Promoting Axonal Extension and Repair After Spinal Cord Injury by Inhibiting the Expression of Rho Gene Based on RNA Interference

Spinal cord injury causes central nervous system damage. Rho inhibits axonal regeneration. This study is intended to analyze the effect of inhibition of Rho expression on axonal repair. The oligodendrocytes were isolated and divided into NC group and shRNA-RhoA group followed by analysis of the average length of axon growth and average microtubule fluorescence density by immunofluorescence, Nogo, MAG and RhoA expression were by Real time PCR. Wistar rats were separated into control group; SCI group and shRNA-RhoA group followed by analysis of the BBB scores and the Reuter score of sensory function, RhoA expression by Real time PCR and Western blot, Caspase3 activity as well as Nogo and MAG expression by Real time PCR. Compared with NC group, shRNA-RhoA group showed significantly increased average length of axon growth and average microtubule fluorescence density at the distal axon and reduced expression of RhoA, Nogo and MAG (P < 0 05). In comparison to control group, SCI group presented significantly increased RhoA expression, decreased BBB score, increased Reuter score and Caspase3 activity as well as elevated Nogo and MAG expression (P < 0 05). The shRNA-RhoA group significantly decreased RhoA expression, increased BBB score, decreased Reuter score and Caspase3 activity, and reduced Nogo and MAG expression compared with SCI group (P < 0 05). Inhibiting RhoA expression can promote axon extension and regenerative repair. Targeting RhoA reduces axon growth inhibitory factor expression, inhibits apoptosis and effectively alleviates SCI.

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An observation of the clinical efficacy of combining Riluzole with mannitol and hyperbaric oxygen in treating acute spinal cord injury

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.37.2.3418 ◽

2021 ◽

Vol 37 (2) ◽

Author(s):

Huan-xia Li ◽

Jing Cui ◽

Jing-shi Fan ◽

Jian-zhou Tong

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Hyperbaric Oxygen ◽

Clinical Efficacy ◽

Acute Spinal Cord Injury ◽

Sensory Function ◽

Control Group ◽

Thoracolumbar Fractures ◽

Cord Injury ◽

Experimental Group

Objective: To examine the clinical efficacy of combining Riluzole with mannitol and hyperbaric oxygen therapy in treating thoracolumbar vertebral fracture-induced acute spinal cord injury (ASCI). Methods: From June 2015 to May 2018, 80 patients with thoracolumbar fractures and ASCI who were treated at Baoding First Central Hospital were selected. All patients underwent posterior laminectomy and screw fixation, and they were randomly divided into two groups using a random number table method. The control group received conventional postoperative treatment, while the experimental group was treated with riluzole combined with mannitol and hyperbaric oxygen on the basis of conventional treatment. The recovery of nerve function which included motor function and sensory function, and the changes of serum IL-6, CRP, BDNF, BFGF and other factors before treatment and four weeks after treatment of the two groups of patients were observed and evaluated. Results: After treatment, the motor function scores and sensory function scores of the two groups of patients were improved compared with those before treatment (p<0.05). Compared with the control group, the experimental group improved significantly, and the difference was statistically significant (p<0.05). The levels of IL-6, BDNF and NFGF in the experimental group were significantly lower than those in the control group (p<0.05). Conclusions: For patients with thoracolumbar fractures and ASCI undergoing laminar decompression and fixation, the comprehensive treatment plan of riluzole combined with mannitol and hyperbaric oxygen has certain advantages. Compared with the conventional therapy, it may significantly improve the movement and sensory functions of patients, relieve the inflammatory response of spinal cord, and promote recovery from the injury. doi: https://doi.org/10.12669/pjms.37.2.3418 How to cite this:Li H, Cui J, Fan J, Tong J. An observation of the clinical efficacy of combining Riluzole with mannitol and hyperbaric oxygen in treating acute spinal cord injury. Pak J Med Sci. 2021;37(2):---------. doi: https://doi.org/10.12669/pjms.37.2.3418 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Zinc Concentration Dynamics Indicate Neurological Impairment Odds after Traumatic Spinal Cord Injury

Antioxidants ◽

10.3390/antiox9050421 ◽

2020 ◽

Vol 9 (5) ◽

pp. 421

Author(s):

Raban Arved Heller ◽

André Sperl ◽

Julian Seelig ◽

Patrick Haubruck ◽

Tobias Bock ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neurological Impairment ◽

