Sensitization of Endothelial Cells to Ionizing Radiation Exacerbates Delayed Radiation Myelopathy in Mice

Delayed radiation myelopathy is a rare, but significant late side effect from radiation therapy that can lead to paralysis. The cellular and molecular mechanisms leading to delayed radiation myelopathy are not completely understood but may be a consequence of damage to oligodendrocyte progenitor cells and vascular endothelial cells. Here, we aimed to determine the contribution of endothelial cell damage to the development of radiation-induced spinal cord injury using a genetically defined mouse model in which endothelial cells are sensitized to radiation due to loss of the tumor suppressor p53. Tie2Cre; p53FL/+ and Tie2Cre; p53FL/– mice, which lack one and both alleles of p53 in endothelial cells, respectively, were treated with focal irradiation that specifically targeted the lumbosacral region of the spinal cord. The development of hindlimb paralysis was followed for up to 18 weeks after either a 26.7 Gy or 28.4 Gy dose of radiation. During 18 weeks of follow-up, 83% and 100% of Tie2Cre; p53FL/– mice developed hindlimb paralysis after 26.7 and 28.4 Gy, respectively. In contrast, during this period only 8% of Tie2Cre; p53FL/+ mice exhibited paralysis after 28.4 Gy. In addition, 8 weeks after 28.4 Gy the irradiated spinal cord from Tie2Cre; p53FL/– mice showed a significantly higher fractional area positive for the neurological injury marker glial fibrillary acidic protein (GFAP) compared with the irradiated spinal cord from Tie2Cre; p53FL/+ mice. Together, our findings show that deletion of p53 in endothelial cells sensitizes mice to the development of delayed radiation myelopathy indicating that endothelial cells are a critical cellular target of radiation that regulates myelopathy.

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Identifying the Biomarkers of Spinal Cord Injury and the effects of Neurotrophin-3 Based on MicroRNA and mRNA Signature

10.21203/rs.3.rs-20687/v1 ◽

2020 ◽

Author(s):

Shuang Qi ◽

Zinan Li ◽

Shanshan Yu

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Molecular Mechanisms ◽

Ion Homeostasis ◽

Metabolic Process ◽

Neurological Injury ◽

Receptor Interaction ◽

Transcription Profile ◽

Neurotrophin 3 ◽

Cord Injury

Abstract Background To gain a better understanding of the molecular mechanisms of spinal cord injury and the effects of Neurotrophin-3, differentially expressed microRNAs (DEmiRNAs) and genes (DEGs) were analyzed. Methods The miRNA transcription profile of GSE82195 and the mRNA transcription profile of GSE82196 were downloaded from the Gene Expression Omnibus (GEO). Then, DERs were identified using limma. The noise-robust soft clustering of the intersection DERs was performed using Mfuzz package. Additionally, the integrated miRNAs–targets regulatory network was constructed using Cytoscape. Finally, the Comparative Toxicogenomics Database 2019 update was used to search the central nervous system injury related pathway. Results A total of 444 DERs including 382 DEGs and 62 DEmiRNAs were screened between group injury and group none whlie 576 DERs including 523 DEGs and 55 DEmiRNAs were screened between group NT-3 and group injury. Moreover, 80 intersections DERs were identified. DREs in cluster 1 were firstly significantly down-regulated in group injury and subsequently were significantly up-regulated in group NT-3. DERs in cluster 2 were firstly up-regulated in group injury and subsequently down-regulated in group NT-3. OPRL1 and GHSR were enriched in the KEGG pathway of Neuroactive ligand-receptor interaction. OPRL1 was involved in the chemical homeostasis and ion homeostasis while GHSR was related to the regulation of fatty acid metabolic process and regulation of cellular ketone metabolic process. Conclusion rno-miR-3072 and rno-miR-667-5p and OPRL1 and GHSR might participate in the pathogenesis of neurological injury and the neurotrophin-3 treatment.

