Journal of neurotrauma最新文献

Spinal cord injury (SCI) is a debilitating condition resulting in the loss of sensorimotor functioning at and below the site of injury. Despite advances in the treatment and management of SCI, there are no current approved pharmacological therapies to augment motor function and functional recovery. NX210c is a 12-amino acid peptide derived from thrombospondin type 1 (TSP1) repeat sequences from the subcommissural organ-spondin protein. TSPs are glycoproteins present in the extracellular matrix, mediating cell-cell and cell-matrix interactions and axon pathfinding. NX210c was previously shown to improve axonal regeneration and functional recovery in thoracic SCI. The aim of this study was to evaluate the ability of NX210c to promote functional recovery and tissue repair in a traumatic cervical SCI rat model. Adult female Wistar rats were subjected to a C6/C7 bilateral clip compression-contusion injury and treated once daily with intraperitoneal injections of NX210c (8 mg/kg) or its vehicle for 8 weeks, beginning 4 h or 8 h post-injury. Administration of NX210c beginning at 4 h post-injury increased forelimb grip strength post-injury and improved several static and dynamic aspects of locomotion, including interlimb coordination. When the first administration was undertaken at 8 h post-injury, NX210c promoted weight gain, improved trunk balance (inclined plane), trended toward accelerated bladder control recovery, and approached significance for skilled reaching at 8 weeks post-injury. Furthermore, for animals that were treated daily with NX210c starting 8 h post-injury, histological analysis demonstrated greater white and gray matter preservation and reduced cavity size, along with the upregulation of neuronal markers. To conclude, NX210c mitigates various aspects of SCI, including motor function and tissue preservation, with preferential results being obtained with the delayed initial administration of NX210c at 8 h post-injury.

Respiratory failure is one of the greatest causes of morbidity and mortality after cervical lesions, the most common type of spinal cord injury (SCI). Fortunately, several pre-clinical and clinical studies have shown spontaneous, but limited, respiratory recovery after injury. However, there are still many unanswered questions about what is driving this recovery, so there is a growing need to further elucidate the neuroplastic potential of the phrenic network. Here, we investigated the structural plasticity of the right and left phrenic networks by analyzing perineuronal net (PNN) changes after a C2 hemisection (C2Hx) in mice. For this purpose, the right and left phrenic systems were traced with a pseudorabies virus, a trans-synaptic retrograde tracer applied to the diaphragm muscle, labeling the entire phrenic motor network. We found most PNN-bearing neurons within the ventral horn in naïve animals, specifically around phrenic motoneurons (PhMNs), but not phrenic spinal interneurons. Right, but not left, C2Hx resulted in a significant increase in PNNs and glutamatergic synapses around ipsilateral PhMNs, suggesting that the right C2Hx requires greater neuroplasticity to overcome respiratory dysfunction. The results from this study uncover profound anatomical and functional asymmetries in left- and right-sided phrenic networks, underlying the complex nature of the spinal respiratory system, and contribute to a more advanced understanding of how the phrenic network adapts to trauma. Overall, this work underscores the importance of studying neuroplasticity and how it holds the potential to help improve outcomes for individuals living with SCI.

Traumatic spinal cord injury (TSCI) is a debilitating disease that results in a heterogeneous set of symptoms. This includes secondary inflammatory mechanisms, which can perpetuate injury to the spinal cord, as well as negatively affect other organ systems. Standard prognostication, such as magnetic resonance imaging, is cumbersome and provides limited resolution; thus, the development of prognostic biofluid tests is of significant clinical importance. The current study systematically reviewed biomarker studies following acute (within 24 h) TSCI. Four databases were searched for this systematic review, PubMed/MEDLINE, Cochrane (OvidSP), Web of Science, and Scopus, resulting in 702 articles to be screened by two independent reviewers. Thirty-two studies met inclusion criteria and were included in the systemic review. About 116 total markers were examined, and 66.4% were found to be associated with TSCI with three major utilities: diagnostic, injury severity, and prognostics. Results generated from the current study highlight discrepancies between biofluids and recommend biomarkers for clinical utility. Future research should associate these acute biomarkers with long-term outcomes using predictive modeling, in addition to curating a clinical TSCI database for optimal prognostication. As TSCI outcomes are variable and impact many systems, the curation of preventative and interventional treatment strategies is crucial.