Sensory Function ◽

Control Group ◽

Binary Logistic Regression Analysis ◽

Traumatic Spinal Cord Injury ◽

Zn Concentration ◽

Cord Injury ◽

Serum Zn

Traumatic Spinal Cord Injury (TSCI) is debilitating and often results in a loss of motor and sensory function caused by an interwoven set of pathological processes. Oxidative stress and inflammatory processes are amongst the critical factors in the secondary injury phase after TSCI. The essential trace element Zinc (Zn) plays a crucial role during this phase as part of the antioxidant defense system. The study aims to determine dynamic patterns in serum Zn concentration in patients with TSCI and test for a correlation with neurological impairment. A total of 42 patients with TSCI were enrolled in this clinical observational study. Serum samples were collected at five different points in time after injury (at admission, and after 4 h, 9 h, 12 h, 24 h, and 3 days). The analysis of the serum Zn concentrations was conducted by total reflection X-ray fluorescence (TXRF). The patients were divided into two groups—a study group S (n = 33) with neurological impairment, including patients with remission (G1, n = 18) and no remission (G0, n = 15) according to a positive AIS (American Spinal Injury Association (ASIA) Impairment Scale) conversion within 3 months after the trauma; and a control group C (n = 9), consisting of subjects with vertebral fractures without neurological impairment. The patient data and serum concentrations were examined and compared by non-parametric test methods to the neurological outcome. The median Zn concentrations in group S dropped within the first 9 h after injury (964 µg/L at admission versus 570 µg/L at 9 h, p < 0.001). This decline was stronger than in control subjects (median of 751 µg/L versus 729 µg/L, p = 0.023). A binary logistic regression analysis including the difference in serum Zn concentration from admission to 9 h after injury yielded an area under the curve (AUC) of 82.2% (CI: 64.0–100.0%) with respect to persistent neurological impairment. Early Zn concentration dynamics differed in relation to the outcome and may constitute a helpful diagnostic indicator for patients with spinal cord trauma. The fast changes in serum Zn concentrations allow an assessment of neurological impairment risk on the first day after trauma. This finding supports strategies for improving patient care by avoiding strong deficits via adjuvant nutritive measures, e.g., in unresponsive patients after trauma.

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Bone Marrow Mesenchymal Stem Cell-Derived Exosome-Educated Macrophages Promote Functional Healing After Spinal Cord Injury

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.725573 ◽

2021 ◽

Vol 15 ◽

Author(s):

Chengjun Li ◽

Tian Qin ◽

Jinyun Zhao ◽

Rundong He ◽

Haicheng Wen ◽

...

Keyword(s):

Spinal Cord ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Cortical Neurons ◽

Axon Growth ◽

Sensory Function ◽

Functional Assay ◽

Cord Injury

The spinal cord injury is a site of severe central nervous system (CNS) trauma and disease without an effective treatment strategy. Neurovascular injuries occur spontaneously following spinal cord injury (SCI), leading to irreversible loss of motor and sensory function. Bone marrow mesenchymal stem cell (BMSC)–derived exosome-educated macrophages (EEM) have great characteristics as therapeutic candidates for SCI treatment. It remains unknown whether EEM could promote functional healing after SCI. The effect of EEM on neurovascular regeneration after SCI needs to be further explored. We generated M2-like macrophages using exosomes isolated from BMSCs, which were known as EEM, and directly used these EEM for SCI treatment. We aimed to investigate the effects of EEM using a spinal cord contusive injury mouse model in vivo combined with an in vitro cell functional assay and compared the results to those of a normal spinal cord without any biological intervention, or PBS treatment or macrophage alone (MQ). Neurological function measurements and histochemical tests were performed to evaluate the effect of EEM on angiogenesis and axon regrowth. In the current study, we found that treatment with EEM effectively promoted the angiogenic activity of HUVECs and axonal growth in cortical neurons. Furthermore, exogenous administration of EEM directly into the injured spinal cord could promote neurological functional healing by modulating angiogenesis and axon growth. EEM treatment could provide a novel strategy to promote healing after SCI and various other neurovascular injury disorders.

