Beneficial effects of IL-37 after spinal cord injury in mice

IL-37, a member of the IL-1 family, broadly reduces innate inflammation as well as acquired immunity. Whether the antiinflammatory properties of IL-37 extend to the central nervous system remains unknown, however. In the present study, we subjected mice transgenic for human IL-37 (hIL-37tg) and wild-type (WT) mice to spinal cord contusion injury and then treated them with recombinant human IL-37 (rIL-37). In the hIL-37tg mice, the expression of IL-37 was barely detectable in the uninjured cords, but was strongly induced at 24 h and 72 h after the spinal cord injury (SCI). Compared with WT mice, hIL-37tg mice exhibited increased myelin and neuronal sparing and protection against locomotor deficits, including 2.5-fold greater speed in a forced treadmill challenge. Reduced levels of cytokines (e.g., an 80% reduction in IL-6) were observed in the injured cords of hIL-37tg mice, along with lower numbers of blood-borne neutrophils, macrophages, and activated microglia. We treated WT mice with a single intraspinal injection of either full-length or processed rIL-37 after the injury and found that the IL-37–treated mice had significantly enhanced locomotor skills in an open field using the Basso Mouse Scale, as well as supported faster speed on a mechanical treadmill. Treatment with both forms of rIL-37 led to similar beneficial effects on locomotor recovery after SCI. This study presents novel data indicating that IL-37 suppresses inflammation in a clinically relevant model of SCI, and suggests that rIL-37 may have therapeutic potential for the treatment of acute SCI.

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Treadmill training promotes spinal changes leading to locomotor recovery after partial spinal cord injury in cats

Journal of Neurophysiology ◽

10.1152/jn.01044.2012 ◽

2013 ◽

Vol 109 (12) ◽

pp. 2909-2922 ◽

Cited By ~ 31

Author(s):

Marina Martinez ◽

Hugo Delivet-Mongrain ◽

Serge Rossignol

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Treadmill Training ◽

Locomotor Training ◽

Locomotor Recovery ◽

Thoracic Level ◽

Spinal Circuitry ◽

Cord Injury ◽

Locomotor Deficits ◽

Spinal Hemisection

After a spinal hemisection at thoracic level in cats, the paretic hindlimb progressively recovers locomotion without treadmill training but asymmetries between hindlimbs persist for several weeks and can be seen even after a further complete spinal transection at T13. To promote optimal locomotor recovery after hemisection, such asymmetrical changes need to be corrected. In the present study we determined if the locomotor deficits induced by a spinal hemisection can be corrected by locomotor training and, if so, whether the spinal stepping after the complete spinal cord transection is also more symmetrical. This would indicate that locomotor training in the hemisected period induces efficient changes in the spinal cord itself. Sixteen adult cats were first submitted to a spinal hemisection at T10. One group received 3 wk of treadmill training, whereas the second group did not. Detailed kinematic and electromyographic analyses showed that a 3-wk period of locomotor training was sufficient to improve the quality and symmetry of walking of the hindlimbs. Moreover, after the complete spinal lesion was performed, all the trained cats reexpressed bilateral and symmetrical hindlimb locomotion within 24 h. By contrast, the locomotor pattern of the untrained cats remained asymmetrical, and the hindlimb on the side of the hemisection was still deficient. This study highlights the beneficial role of locomotor training in facilitating bilateral and symmetrical functional plastic changes within the spinal circuitry and in promoting locomotor recovery after an incomplete spinal cord injury.

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Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

Neural Plasticity ◽

10.1155/2016/1279051 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Ping Li ◽

Zhao-Qian Teng ◽

Chang-Mei Liu

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Axon Regeneration ◽

Therapeutic Potential ◽

Glial Scar ◽

Scar Formation ◽

Extrinsic Factors ◽

Cord Injury ◽

The Central Nervous System

Spinal cord injury is a devastating disease which disrupts the connections between the brain and spinal cord, often resulting in the loss of sensory and motor function below the lesion site. Most injured neurons fail to regenerate in the central nervous system after injury. Multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration after injury. MicroRNAs can modulate multiple genes’ expression and are tightly controlled during nerve development or the injury process. Evidence has demonstrated that microRNAs and their signaling pathways play important roles in mediating axon regeneration and glial scar formation after spinal cord injury. This article reviews the role and mechanism of differentially expressed microRNAs in regulating axon regeneration and glial scar formation after spinal cord injury, as well as their therapeutic potential for promoting axonal regeneration and repair of the injured spinal cord.

