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Free radicals are formed as a part of normal metabolic activities but are neutralized by the endogenous antioxidants present in cells/tissue, thus maintaining the redox balance. This redox balance is disrupted in certain neuropathophysiological conditions, causing oxidative stress, which is implicated in several progressive neurodegenerative diseases. Following neuronal injury, secondary injury progression is also caused by excessive production of free radicals. Highly reactive free radicals, mainly the reactive oxygen species (ROS) and reactive nitrogen species (RNS), damage the cell membrane, proteins, and DNA, which triggers a self-propagating inflammatory cascade of degenerative events. Dysfunctional mitochondria under oxidative stress conditions are considered a key mediator in progressive neurodegeneration. Exogenous delivery of antioxidants holds promise to alleviate oxidative stress to regain the redox balance. In this regard, natural and synthetic antioxidants have been evaluated. Despite promising results in preclinical studies, clinical translation of antioxidants as a therapy to treat neurodegenerative diseases remains elusive. The issues could be their low bioavailability, instability, limited transport to the target tissue, and/or poor antioxidant capacity, requiring repeated and high dosing, which cannot be administered to humans because of dose-limiting toxicity. Our laboratory is investigating nanoparticle-mediated delivery of antioxidant enzymes to address some of the above issues. Apart from being endogenous, the main advantage of antioxidant enzymes is their catalytic mechanism of action; hence, they are significantly more effective at lower doses in detoxifying the deleterious effects of free radicals than nonenzymatic antioxidants. This review provides a comprehensive analysis of the potential of antioxidant therapy, challenges in their clinical translation, and the role nanoparticles/drug delivery systems could play in addressing these challenges.

Abstract BACKGROUND: Traumatic spinal cord injuries (SCI) have devastating consequences for the physical, financial, and psychosocial well-being of patients and their caregivers. Expediently delivering interventions during the early postinjury period can have a tremendous impact on long-term functional recovery. PATHOPHYSIOLOGY: This is largely due to the unique pathophysiology of SCI where the initial traumatic insult (primary injury) is followed by a progressive secondary injury cascade characterized by ischemia, proapoptotic signaling, and peripheral inflammatory cell infiltration. Over the subsequent hours, release of proinflammatory cytokines and cytotoxic debris (DNA, ATP, reactive oxygen species) cyclically adds to the harsh postinjury microenvironment. As the lesions mature into the chronic phase, regeneration is severely impeded by the development of an astroglial-fibrous scar surrounding coalesced cystic cavities. Addressing these challenges forms the basis of current and upcoming treatments for SCI. MANAGEMENT: This paper discusses the evidence-based management of a patient with SCI while emphasizing the importance of early definitive care. Key neuroprotective therapies are summarized including surgical decompression, methylprednisolone, and blood pressure augmentation. We then review exciting neuroprotective interventions on the cusp of translation such as Riluzole, Minocycline, magnesium, therapeutic hypothermia, and CSF drainage. We also explore the most promising neuroregenerative strategies in trial today including Cethrin™, anti-NOGO antibody, cell-based approaches, and bioengineered biomaterials. Each section provides a working knowledge of the key preclinical and patient trials relevant to clinicians while highlighting the pathophysiologic rationale for the therapies. CONCLUSION: We conclude with our perspectives on the future of treatment and research in this rapidly evolving field.

Significance: Pulse oximetry is widely used in clinical practice to monitor changes in arterial oxygen saturation (SpO2). However, decreases in SpO2 can be delayed relative to the actual clinical event, and near-infrared spectroscopy (NIRS) may detect alterations in oxygenation earlier than pulse oximetry, as shown in previous cerebral oxygenation monitoring studies. Aim: We aim to compare the response of transcutaneous muscle NIRS measures of the tissue saturation index with pulse oximetry SpO2 during hypoxia. Approach: Episodes of acute hypoxia were induced in nine anesthetized Yucatan miniature pigs. A standard pulse oximeter was attached to the ear of the animal, and a transcutaneous NIRS sensor was placed on the hind limb muscle. Hypoxia was induced by detaching the ventilator from the animal and reattaching it once the pulse oximeter reported 70% SpO2. Results: Twenty-four episodes of acute hypoxia were analyzed. Upon the start of hypoxia, the transcutaneous NIRS measures changed in 5.3  ±  0.4  s, whereas the pulse oximetry measures changed in 14.9  ±  1.0  s (p  <  0.0001). Conclusions: Transcutaneous muscle NIRS can detect the effects of hypoxia significantly sooner than pulse oximetry in the Yucatan miniature pig. A transcutaneous NIRS sensor may be used as an earlier detector of oxygen saturation changes in the clinical setting than the standard pulse oximeter.

To determine the influence of time from injury to surgery on neurological recovery and length of stay (LOS) in an observational cohort of individuals with traumatic spinal cord injury (tSCI), we analyzed the baseline and follow-up motor scores of participants in the Rick Hansen Spinal Cord Injury Registry to specifically assess the effect of an early (less than 24 h from injury) surgical procedure on motor recovery and on LOS. One thousand four hundred and ten patients who sustained acute tSCIs with baseline American Spinal Injury Association Impairment Scale (AIS) grades A, B, C, or D and were treated surgically were analyzed to determine the effect of the timing of surgery (24, 48, or 72 h from injury) on motor recovery and LOS. Depending on the distribution of data, we used different types of generalized linear models, including multiple linear regression, gamma regression, and negative binomial regression. Persons with incomplete AIS B, C, and D injuries from C2 to L2 demonstrated motor recovery improvement of an additional 6.3 motor points (SE=2.8 p<0.03) when they underwent surgical treatment within 24 h from the time of injury, compared with those who had surgery later than 24 h post-injury. This beneficial effect of early surgery on motor recovery was not seen in the patients with AIS A complete SCI. AIS A and B patients who received early surgery experienced shorter hospital LOS. While the issues of when to perform surgery and what specific operation to perform remain controversial, this work provides evidence that for an incomplete acute tSCI in the cervical, thoracic, or thoracolumbar spine, surgery performed within 24 h from injury improves motor neurological recovery. Early surgery also reduces LOS.

