Darryl C. Baptiste

A Systematic Review of Non-Invasive Pharmacologic Neuroprotective Treatments for Acute Spinal Cord 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 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.

Update on the treatment of spinal cord injury

Acute spinal cord injury (SCI) is a devastating neurological disorder that can affect any individual at a given instance. Current treatment options for SCI include the use of high dose methylprednisolone sodium succinate, a corticosteroid, surgical interventions to stabilize and decompress the spinal cord, intensive multisystem medical management, and rehabilitative care. While utility of these therapeutic options provides modest benefits, there is a critical need to identify novel approaches to treat or repair the injured spinal cord in hope to, at the very least, improve upon the patients quality of life. Thankfully, several discoveries at the preclinical level are now transitioning into the clinical arena. These include the Surgical Treatment for Acute Spinal Cord Injury Study (STASCIS) Trial to evaluate the role and timing of surgical decompression for acute SCI, neuroprotection with the semisynthetic second generation tetracycline derivative, minocycline; aiding axonal conduction with the potassium channel blockers, neuroregenerative/neuroprotective approaches with the Rho antagonist, Cethrin; the use of anti-NOGO monoclonal antibodies to augment plasticity and regeneration; as well as cell-mediated repair with stem cells, bone marrow stromal cells, and olfactory ensheathing cells. This review overviews the pathobiology of SCI and current treatment choices before focusing the rest of the discussion on the variety of promising neuroprotective and cell-based approaches that have recently moved, or are very close, to clinical testing.

A Systematic Review of Directly Applied Biologic Therapies for Acute Spinal Cord 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.

Emerging drugs for spinal cord injury

Background: This review summarizes several promising pharmacological approaches for the therapeutic management of traumatic spinal cord injury (SCI), which are either in early-phase clinical trials or nearing clinical translation. Objective: This review provides the reader with an understanding of the key pathophysiological mechanisms that contribute to neurological deficits after SCI. Through discussion of the mechanism(s) of action of the selected therapeutic approaches potentially important targets to aid further drug discovery will be highlighted. Methods: Systematic literature review of the pre-clinical literature and clinical SCI trials related to neuroprotective, immunomodulatory and regenerative therapeutic approaches. Results/conclusion: The next decade will witness an unprecedented number of clinical trials which will seek to translate key biomedical research discoveries. The promising drug-based therapeutic approaches include regenerative strategies to neutralize myelin-mediated neurite outgrowth inhibition, neuroprotective strategies to reduce apoptotic triggers, the targeting of cationic/glutamatergic toxicity, anti-inflammatory strategies and the use of approaches to stabilize disrupted cell membranes.

Molecular mechanisms of spinal cord dysfunction and cell death in the spinal hyperostotic mouse: implications for the pathophysiology of human cervical spondylotic myelopathy.

Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction in adults in Western society. Paradoxically, relatively little is known about the pathobiological mechanisms associated with the progressive loss of neural tissue in the spinal cord of CSM patients. In this report we have utilized the twy/twy mutant mouse, which develops ossification of the ligamentum flavum at C2-C3 and exhibits progressive paralysis. This animal model represents an excellent in vivo model of CSM. This study reports novel evidence, which demonstrates that chronic extrinsic cervical spinal cord compression leads to Fas-mediated apoptosis of neurons and oligodendrocytes which is associated with activation of caspase-8, -9 and -3 and progressive neurological deficits. While surgical decompression will remain the mainstay of management of CSM, molecular therapies, which target Fas-mediated apoptosis could show promise as a complementary approach to maximize neurological recovery in this common spinal cord condition.

NIH Roundtable on Emergency Trauma Research

STUDY OBJECTIVE The National Institutes of Health (NIH) formed an NIH Task Force on Research in Emergency Medicine to enhance NIH support for emergency care research. The NIH Trauma Research Roundtable was convened on June 22 to 23, 2009. The objectives of the roundtable are to identify key research questions essential to advancing the scientific underpinnings of emergency trauma care and to discuss the barriers and best means to advance research by exploring the role of trauma research networks and collaboration between NIH and the emergency trauma care community. METHODS Before the roundtable, the emergency care domains to be discussed were selected and experts in each of the fields were invited to participate in the roundtable. Domain experts were asked to identify research priorities and challenges and separate them into mechanistic, translational, and clinical categories. During and after the conference, the lists were circulated among the participants and revised to reach a consensus. RESULTS Emergency trauma care research is characterized by focus on the timing, sequence, and time sensitivity of disease processes and treatment effects. Rapidly identifying the phenotype of patients on the time spectrum of acuity and severity after injury and the mechanistic reasons for heterogeneity in outcome are important challenges in emergency trauma research. Other research priorities include the need to elucidate the timing, sequence, and duration of causal molecular and cellular events involved in time-critical injuries, and the development of treatments capable of halting or reversing them; the need for novel experimental models of acute injury; the need to assess the effect of development and aging on the postinjury response; and the need to understand why there are regional differences in outcomes after injury. Important barriers to emergency care research include a limited number of trained investigators and experienced mentors, limited research infrastructure and support, and regulatory hurdles. CONCLUSION The science of emergency trauma care may be advanced by facilitating the following: (1) development of an acute injury template for clinical research; (2) developing emergency trauma clinical research networks; (3) integrating emergency trauma research into Clinical and Translational Science Awards; (4) developing emergency care-specific initiatives within the existing structure of NIH institutes and centers; (5) involving acute trauma and emergency specialists in grant review and research advisory processes; (6) supporting learn-phase or small, clinical trials; (7) performing research to address ethical and regulatory issues; and (8) training emergency care investigators with research training programs.

Systemic Polyethylene Glycol Promotes Neurological Recovery and Tissue Sparing in Rats After Cervical Spinal Cord Injury

Polyethylene glycol (PEG) has been reported to possess fusogenic properties that may confer neuroprotection after spinal cord injury (SCI), but there is uncertainty regarding the mechanisms of PEG in vivo and the robustness of its protective effects. We hypothesized that PEG promotes preservation of cytoskeletal proteins associated with white matter protection and neurobehavioral recovery after SCI. In proof-of-principle experiments using a pin-drop organotypic culture model of SCI, PEG attenuated neural cell death. Adult rats underwent 35-g clip compression SCI at C8 and were randomized postinjury to receive intravenous 30% PEG or sterile Ringers lactate solution. Confocal microscopy and high-performance liquid chromatography of fluorescein-conjugated PEG permitted in vivo quantification of PEG concentrations in the injured and uninjured spinal cord. Western blot, immunohistochemistry, and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining demonstrated that PEG reduced 200-kd neurofilament degradation and apoptotic cell death. Polyethylene glycol also promoted spinal cord tissue sparing based on retrograde axonal Fluoro-Gold tracing and morphometric histological assessment. Polyethylene glycol also promoted significant, although modest, neurobehavioral recovery after SCI. Collectively, these results indicate that PEG protects key axonal cytoskeletal proteins after SCI, and that the protection is associated with axonal preservation. The modest extent of locomotor recovery after treatment with PEG suggests, however, that this compound may notconfer sufficient neuroprotection to be used clinically as a single treatment.