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STEREOTACTIC RADIOSURGERY IMPROVES LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY IN RATS

Neurosurgery ◽

10.1227/01.neu.0000330404.37092.3e ◽

2008 ◽

Vol 63 (5) ◽

pp. 981-988 ◽

Cited By ~ 5

Author(s):

Richard J. Zeman ◽

Xialing Wen ◽

Nengtai Ouyang ◽

Ronald Rocchio ◽

Lynn Shih ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stereotactic Radiosurgery ◽

Spinal Cord Tissue ◽

Injured Spinal Cord ◽

Locomotor Recovery ◽

Locomotor Function ◽

Cord Injury ◽

Contusion Injury ◽

X Irradiation

Abstract OBJECTIVE Currently, because of the precision of stereotactic radiosurgery, radiation can now be delivered by techniques that shape the radiation beam to the tissue target for a variety of clinical applications. This avoids unnecessary and potentially damaging irradiation of surrounding tissues inherent in conventional irradiation, so that irradiation of the minimum volume of tissue necessary for optimal therapeutic benefit can be achieved. Although conventional x-irradiation has been shown to improve recovery from spinal cord injury in animals, the efficacy of targeted irradiation of the injured spinal cord has not been demonstrated previously. The purpose of these studies was to determine whether stereotactic x-irradiation of the injured spinal cord can enhance locomotor function and spare spinal cord tissue after contusion injury in a standard experimental model of spinal cord injury. METHODS Contusion injury was produced in rats at the level of T10 with a weight-drop device, and doses of x-irradiation were delivered 2 hours after injury via a Novalis, 6-MeV linear accelerator shaped beam radiosurgery system (BrainLAB USA, Westchester, IL) in 4 sequential fractions, with beam angles 60 to 70 degrees apart, at a rate of 6.4 Gy/minute. The target volume was a 4 × 15-mm cylinder along the axis of the spinal cord, with the isocenter positioned at the contusion epicenter. Locomotor function was determined for 6 weeks after injury with the 21-point Basso, Beattie, and Bresnahan (BBB) locomotor scale and tissue sparing in histological sections of the spinal cord. RESULTS Locomotor function recovered progressively during the 6-week postinjury observation period. BBB scores were significantly greater in the 10-Gy x-irradiated group compared with controls (9.4 versus 7.3; P < 0.05), indicating hind limb weight support or dorsal stepping in contrast to hind limb joint mobility without weight bearing. Doses in the range of 2 to 10 Gy increased BBB scores progressively, whereas greater doses of 15 to 25 Gy were associated with lower BBB scores. The extent of locomotor recovery after treatment with x-irradiation correlated with measurements of spared spinal cord tissue at the contusion epicenter. CONCLUSION These results suggest a beneficial role for stereotactic radiosurgery in a rat model of acute spinal cord contusion injury and raise hopes for human treatment strategies. Additional animal studies are needed to further define potential benefits.

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Grafted human induced pluripotent stem cells improve the outcome of spinal cord injury: modulation of the lesion microenvironment

Scientific Reports ◽

10.1038/s41598-020-79846-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tamás Bellák ◽

Zoltán Fekécs ◽

Dénes Török ◽

Zsuzsanna Táncos ◽

Csilla Nemes ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Pluripotent Stem Cells ◽

Functional Improvement ◽

Cord Injury ◽

Contusion Injury ◽

Spinal Cord Contusion ◽

Induced Pluripotent

AbstractSpinal cord injury results in irreversible tissue damage followed by a very limited recovery of function. In this study we investigated whether transplantation of undifferentiated human induced pluripotent stem cells (hiPSCs) into the injured rat spinal cord is able to induce morphological and functional improvement. hiPSCs were grafted intraspinally or intravenously one week after a thoracic (T11) spinal cord contusion injury performed in Fischer 344 rats. Grafted animals showed significantly better functional recovery than the control rats which received only contusion injury. Morphologically, the contusion cavity was significantly smaller, and the amount of spared tissue was significantly greater in grafted animals than in controls. Retrograde tracing studies showed a statistically significant increase in the number of FB-labeled neurons in different segments of the spinal cord, the brainstem and the sensorimotor cortex. The extent of functional improvement was inversely related to the amount of chondroitin-sulphate around the cavity and the astrocytic and microglial reactions in the injured segment. The grafts produced GDNF, IL-10 and MIP1-alpha for at least one week. These data suggest that grafted undifferentiated hiPSCs are able to induce morphological and functional recovery after spinal cord contusion injury.

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Schwann Cells Transplantation Improves Locomotor Recovery in Rat Models with Spinal Cord Injury: a Systematic Review and Meta-Analysis

Cellular Physiology and Biochemistry ◽

10.1159/000438574 ◽

2015 ◽

Vol 37 (6) ◽

pp. 2171-2182 ◽

Cited By ~ 9

Author(s):