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Epidemiology of Spinal Cord Injuries and Their Outcomes: A Study at King Khalid Hospital (KKH), Najran, Saudi Arabia, June 2018–June 2019

Journal of Spine Practice (JSP) ◽

10.18502/jsp.v1i1.9789 ◽

2021 ◽

pp. 30

Author(s):

Ahood Mahjari

Keyword(s):

Spinal Cord ◽

Saudi Arabia ◽

Traffic Accident ◽

Spinal Cord Injuries ◽

Road Traffic ◽

Neurological Injury ◽

National Data ◽

Common Cause ◽

Younger Age ◽

Cord Injury

Introduction: Spinal cord injury (SCI) is a life-changing neurological injury that puts a significant load on the healthcare system. SCI can be caused by several reasons such as road traffic accident (RTA), motor traffic accident (MTA), fall, gunshots, or bomb blast. There is not much national data concerning the etiology of SCI in Saudi Arabia. Therefore, we conducted this study to quantify the number of SCI incidence at King Khalid Hospital (KKH), Najran between June 2018 and June 2019. The study aimed at reviewing the rate and epidemiology of SCI at KKH for all patients admitted to the hospital during the study period and examining the causes of SCI for suggesting prevention strategies. Methodology: This retrospective study included all patients with SCI admitted to KKH during the mentioned period. Several factors for each patient were recorded including their age, gender, nationality, cause of SCI, and the outcomes of neurological injury. Result: In total, 182 SCI patients were admitted during the study period: 53% of them were male, and those aged 16–30 years were most vulnerable to SCI. RTA was the most common cause of SCI for males (59%), followed by bomb blasts (15%). While fall was ranked as the second cause of SCI in males (15.4%), it was the main reason for SCI in females 13%, followed by RTA. The majority of admitted cases in younger age was stable and improved, however, after RTA four patients had quadriplegia and six cases had paraplegia. Conclusion: RTA is the most common cause of SCI followed by fall and bomb blast. Younger patients are more likely to improve after SCI compared to elderly patients.

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Epidural electrical stimulation to facilitate locomotor recovery after spinal cord injury

Journal of Neurophysiology ◽

10.1152/jn.00261.2021 ◽

2021 ◽

Author(s):

Johannie Audet ◽

Charly G. Lecomte

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Electrical Stimulation ◽

Clinical Implementation ◽

Preclinical Models ◽

Lumbosacral Region ◽

Locomotor Recovery ◽

Promising Therapeutic Approach ◽

Cord Injury ◽

Stimulation Of

Tonic or phasic electrical epidural stimulation of the lumbosacral region of the spinal cord facilitates locomotion and standing in a variety of preclinical models with severe spinal cord injury. However, the mechanisms of epidural electrical stimulation that facilitate sensorimotor functions remain largely unknown. This review aims to address how epidural electrical stimulation interacts with spinal sensorimotor circuits and discusses the limitations that currently restrict the clinical implementation of this promising therapeutic approach.

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The Organotypic Longitudinal Spinal Cord Slice Culture for Stem Cell Study

Stem Cells International ◽

10.1155/2015/471216 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 11

Author(s):

Joanna Sypecka ◽

Sylwia Koniusz ◽

Maria Kawalec ◽

Anna Sarnowska

Keyword(s):

