Spinal Cord Tissue Bridges Validation Study: Predictive Relationships With Sensory Scores Following Cervical Spinal Cord Injury

Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. The acute tissue hypoxia resulting from spinal cord injury (SCI) activates acid-sensing ion channel 1a (ASIC1a). We surmised that antagonism of this channel should provide neuroprotection and functional preservation after SCI. We show that systemic administration of the spider-venom peptide PcTx1, a selective inhibitor of ASIC1a, improves locomotor function in adult Sprague Dawley rats after thoracic SCI. The degree of functional improvement correlated with the degree of tissue preservation in descending white matter tracts involved in hind limb locomotor function. Transcriptomic analysis suggests that PcTx1-induced preservation of spinal cord tissue does not result from a reduction in apoptosis, with no evidence of down-regulation of key genes involved in either the intrinsic or extrinsic apoptotic pathways. We also demonstrate that trauma-induced disruption of blood-spinal cord barrier function persists for at least 4 days post-injury for compounds up to 10 kDa in size, whereas barrier function is restored for larger molecules within a few hours. This temporary loss of barrier function provides a “treatment window” through which systemically administered drugs have unrestricted access to spinal tissue in and around the sites of trauma. Taken together, our data provide evidence to support the use of ASIC1a inhibitors as a therapeutic treatment for SCI. This study also emphasizes the importance of objectively grading the functional severity of initial injuries (even when using standardized impacts) and we describe a simple scoring system based on hind limb function that could be adopted in future studies.

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347 Histopathology of Necrotic Spinal Cord Tissue Exudate Collected During Surgical Implantation of a Biodegradable Scaffold Following Acute Spinal Cord Injury: Pre-clinical and Clinical Findings

Neurosurgery ◽

10.1093/neuros/nyx417.347 ◽

2017 ◽

Vol 64 (CN_suppl_1) ◽

pp. 278-279

Author(s):

K Stuart Lee ◽

Philip J Boyer ◽

Patrick C Hsieh ◽

Kyle M Hurth ◽

James D Guest ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Human Tissue ◽

Surgical Procedure ◽

Tissue Sample ◽

Spinal Cord Tissue ◽

Compression Injury ◽

Post Injury ◽

Tissue Samples ◽

Cord Injury

Abstract INTRODUCTION Acute implantation of biodegradable scaffolds following spinal cord injury (SCI) has been shown pre-clinically to reduce chronic cavitation, increase white matter sparing, and increase the deposition of neuropermissive remodeled tissue. The surgical procedure of scaffold implantation allows for the gentle removal of acutely necrotic tissue resulting in a cavity in which the scaffold is placed. Here we report for the first time on the histopathological findings in both animal and human tissue specimens. METHODS Pre-clinically, experimental spinal cord contusion injuries were performed as previously reported in pigs. Clinically, the ongoing INSPIRE study (NCT02138110) is currently enrolling baseline T2-T12/L1 subjects with neurologically complete (AIS A) SCI within 96 hours of injury. The surgical procedure for implantation consists of durotomy and sometimes myelotomy. Commonly, damaged spinal cord tissue under pressure spontaneously extrudes after piotomy in pure contusion injuries. This tissue sample is collected and submitted for histopathologic analysis. RESULTS >24 hours post severe contusion/compression injury in a pig model, hematoxylin and eosin-stained (H&E) paraffin sections revealed myelin and axonal degeneration along with numerous scattered spheroids (swollen axons) with hemorrhage and acute inflammation at the wound site. Surgical pathology reports document neuropil disruption and devitalization in samples collected during surgery at 40 and 82 hours post-injury. In the patient implanted at 40 hours, the tissue specimen contained fragments of disrupted neuropil with swollen and fragmented axons as evaluated by H&E and neurofilament immunohistochemistry. CONCLUSION Severe SCI leads to the rapid formation of irreversibly damaged parenchyma. Our findings in animal and human tissue samples revealed acute tissue disruption and devitalization within 24–82 hours post-injury. This time frame was too short to appreciate phagocytosis, gliosis, or axon sprouts. Future patient enrollment and tissue collection in the ongoing clinical study will continue to build upon these initial observations.