High-level spinal cord injury (SCI) often disrupts supraspinal control of sympathetic input to the heart. The resulting imbalance in the autonomic nervous system increases the risk of developing cardiac arrhythmias. It was previously demonstrated that passive hindlimb cycling (PHLC) effectively maintains or improves bodily function including cardiovascular performance following SCI. However, it remains unclear whether the exercise can affect cardiac electrical disorders. To address this specific question, we complemented a complete SCI at a high-thoracic level in rats and then performed PHLC for 5 or 10 weeks. Naive rats or those receiving injury alone served as controls. Subsequently, a telemetric transmitter was implanted to record blood pressure and electrocardiogram. In 24-h resting recordings, cycling training did not influence SCI-induced hypotension but significantly reduced the events of spontaneous autonomic dysreflexia. When colorectal distension was employed to artificially trigger autonomic dysreflexia, a fewer number of severe arrhythmias (e.g., atrioventricular block, premature ventricular contraction single, and sinus pause) were found in animals with 10-week PHLC compared with injury controls. As a stress test, a series of increasing concentrations of dobutamine was administered to stimulate cardiac sympathetic activity. Consequently, various types of arrhythmias occurred in animals with SCI alone, whereas very few were detected in animals obtaining exercise training for 10 weeks. Furthermore, pharmacological intervention disclosed that exercise appeared to reduce unopposed parasympathetic tone that arose post to injury. Thus, the results suggest that activity-based training for the long term improves autonomic balance to enhance tolerance of cardiac electrical conduction following SCI.

Spinal cord injury (SCI) results in an array of debilitating, sometimes permanent-and at times life-threatening-motor, sensory, and autonomic deficits. A broad range of therapies have been tested pre-clinically, and there has been a significant acceleration in recent years of clinical translation of potential treatments. However, it is widely appreciated among scientists and clinical professionals alike that there likely is no "silver bullet" (single treatment) that will result in complete functional restoration after SCI. The combination of more than one treatment approach, especially treatments that can have distinct beneficial effects, increases the probability of functional improvement. This review highlights the mounting interest in the pre-clinical development and application of combination strategies to treat SCI, and some of the translational efforts made to combine promising therapies for clinical evaluation. Special attention is given to barriers and limitations faced in translating treatments for people living with SCI.

Spinal cord injury (SCI) can result in partial or full paralysis, depending on the level and completeness of injury. Locomotor function is often used as a measure of recovery and treatment outcomes. The Basso, Beattie, and Bresnahan scale and Basso Mouse Scale (BMS) are gold standards used in rodent SCI studies to evaluate changes in locomotor recovery. However, these scoring systems are observer-dependent measures that may be affected by the presence of an experimenter, particularly in studies where blinding is difficult. Observer-independent methods measure outcomes without an operator present, thus reducing bias and increasing reproducibility between research groups. Changes in locomotor recovery were evaluated after contusive SCI using the Advanced Dynamic Weight Bearing (ADWB) system, previously used successfully to assess acute and chronic pain. We observed a shift in body weight early after injury, with increased surface area and weight placement to the front paws and the trunk/tail region. Concurrently, there was a reduction in rear paw surface area and weight placement. As functional recovery occurred over time, there was a shift toward reduced weight placement on the front paws. As with locomotor recovery, these changes did not return to preinjury levels. We also found that the rate and degree to which mice shifted weight onto front paws depended on injury severity. Importantly, changes in weight distribution and surface area showed a strong correlation with BMS scores, suggesting that the observer-independent ADWB test is a viable measure to assess changes in locomotor function over time after SCI.