Biomarkers of acute human spinal cord injury (SCI) could provide a more objective measure of spinal cord damage and a better predictor of neurological outcome than current standardized neurological assessments. In SCI, there is growing interest in establishing biomarkers from cerebrospinal fluid (CSF) and from magnetic resonance imaging (MRI). Here, we compared the ability of CSF and MRI biomarkers to classify injury severity and predict neurological recovery in a cohort of acute cervical SCI patients. CSF samples and MRI scans from 36 acute cervical SCI patients were examined. From the CSF samples taken 24 h post-injury, the concentrations of inflammatory cytokines (interleukin [IL]-6, IL-8, monocyte chemotactic protein-1), and structural proteins (tau, glial fibrillary acidic protein, and S100β) were measured. From the pre-operative MRI scans, we measured intramedullary lesion length, hematoma length, hematoma extent, CSF effacement, cord expansion, and maximal spinal cord compression. Baseline and 6-month post-injury assessments of American Spine Injury Association Impairment Scale (AIS) grade and motor score were conducted. Both MRI measures and CSF biomarker levels were found to correlate with baseline injury grade, and in combination they provided a stronger model for classifying baseline AIS grade than CSF or MRI biomarkers alone. For predicting neurological recovery, the inflammatory CSF biomarkers best predicted AIS grade conversion, whereas structural biomarker levels best predicted motor score improvement. A logistic regression model utilizing CSF biomarkers alone had a 91.2% accuracy at predicting AIS conversion, and was not strengthened by adding MRI features or even knowledge of the baseline AIS grade. In a direct comparison of MRI and CSF biomarkers, the CSF biomarkers discriminate better between different injury severities, and are stronger predictors of neurological recovery in terms of AIS grade and motor score improvement. These findings demonstrate the utility of measuring the acute biological responses to SCI as biomarkers of injury severity and neurological prognosis.

Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem/progenitor cells, fate-restricted neural/glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same “type” exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.

The course, treatment response, and recovery potential after acute traumatic spinal cord injury (SCI) have been shown to differ depending on the neurological level of injury. There are limited data focused on thoracic-level injuries, however. A cohort of 86 patients from the prospectively maintained North American Clinical Trials Network SCI registry were identified and studied to characterize the patterns of neurological recovery and to determine rates of acute hospital death and pulmonary complications. Regression analyses were used to examine the relationship between timing of surgery and administration of methylprednisolone on neurologic and clinical outcomes. Neurological conversion (≥1 American Spinal Injury Association Impairment Scale [AIS] grade improvement) was poorest for AIS grade A patients; 14.3% converted at last available follow-up (mean eight months). While rates of conversion were more optimistic for AIS-B patients (54.5%) and AIS C injuries (77.8%) at the same time point, none of the AIS grade D patients converted to AIS E. At last available follow-up (mean eight months), the magnitudes of lower motor extremity score (LEMS) change were highest for AIS C injuries (21.9 points), then AIS B (17.7 points), AIS D (16.4 points), and finally AIS A (2.5 points) (p < 0.05). Early surgical intervention (<24 h post-injury) was independently associated with an additional seven points in motor recovery and a 60% decreased incidence of pulmonary events (p < 0.05). Methylprednisolone administration was not an independent predictor of neurological outcome or pulmonary complications. Evaluation of this cohort obtained from a modern multi-center SCI registry provides an update on the natural history, acute death, and incidence of pulmonary complications after traumatic thoracic SCI. Although small sample size limited the extent of analyses possible, early surgical treatment was associated with significantly larger motor recovery and lower rates of pulmonary complications.

High fat, low carbohydrate ketogenic diets (KD) are validated non-pharmacological treatments for some forms of drug-resistant epilepsy. Ketones reduce neuronal excitation and promote neuroprotection. Here, we investigated the efficacy of KD as a treatment for acute cervical spinal cord injury (SCI) in rats. Starting 4 hours following C5 hemi-contusion injury animals were fed either a standard carbohydrate based diet or a KD formulation with lipid to carbohydrate plus protein ratio of 3:1. The forelimb functional recovery was evaluated for 14 weeks, followed by quantitative histopathology. Post-injury 3:1 KD treatment resulted in increased usage and range of motion of the affected forepaw. Furthermore, KD improved pellet retrieval with recovery of wrist and digit movements. Importantly, after returning to a standard diet after 12 weeks of KD treatment, the improved forelimb function remained stable. Histologically, the spinal cords of KD treated animals displayed smaller lesion areas and more grey matter sparing. In addition, KD treatment increased the number of glucose transporter-1 positive blood vessels in the lesion penumbra and monocarboxylate transporter-1 (MCT1) expression. Pharmacological inhibition of MCTs with 4-CIN (α-cyano-4-hydroxycinnamate) prevented the KD-induced neuroprotection after SCI, In conclusion, post-injury KD effectively promotes functional recovery and is neuroprotective after cervical SCI. These beneficial effects require the function of monocarboxylate transporters responsible for ketone uptake and link the observed neuroprotection directly to the function of ketones, which are known to exert neuroprotection by multiple mechanisms. Our data suggest that current clinical nutritional guidelines, which include relatively high carbohydrate contents, should be revisited.

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 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.