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Longitudinal Trends and Prevalence of Bowel Management in Individuals With Spinal Cord Injury

Topics in Spinal Cord Injury Rehabilitation ◽

10.46292/sci21-00008 ◽

2021 ◽

Vol 27 (4) ◽

pp. 53-67

Author(s):

Nicholas Dietz ◽

Kwadwo Sarpong ◽

Beatrice Ugiliweneza ◽

Dengzhi Wang ◽

Sevda S. Aslan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inpatient Rehabilitation ◽

Model Systems ◽

Significant Shift ◽

Post Injury ◽

Bowel Management ◽

Cord Injury ◽

Over Time

Background: Neurogenic bowel dysfunction (NBD) following spinal cord injury (SCI) represents a major source of morbidity, negatively impacting quality of life and overall independence. The long-term changes in bowel care needs are not well-reported, preventing consensus on the natural course and optimal management of NBD following injury. Objectives: To understand the changes in bowel management needs over time following SCI. Methods: A retrospective observational study using the National Spinal Cord Injury Model Systems database evaluated the degree of independence with bowel management at discharge from inpatient rehabilitation across time (1988–2016). The prevalence and consecutive trajectory of bowel management was also evaluated at discharge and at each 5-year follow-up period, for 25 years. Results: The majority of individuals discharged from inpatient rehabilitation (n = 17,492) required total assistance with bowel management, a trend that significantly increased over time. However, by 5-years post injury, there was a significant shift in bowel management needs from total assistance to modified independence. In those with consecutive 25-year follow-up data (n = 11,131), a similar shift in bowel management to a less dependent strategy occurred even at chronic time points post injury, primarily in individuals with paraplegia and classified as motor and sensory complete. Conclusion: The findings of this study highlight the need for providing continued multipronged interventions (e.g., rehabilitative, educational, psycho-social) at the different stages of SCI to support individuals not only in the immediate years after discharge but also well into the chronic stages after injury.

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Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury

F1000Research ◽

10.12688/f1000research.9094.2 ◽

2016 ◽

Vol 5 ◽

pp. 1822 ◽

Cited By ~ 3

Author(s):

Liam M. Koehn ◽

Natassya M. Noor ◽

Qing Dong ◽

Sing-Yan Er ◽

Lachlan D. Rash ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Barrier Function ◽

Hind Limb ◽

Tissue Loss ◽

Functional Improvement ◽

Spinal Cord Tissue ◽

Post Injury ◽

Locomotor Function ◽

Cord Injury

Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. The acute tissue hypoxia resulting from spinal cord injury (SCI) activates acid-sensing ion channel 1a (ASIC1a). We surmised that antagonism of this channel should provide neuroprotection and functional preservation after SCI. We show that systemic administration of the spider-venom peptide PcTx1, a selective inhibitor of ASIC1a, improves locomotor function in adult Sprague Dawley rats after thoracic SCI. The degree of functional improvement correlated with the degree of tissue preservation in descending white matter tracts involved in hind limb locomotor function. Transcriptomic analysis suggests that PcTx1-induced preservation of spinal cord tissue does not result from a reduction in apoptosis, with no evidence of down-regulation of key genes involved in either the intrinsic or extrinsic apoptotic pathways. We also demonstrate that trauma-induced disruption of blood-spinal cord barrier function persists for at least 4 days post-injury for compounds up to 10 kDa in size, whereas barrier function is restored for larger molecules within a few hours. This temporary loss of barrier function provides a “treatment window” through which systemically administered drugs have unrestricted access to spinal tissue in and around the sites of trauma. Taken together, our data provide evidence to support the use of ASIC1a inhibitors as a therapeutic treatment for SCI. This study also emphasizes the importance of objectively grading the functional severity of initial injuries (even when using standardized impacts) and we describe a simple scoring system based on hind limb function that could be adopted in future studies.

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D-dopachrome tautomerase activates COX2/PGE2 pathway of astrocytes to mediate inflammation following spinal cord injury

Journal of Neuroinflammation ◽

10.1186/s12974-021-02186-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Huiyuan Ji ◽

Yuxin Zhang ◽

Chen Chen ◽

Hui Li ◽

Bingqiang He ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Signal Pathways ◽

Post Injury ◽

Dopachrome Tautomerase ◽

Protein Levels ◽

Cytokines And Chemokines ◽

Cord Injury ◽

Mitogen Activated Protein ◽

Spinal Cord Contusion

Abstract Background Astrocytes are the predominant glial cell type in the central nervous system (CNS) that can secrete various cytokines and chemokines mediating neuropathology in response to danger signals. D-dopachrome tautomerase (D-DT), a newly described cytokine and a close homolog of macrophage migration inhibitory factor (MIF) protein, has been revealed to share an overlapping function with MIF in some ways. However, its cellular distribution pattern and mediated astrocyte neuropathological function in the CNS remain unclear. Methods A contusion model of the rat spinal cord was established. The protein levels of D-DT and PGE2 synthesis-related proteinase were assayed by Western blot and immunohistochemistry. Primary astrocytes were stimulated by different concentrations of D-DT in the presence or absence of various inhibitors to examine relevant signal pathways. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale. Results D-DT was inducibly expressed within astrocytes and neurons, rather than in microglia following spinal cord contusion. D-DT was able to activate the COX2/PGE2 signal pathway of astrocytes through CD74 receptor, and the intracellular activation of mitogen-activated protein kinases (MAPKs) was involved in the regulation of D-DT action. The selective inhibitor of D-DT was efficient in attenuating D-DT-induced astrocyte production of PGE2 following spinal cord injury, which contributed to the improvement of locomotor functions. Conclusion Collectively, these data reveal a novel inflammatory activator of astrocytes following spinal cord injury, which might be beneficial for the development of anti-inflammation drug in neuropathological CNS.