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Inhibition of TGF-β repairs spinal cord injury by attenuating EphrinB2 expressing through inducing miR-484 from fibroblast

Cell Death Discovery ◽

10.1038/s41420-021-00705-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Dayu Pan ◽

Fuhan Yang ◽

Shibo Zhu ◽

Yongjin Li ◽

Guangzhi Ning ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Axon Growth ◽

Neutralizing Antibody ◽

Mapk Signaling ◽

Sensory Function ◽

Systemic Injection ◽

Cord Injury ◽

Fibrotic Scar

AbstractSpinal cord injury (SCI) can lead to severe loss of motor and sensory function with high disability and mortality. The effective treatment of SCI remains unknown. Here we find systemic injection of TGF-β neutralizing antibody induces the protection of axon growth, survival of neurons, and functional recovery, whereas erythropoietin-producing hepatoma interactor B2 (EphrinB2) expression and fibroblasts distribution are attenuated. Knockout of TGF-β type II receptor in fibroblasts can also decrease EphrinB2 expression and improve spinal cord injury recovery. Moreover, miR-488 was confirmed to be the most upregulated gene related to EphrinB2 releasing in fibroblasts after SCI and miR-488 initiates EphrinB2 expression and physical barrier building through MAPK signaling after SCI. Our study points toward elevated levels of active TGF-β as inducer and promoters of fibroblasts distribution, fibrotic scar formation, and EphrinB2 expression, and deletion of global TGF-β or the receptor of TGF-β in Col1α2 lineage fibroblasts significantly improve functional recovery after SCI, which suggest that TGF-β might be a therapeutic target in SCI.

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Pannexin-1 Characterization after Spinal Cord Injury in Rats

10.21203/rs.3.rs-62854/v1 ◽

2020 ◽

Author(s):

Yu Huang ◽

Jin Lin ◽

Xuanwei Chen ◽

Jianhua Lin

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Western Blot ◽

Real Time ◽

Motor Function ◽

Real Time Pcr ◽

Hind Limb ◽

Pannexin 1 ◽

Cord Injury

Abstract Background Pannexin-1 (Panx-1) is a homomeric membrane semi-channel mostly expressed in the central nervous system of mammals, including neurons and glial cells. Panx-1 channels are highly permeable to calcium and Adenosine Triphosphatase (ATP), it plays an important role in Hypoxic injury of cerebral ischemia through a variety of signal pathways, nerve cell apoptosis and inflammatory response. However, its specific role in spinal cord injury (SCI) is not clear. In the current study, we aimed to investigate the characterization of Panx-1 after SCI in rats, and further analysis were made on its effect and possible mechanism in SCI in order to provide the experimental evidence for potential interfering target spot on SCI therapy. Methods A rat SCI model (Allen’s model) was established by NYU Impactor-III and the hind limb motor function of rats was observed by BBB score. The expression of Panx-1 was detected by Real-time PCR and Western Blot. The correlation between Panx-1 expression and the BBB score in rats after SCI was analyzed to reveal the role of Panx-1 in SCI. Results We found that the BBB score gradually recovered after SCI, but declined significantly at day 2 after SCI. Real-time PCR and Western Blot detection showed that compared with the normal control group and the sham operation group, the expression of Panx-1 increased significantly with time after SCI, and reached a peak at day 2 after SCI. Moreover, there was a significant negative correlation between the expression of Panx-1 protein and the BBB score of rat hind limb motor function at day 1, day 2, day 3 and day 5 after SCI. Conclusions The characterization of of Panx-1 expression after SCI in rats suggests that Panx-1 had a significant effect on the motor function recovery after SCI, and it was one of the important mechanisms that aggravate the secondary injury after SCI in rats. This provided experimental basis for further exploring the potential intervention target of SCI.

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Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation

Cells ◽

10.3390/cells10010143 ◽

2021 ◽

Vol 10 (1) ◽

pp. 143

Author(s):

Ganchimeg Davaa ◽

Jin Young Hong ◽

Tae Uk Kim ◽

Seong Jae Lee ◽

Seo Young Kim ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Cortex ◽

Functional Recovery ◽

Treadmill Exercise ◽

Exercise Group ◽

Control Group ◽

Epigenetic Changes ◽

Cord Injury ◽

The Brain

Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements.

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AAV2-mediated and hypoxia response element-directed expression of bFGF in neural stem cells showed therapeutic effects on spinal cord injury in rats

Cell Death and Disease ◽

10.1038/s41419-021-03546-6 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Sipin Zhu ◽