Lei Yang ◽

Yingbin Ge ◽

Jian Tang ◽

Jinxia Yuan ◽

Dawei Ge ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Schwann Cells ◽

Meta Analysis ◽

Cochrane Library ◽

Locomotor Recovery ◽

Rat Models ◽

Beneficial Effects ◽

Cord Injury ◽

Different Sources

Background/Aims: Schwann cells (SCs) which were demonstrated to be responsible for axonal myelination and ensheathing are widely studied and commonly used for cell transplantation to treat spinal cord injury (SCI). We performed this meta-analysis to summarize the effects of SCs versus controls for locomotor recovery in rat models of traumatic SCI. Methods: Studies of the BBB scores after transplantation of SCs were searched out from Pubmed, Cochrane Library Medline databases and analyzed by Review Manager 5.2.5. Results: Thirteen randomized controlled animal trials were selected with 283 rats enrolled. The studies were divided to different subgroups by different models of SCI, different cell doses for transplantation, different sources of SCs and different transplantation ways. The pooled results of this meta-analysis suggested that SCs transplantation cannot significantly improve the locomotor recovery at a short time after intervention (1 week after transplantation) in both impacted and hemi-sected SCI models. However, at a longer time after intervention (3, 5-7 and over 8 weeks after transplantation), significant improvement of BBB score emerged in SCs groups compared with control groups. Subgroup analyses revealed that SCs transplantation can significantly promote locomotor recovery regardless of in high or low doses of cells, from different sources (isolated from sciatic nerves or differentiated from bone marrow stromal cells(BMSCs)) and with or without scaffolding. Conclusion: SCs seem to demonstrate substantial beneficial effects on locomotor recovery in a widely-used animal models of SCI.

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Role of GDNF in Spinal Cord Injury Repair

10.20944/preprints201805.0247.v1 ◽

2018 ◽

Author(s):

Melissa J. Walker ◽

Xiao-Ming Xu

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Therapeutic Potential ◽

Secondary Wave ◽

Future Directions ◽

Cord Injury ◽

Combinational Treatment ◽

The Central Nervous System ◽

Mechanical Insult

Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, also in combination with other factors and cell transplantations, for repairing the injured spinal cord. As recent decades of studies strongly suggest combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed.

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Stem Cell Transplantation: A Promising Therapy for Spinal Cord Injury

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190823144424 ◽

2020 ◽

Vol 15 (4) ◽

pp. 321-331 ◽

Cited By ~ 2

Author(s):

Zhe Gong ◽

Kaishun Xia ◽

Ankai Xu ◽

Chao Yu ◽

Chenggui Wang ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Therapeutic Potential ◽

Embryonic Stem ◽

Current Status ◽

Cord Injury

Spinal Cord Injury (SCI) causes irreversible functional loss of the affected population. The incidence of SCI keeps increasing, resulting in huge burden on the society. The pathogenesis of SCI involves neuron death and exotic reaction, which could impede neuron regeneration. In clinic, the limited regenerative capacity of endogenous cells after SCI is a major problem. Recent studies have demonstrated that a variety of stem cells such as induced Pluripotent Stem Cells (iPSCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs) and Neural Progenitor Cells (NPCs) /Neural Stem Cells (NSCs) have therapeutic potential for SCI. However, the efficacy and safety of these stem cellbased therapy for SCI remain controversial. In this review, we introduce the pathogenesis of SCI, summarize the current status of the application of these stem cells in SCI repair, and discuss possible mechanisms responsible for functional recovery of SCI after stem cell transplantation. Finally, we highlight several areas for further exploitation of stem cells as a promising regenerative therapy of SCI.

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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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A Collagen-Based Scaffold for Promoting Neural Plasticity in a Rat Model of Spinal Cord Injury

Polymers ◽

10.3390/polym12102245 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2245

Author(s):

Jue-Zong Yeh ◽

Ding-Han Wang ◽

Juin-Hong Cherng ◽

Yi-Wen Wang ◽

Gang-Yi Fan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Neural Plasticity ◽

Collagen Scaffold ◽

Glial Scar ◽

Beneficial Effects ◽

Cord Injury

In spinal cord injury (SCI) therapy, glial scarring formed by activated astrocytes is a primary problem that needs to be solved to enhance axonal regeneration. In this study, we developed and used a collagen scaffold for glial scar replacement to create an appropriate environment in an SCI rat model and determined whether neural plasticity can be manipulated using this approach. We used four experimental groups, as follows: SCI-collagen scaffold, SCI control, normal spinal cord-collagen scaffold, and normal control. The collagen scaffold showed excellent in vitro and in vivo biocompatibility. Immunofluorescence staining revealed increased expression of neurofilament and fibronectin and reduced expression of glial fibrillary acidic protein and anti-chondroitin sulfate in the collagen scaffold-treated SCI rats at 1 and 4 weeks post-implantation compared with that in untreated SCI control. This indicates that the collagen scaffold implantation promoted neuronal survival and axonal growth within the injured site and prevented glial scar formation by controlling astrocyte production for their normal functioning. Our study highlights the feasibility of using the collagen scaffold in SCI repair. The collagen scaffold was found to exert beneficial effects on neuronal activity and may help in manipulating synaptic plasticity, implying its great potential for clinical application in SCI.

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