and Sygen) have demonstrated modest, albeit potentially important therapeutic benefits. In light of the overwhelming impact of SCI on the individual, other therapeutic interventions are urgently needed. A number of promising pharmacological therapies are currently under investigation for neuroprotective abilities in animal models of SCI. These include the sodium (Na+) channel blocker riluzole, the tetracycline derivative minocycline, the fusogen copolymer polyethylene glycol (PEG), and the tissue-protective hormone erythropoietin (EPO). Moreover, clinical trials investigating the putative neuroprotective and neuroregenerative properties ascribed to the Rho pathway antagonist, Cethrin (BioAxone Therapeutic, Inc.), and implantation of activated autologous macrophages (ProCord; Proneuron Biotechnologies) in patients with thoracic and cervical SCI are now underway. We anticipate that these studies will harken an era of renewed interest in translational clinical trials. Ultimately, due to the multi-factorial pathophysiology of traumatic SCI, effective therapies will require combined approaches.     

Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats.

In these studies, we examined the neuroprotective effects of the potent antiinflammatory cytokine interleukin-10 (IL-10) following spinal cord injury (SCI). Neuroprotection was assessed by using behavioral and morphological end points. We hypothesized that injury-induced inflammation contributes to the resulting neuropathology and subsequent loss of function. Therefore, by attenuating injury-induced inflammation, we should promote functional recovery. The New York University device was used to induce moderate SCI and study the resulting inflammatory response and functional consequences of inhibiting this response in rats. We determined that SCI induces the expression of tumor necrosis factor-alpha (TNF-alpha) in the spinal cord and by SCI-activated monocytes isolated from the peripheral circulation. IL-10 (5.0 microg) administered 30 minutes after-injury significantly reduced the expression of TNF-alpha protein in the spinal cord and in vitro by SCI-activated monocytes. Next, we investigated whether IL-10 would improve functional recovery after SCI. Randomized, double-blinded studies demonstrated that a single injection of IL-10 significantly improves hind limb motor function 2 months after injury, as determined by the Basso, Beattie and Bresnahan (BBB) open-field behavioral test. IL-10-treated animals had a mean BBB score of 18.0+/-0.5 (SEM, n = 9) compared with a score of 12.9+/-0.6 (SEM, n = 9) for the saline-treated controls. Morphological analysis demonstrated that IL-10 reduces lesion volume by approximately 49% 2 months after injury. These data suggest that acute administration of IL-10 reduces TNF-alpha synthesis in the spinal cord and by activated macrophages, is neuroprotective, and promotes functional recovery following SCI.     

Magnesium sulfate treatment in experimental spinal cord injury: emphasis on vascular changes and early clinical results

Injury to the spinal cord results in disruption of neurons, cell membranes, axons, myelin, and endothelial cells. The aim of this study was to demonstrate the protective effect of magnesium sulfate on the blood-spinal cord barrier after acute spinal cord injury (SCI). This experiment was conducted in two parts. In the first, rats were injected intravenously with Evans blue 2 h after SCI. The laminectomy-only group had no trauma. Contusion injury (50 g-cm) was applied to the trauma and treatment groups. Magnesium sulfate (600 mg/kg) was given to the treatment group immediately after injury. For the second part, clinical evaluations were performed 24 h post surgery. Then, following Evans blue injection, spinal cord samples were obtained from the laminectomy-only, trauma, and treatment groups. For the control group, nontraumatized spinal cord samples were taken after Evans blue injection following clinical examination. Laminectomy did not affect the spinal cord Evans blue content in 2-h and 24-h groups. The trauma increased tissue Evans blue content, and 24-h samples showed more remarkable tissue Evans blue content, suggesting secondary injury. Application of 600 mg/kg of magnesium resulted in lower Evans blue content in the spinal cord than with injury. Remarkable clinical neuroprotection was observed in the treatment groups. Magnesium sulfate showed vaso- and neuroprotective properties after contusion injury to the rat spinal cord. The authors also demonstrated secondary injury of the blood-spinal cord barrier with the Evans blue clearance technique for the first time.     

Cyclosporin A treatment following spinal cord injury to the rat: behavioral effects and stereological assessment of tissue sparing

The immunosuppressant drug cyclosporin A (CsA) has significant neuroprotective properties following CNS injury. In the present study, we assessed the efficacy of CsA therapy following a moderate spinal cord injury (SCI). Adult female rats were injured with the NYU impactor from a height of 12.5 mm, and CsA or vehicle therapy was initiated 15 min after the injury. All animals were behaviorally tested with the BBB locomotor rating scale prior to morphological assessment of changes in the spinal cord. CsA therapy failed to significantly improve the behavioral recovery following the injury. Using a unique stereological approach to assess tissue damage, it was determined that CsA did not alter the amount of spared tissue. The possible neuroprotective effects of CsA, observed in other models of CNS injury, do not appear to influence SCI pathology, perhaps reflecting both anatomical and physiological differences between these distinct regions of the CNS.