Yibo Ying ◽

Jiahui Ye ◽

Min Chen ◽

Qiuji Wu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Control Group ◽

Therapeutic Effects ◽

Hypoxia Response Element ◽

Neurofilament Protein ◽

Response Element ◽

Hypoxia Response ◽

Cord Injury

AbstractNeural stem cell (NSCs) transplantation has been one of the hot topics in the repair of spinal cord injury (SCI). Fibroblast growth factor (FGF) is considered a promising nerve injury therapy after SCI. However, owing to a hostile hypoxia condition in SCI, there remains a challenging issue in implementing these tactics to repair SCI. In this report, we used adeno-associated virus 2 (AAV2), a prototype AAV used in clinical trials for human neuron disorders, basic FGF (bFGF) gene under the regulation of hypoxia response element (HRE) was constructed and transduced into NSCs to yield AAV2-5HRE-bFGF-NSCs. Our results showed that its treatment yielded temporally increased expression of bFGF in SCI, and improved scores of functional recovery after SCI compared to vehicle control (AAV2-5HRE-NSCs) based on the analyses of the inclined plane test, Basso–Beattie–Bresnahan (BBB) scale and footprint analysis. Mechanistic studies showed that AAV2-5HRE-bFGF-NSCs treatment increased the expression of neuron-specific neuronal nuclei protein (NeuN), neuromodulin GAP43, and neurofilament protein NF200 while decreased the expression of glial fibrillary acidic protein (GFAP) as compared to the control group. Further, the expressions of autophagy-associated proteins LC3-II and Beclin 1 were decreased, whereas the expression of P62 protein was increased in AAV2-5HRE-bFGF-NSCs treatment group. Taken together, our data indicate that AAV2-5HRE-bFGF-NSCs treatment improved the recovery of SCI rats, which is accompanied by evidence of nerve regeneration, and inhibition of SCI-induced glial scar formation and cell autophagy. Thus, this study represents a step forward towards the potential use of AAV2-5HRE-bFGF-NSCs for future clinical trials of SCI repair.

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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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Depolarization and electrical stimulation enhance in vitro and in vivo sensory axon growth after spinal cord injury

Experimental Neurology ◽

10.1016/j.expneurol.2017.11.011 ◽

2018 ◽

Vol 300 ◽

pp. 247-258 ◽

Cited By ~ 12

Author(s):

Ioana Goganau ◽

Beatrice Sandner ◽

Norbert Weidner ◽

Karim Fouad ◽

Armin Blesch

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Electrical Stimulation ◽

Axon Growth ◽

Sensory Axon ◽

Cord Injury

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Transplantation of Neural Stem/Progenitor Cells at Different Locations in Mice with Spinal Cord Injury

Cell Transplantation ◽

10.3727/096368913x670967 ◽

2014 ◽

Vol 23 (11) ◽

pp. 1451-1464 ◽

Cited By ~ 21

Author(s):

Hiroki Iwai ◽

Satoshi Nori ◽

Soraya Nishimura ◽

Akimasa Yasuda ◽

Morito Takano ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Progenitor Cells ◽

Functional Recovery ◽

Control Group ◽

Cord Injury ◽

Neural Stem Progenitor Cells ◽

Neurotropic Factor ◽

Transplantation Site

Transplantation of neural stem/progenitor cells (NS/PCs) promotes functional recovery after spinal cord injury (SCI); however, few studies have examined the optimal site of NS/PC transplantation in the spinal cord. The purpose of this study was to determine the optimal transplantation site of NS/PCs for the treatment of SCI. Wild-type mice were generated with contusive SCI at the T10 level, and NS/PCs were derived from fetal transgenic mice. These NS/PCs ubiquitously expressed ffLuc-cp156 protein (Venus and luciferase fusion protein) and so could be detected by in vivo bioluminescence imaging 9 days postinjury. NS/PCs (low: 250,000 cells per mouse; high: 1 million cells per mouse) were grafted into the spinal cord at the lesion epicenter (E) or at rostral and caudal (RC) sites. Phosphate-buffered saline was injected into E as a control. Motor functional recovery was better in each of the transplantation groups (E-Low, E-High, RC-Low, and RC-High) than in the control group. The photon counts of the grafted NS/PCs were similar in each of the four transplantation groups, suggesting that the survival of NS/PCs was fairly uniform when more than a certain threshold number of cells were transplanted. Quantitative RT-PCR analyses demonstrated that brain-derived neurotropic factor expression was higher in the RC segment than in the E segment, and this may underlie why NS/PCs more readily differentiated into neurons than into astrocytes in the RC group. The location of the transplantation site did not affect the area of spared fibers, angiogenesis, or the expression of any other mediators. These findings indicated that the microenvironments of the E and RC sites are able to support NS/PCs transplanted during the subacute phase of SCI similarly. Optimally, a certain threshold number of NS/PCs should be grafted into the E segment to avoid damaging sites adjacent to the lesion during the injection procedure.

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