Spinal Cord ◽

Molecular Mechanisms ◽

Synapse Formation ◽

Scientific Basis ◽

Slice Culture ◽

Spinal Cord Regeneration ◽

Spinal Cord Slice ◽

Detailed Method ◽

Cord Injury

The objective of this paper is to describe in detail the method of organotypic longitudinal spinal cord slice culture and the scientific basis for its potential utility. The technique is based on the interface method, which was described previously and thereafter was modified in our laboratory. The most important advantage of the presented model is the preservation of the intrinsic spinal cord fiber tract and the ventrodorsal polarity of the spinal cord. All the processes occurring during axonal growth, regeneration, synapse formation, and myelination could be visualized while being culturedin vitrofor up to 4-5 weeks after the slices had been isolated. Both pups and adult animals can undergo the same, equally efficient procedures when going by the protocol in question. The urgent need for an appropriatein vitromodel for spinal cord regeneration results from a greater number of clinical trials concerning regenerative medicine in the spinal cord injury and from still insufficient knowledge of the molecular mechanisms involved in the neuroreparative processes. The detailed method of organotypic longitudinal spinal cord slice culture is accompanied by examples of its application to studying biological processes to which both the CNS inhabiting and grafted cells are subjected.

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Activation of SIRT1 by Hyperbaric Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

10.21203/rs.2.23545/v1 ◽

2020 ◽

Author(s):

Huiqiang Chen ◽

Mengyu Yao ◽

Zhibo Li ◽

Ranran Xing ◽

Cheng Zhang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Molecular Mechanisms ◽

Hyperbaric Oxygenation ◽

Rating Scale ◽

Motor Dysfunction ◽

Sprague Dawley ◽

Inflammatory Cascade ◽

Locomotor Function ◽

Cord Injury

Abstract Background: Emerging evidence demonstrated that hyperbaric oxygenation (HBO) therapy improved the locomotor dysfunction following spinal cord injury (SCI). Sirtuin1(SIRT1) has been characterized as neuroprotection in nerve system. However, whether SIRT1 is involved in alleviation of locomotor function by HBO therapy is unclear. Methods: The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms in adult Sprague-Dawley rats. Results: We found that series HBO therapy significantly improved the locomotor dysfunction and ameliorated the decrease mRNA, protein and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection SIRT1 antagonist EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits and SIRT1 activity loss caused by traumatic SCI injury. However, the rats undergone both series HBO therapy and SIRT1 agonist SRT1720 got the higher BBB score than that undergone series HBO treatment only. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with HBO application. Conclusion: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of inflammatory cascade, apoptosis and autophagy, which contributed to the recovery of motor dysfunction. Key words: HBO, SIRT1, motor dysfunction, inflammation, autophagy, apoptosis

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Managing spinal cord trauma

Oxford Textbook of Neurological Surgery ◽

10.1093/med/9780198746706.003.0067 ◽

2019 ◽

pp. 781-788

Author(s):

Saksith Smithason ◽

Bryan S. Lee ◽

Edward C. Benzel

Keyword(s):

Spinal Cord ◽

Cell Damage ◽

Spinal Cord Trauma ◽

Prolonged Hospital Stay ◽

Cord Injury ◽

Prolonged Hospital ◽

Adequate Management ◽

Spinal Cord Function ◽

Underlying Pathophysiology

Spinal cord injury (SCI), either traumatic or non-traumatic in aetiology, leads to temporary or permanent damage to the spinal cord function. Significant efforts have been directed towards the elucidation of the underlying pathophysiology of SCI. Both primary and secondary mechanisms of SCI exist, leading to immediate and often irreversible cell damage. Immediate treatment and adequate management in the setting of acute SCI are essential, preservation of even a small amount of functional neuronal tissue can permit ambulation. SCI is associated with a prolonged hospital stay, rehabilitation stay, and often associated with enormous monetary costs. Neurological recovery after SCI is largely dependent on the extent of injury. The management of SCI and the determination of the role and timing of surgical decompression remain crucial and yet controversial. Further epidemiological research and studies are warranted in order to enhance healthcare planning and cost-effectiveness.