Acutely after traumatic spinal cord injury (SCI), the immune system responds with an inflammatory cascade that promotes secondary damage to the spinal cord and systemic inflammation, which promotes persistent medical consequences. Here, we combined clinical and research data to evaluate cellular and molecular changes in the systemic immune system of individuals with SCI (SCI, N = 36) within 0-4 days after injury compared to uninjured individuals (CTL, N = 36). Analyzing blood samples by bulk-RNA Seq, 4752 differentially expressed (DE) gene transcripts were identified in SCI compared with CTLs, including increased expression of genes associated with inflammation and innate immunity (e.g., Neutrophil degranulation, Toll-Like Receptor signaling). Most participants with SCI had complete blood count data available, of whom 36% had elevated white blood cell and neutrophil counts, 24% had elevated monocytes, and 36% had lymphopenia. Significantly reduced expression of canonical natural killer (NK) cell, T cell and dendritic cell (DC) genes were identified, consistent with reduced frequencies of these cell types, determined by flow cytometry. Some molecular changes appeared to be influenced by motor completeness of injury. C-reactive protein, a validated clinical biomarker of inflammation, was significantly elevated after SCI, with levels higher in motor complete compared to motor incomplete injuries. This was also apparent for several other proinflammatory cytokines (e.g., High Mobility Group Box 1 protein, IL-6, IL-8). These data confirm and extend prior observations of cellular and molecular immunological changes, that may serve as potential biomarkers of injury severity, or as future therapeutic targets to improve health.

Previous studies have shown that administration of high doses of morphine in the acute phase of spinal cord injury (SCI) significantly undermines locomotor recovery and increases symptoms of chronic pain in a rat spinal contusion model. Similarly, SCI patients treated with high doses of opioid for the first 24 h postinjury have increased symptoms of chronic pain 1 year later. Whether these adverse effects are driven by morphine only or all opioids compromise recovery after SCI, however, is unknown. Based on our previous findings we hypothesized that activation of the kappa opioid receptor (KOR) is key in the morphine-induced attenuation of locomotor recovery after SCI. Thus, we posited that opioids that engage KOR-mediated signaling pathways (morphine, oxycodone) would undermine recovery, and clinically relevant opioids with less KOR activity (fentanyl and buprenorphine) would not. To test this, we compared the effects of the clinically relevant opioids on locomotor recovery and pain in a male rat spinal contusion model. Rats were given a moderate spinal contusion injury followed by 7 days of intravenous morphine, oxycodone, fentanyl, buprenorphine, or saline, and recovery was assessed for 28 days. All opioids produced analgesia on tests of thermal, mechanical, and incremented shock reactivity. However, tolerance developed rapidly with buprenorphine administration, particularly with daily administrations of 5 morphine milligram equivalent (MME) buprenorphine. Opioid-induced hyperalgesia (OIH) also developed across days following administration of higher doses (10 MME, 20 MME) of morphine and oxycodone. Fentanyl and buprenorphine did not produce OIH. Contrary to our hypothesis, however, we found that high doses of all opioids reduced recovery of locomotor function. Unlike the other opioids, the effects of buprenorphine on locomotor recovery appeared transient, but it also produced chronic pain. Morphine, oxycodone, and buprenorphine decreased reactivity thresholds on tests of mechanical and incremented shock stimulation. In sum, all opioids undermined long-term recovery in the rat model. Further interrogation of the molecular mechanisms driving the adverse effects is essential. This study provides critical insight into pain management strategies in the acute phase of SCI and potential long-term consequences of early opioid administration.

Spinal cord injury (SCI) represents a major public health issue, as the consequences are often irreversible with no treatment currently available. This results in a growing population living with long-lasting motor, sensory, and/or autonomic impairments directly related to their SCI. Here, we have evaluated the therapeutic potential of a thrombospondin repeats peptide analogue, named NX210, in a mouse hemisection model of SCI. Adult female mice were subjected to a thoracic level 8 dorsal hemisection, and treated with intraperitoneal injections of NX210 starting at 4 h post-injury and then twice a week at 4, 8, or 16 mg/kg. Hind limb motor function was assessed once a week for 10 weeks post-injury using the Basso Mouse Scale (BMS) score and sub-score, the rotarod, and the activity chamber tests. Mice were then sacrificed, and the spinal cords were collected for immunohistochemistry. Interestingly, NX210 improved functional recovery (BMS score and sub-score, latency to fall from the rotarod, spontaneous locomotor activity) with rapid rises in function that were maintained throughout the 10-week study. This was accompanied by a reduction of nociceptive reactivity assessed by the tail flick test. NX210 treatment also increased myelin basic protein and reduced neuron/glial antigen 2 at the injury site 10 weeks post-injury while no significant effects were observed on lesion size, inflammation, and neuron survival. Overall, this study highlights a potential new therapeutic strategy to promote repair and decrease long-lasting functional impairments after SCI.