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Spinal Cord Injury Increases Pro-inflammatory Cytokine Expression in Kidney at Acute and Sub-chronic Stages

Inflammation ◽

10.1007/s10753-021-01507-x ◽

2021 ◽

Author(s):

Shangrila Parvin ◽

Clintoria R. Williams ◽

Simone A. Jarrett ◽

Sandra M. Garraway

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Inflammatory Cytokine ◽

Cardiovascular Health ◽

Mrna Levels ◽

Post Injury ◽

Cord Injury ◽

And Function ◽

The Impact

Abstract— Accumulating evidence supports that spinal cord injury (SCI) produces robust inflammatory plasticity. We previously showed that the pro-inflammatory cytokine tumor necrosis factor (TNF)α is increased in the spinal cord after SCI. SCI also induces a systemic inflammatory response that can impact peripheral organ functions. The kidney plays an important role in maintaining cardiovascular health. However, SCI-induced inflammatory response in the kidney and the subsequent effect on renal function have not been well characterized. This study investigated the impact of high and low thoracic (T) SCI on C-fos, TNFα, interleukin (IL)-1β, and IL-6 expression in the kidney at acute and sub-chronic timepoints. Adult C57BL/6 mice received a moderate contusion SCI or sham procedures at T4 or T10. Uninjured mice served as naïve controls. mRNA levels of the proinflammatory cytokines IL-1β, IL-6, TNFα, and C-fos, and TNFα and C-fos protein expression were assessed in the kidney and spinal cord 1 day and 14 days post-injury. The mRNA levels of all targets were robustly increased in the kidney and spinal cord, 1 day after both injuries. Whereas IL-6 and TNFα remained elevated in the spinal cord at 14 days after SCI, C-fos, IL-6, and TNFα levels were sustained in the kidney only after T10 SCI. TNFα protein was significantly upregulated in the kidney 1 day after both T4 and T10 SCI. Overall, these results clearly demonstrate that SCI induces robust systemic inflammation that extends to the kidney. Hence, the presence of renal inflammation can substantially impact renal pathophysiology and function after SCI.

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Effect of pelvic laparoscopic implantation of neuroprosthesis in spinal cord injured subjects: a 1-year prospective randomized controlled study

Spinal Cord ◽

10.1038/s41393-021-00693-7 ◽

2021 ◽

Author(s):

Helge Kasch ◽

Uffe Schou Løve ◽

Anette Bach Jønsson ◽

Kaare Eg Severinsen ◽

Marc Possover ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Outcome Measures ◽

Outcome Measure ◽

Secondary Outcome ◽

Controlled Study ◽

Control Group ◽

Walking Ability ◽

Data Set ◽

Cord Injury

Abstract Study design 1-year prospective RCT. Objective Examine the effect of implantable pulse generator and low-frequency stimulation of the pelvic nerves using laparoscopic implantation of neuroprosthesis (LION) compared with neuromuscular electrical stimulation (NMES) in SCI. Methods Inclusion criteria: traumatic spinal cord injury (SCI), age 18–55 years, neurological level-of-injury Th4–L1, time-since-injury >1 year, and AIS-grades A–B. Participants were randomized to (A) LION procedure or (B) control group receiving NMES. Primary outcome measure: Walking Index for Spinal Cord Injury (WISCI-II), which is a SCI specific outcome measure assessing ability to ambulate. Secondary outcome measures: Spinal Cord Independence Measure III (SCIM III), Patient Global Impression of Change (PGIC), Penn Spasm Frequency Scale (PSFS), severity of spasticity measured by Numeric Rating Scale (NRS-11); International Spinal Cord Injury data sets-Quality of Life Basic Data Set (QoLBDS), and Brief Pain Inventory (BPI). Results Seventeen SCI individuals, AIS grade A, neurological level ranging from Th4–L1, were randomized to the study. One individual was excluded prior to intervention. Eight participants (7 males) with a mean age (SD) of 35.5 (12.4) years were allocated to the LION procedure, 8 participants (7 males) with age of 38.8 (15.1) years were allocated to NMES. Significantly, 5 LION group participants gained 1 point on the WISCI II scale, (p < 0.013; Fisher´s exact test). WISCI II scale score did not change in controls. No significant changes were observed in the secondary outcome measures. Conclusion The LION procedure is a promising new treatment for individuals with SCI with significant one-year improvement in walking ability.

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