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The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

Glia ◽

10.1002/glia.23706 ◽

2019 ◽

Vol 68 (2) ◽

pp. 227-245 ◽

Cited By ~ 5

Author(s):

Greg J. Duncan ◽

Sohrab B. Manesh ◽

Brett J. Hilton ◽

Peggy Assinck ◽

Jason R. Plemel ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Progenitor Cells ◽

Traumatic Spinal Cord Injury ◽

Oligodendrocyte Progenitor Cells ◽

Oligodendrocyte Progenitor ◽

Cord Injury ◽

And Function

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Robotic-Assisted, Body-Weight–Supported Treadmill Training in Individuals Following Motor Incomplete Spinal Cord Injury

Physical Therapy ◽

10.1093/ptj/85.1.52 ◽

2005 ◽

Vol 85 (1) ◽

pp. 52-66 ◽

Cited By ~ 165

Author(s):

T George Hornby ◽

David H Zemon ◽

Donielle Campbell

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Body Weight ◽

Physical Therapists ◽

Treadmill Training ◽

Neurological Injury ◽

Walking Ability ◽

Incomplete Spinal Cord Injury ◽

Robotic Assisted ◽

Cord Injury

AbstractBackground and Purpose. Performance of therapist-assisted, body-weight–supported treadmill training (BWSTT) to enhance walking ability of people with neurological injury is an area of intense research. Its application in the clinical setting, however, is limited by the personnel and labor requirements placed on physical therapists. Recent development of motorized (“robotic”) rehabilitative devices that provide assistance during stepping may improve delivery of BWSTT. Case Description. This case report describes the use of a robotic device to enhance motor recovery and ambulation in 3 people following motor incomplete spinal cord injury. Interventions. Changes in motor impairment, functional limitations, and locomotor disability were monitored weekly during robotic-assisted BWSTT and following transition to therapist-assisted BWSTT with the assistance of one therapist. Outcomes. Following this training, 2 patients recovered independent over-ground walking and another improved his gait speed and endurance. Discussion. The use of robotic devices may assist physical therapists by providing task-specific practice of stepping in people following neurological injury.

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Sodium Tanshinone IIA Silate Exerts Microcirculation Protective Effects against Spinal Cord Injury In Vitro and In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3949575 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Xing Li ◽

Dan Luo ◽

Yu Hou ◽

Yonghui Hou ◽

Shudong Chen ◽

...

Keyword(s):

Spinal Cord ◽

Endothelial Cells ◽

Notch Signaling ◽

Signaling Pathway ◽

Notch Signaling Pathway ◽

Tanshinone Iia ◽

Protective Effects ◽

Cord Injury

Spinal cord microcirculation involves functioning endothelial cells at the blood spinal cord barrier (BSCB) and maintains normal functioning of spinal cord neurons, axons, and glial cells. Protection of both the function and integrity of endothelial cells as well as the prevention of BSCB disruption may be a strong strategy for the treatment of spinal cord injury (SCI) cases. Sodium Tanshinone IIA silate (STS) is used for the treatment of coronary heart disease and improves microcirculation. Whether STS exhibits protective effects for SCI microcirculation is not yet clear. The purpose of this study is to investigate the protective effects of STS on oxygen-glucose deprivation- (OGD-) induced injury of spinal cord endothelial cells (SCMECs) in vitro and to explore effects on BSCB and neurovascular protection in vivo. SCMECs were treated with various concentrations of STS (1 μM, 3 μM, and 10 μM) for 24 h with or without OGD-induction. Cell viability, tube formation, migration, and expression of Notch signaling pathway components were evaluated. Histopathological evaluation (H&E), Nissl staining, BSCB permeability, and the expression levels of von Willebrand Factor (vWF), CD31, NeuN, and Notch signaling pathway components were analyzed. STS was found to improve SCMEC functions and reduce inflammatory mediators after OGD. STS also relieved histopathological damage, increased zonula occludens-1 (ZO-1), inhibited BSCB permeability, rescued microvessels, protected motor neuromas, and improved functional recovery in a SCI model. Moreover, we uncovered that the Notch signaling pathway plays an important role during these processes. These results indicated that STS protects microcirculation in SCI, which may be used as a therapeutic strategy for SCI in the future.

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