scholarly journals Jia-Ji Electro-Acupuncture Improves Locomotor Function With Spinal Cord Injury by Regulation of Autophagy Flux and Inhibition of Necroptosis

2021 ◽  
Vol 14 ◽  
Author(s):  
Yin Hongna ◽  
Tian Hongzhao ◽  
Li Quan ◽  
Feng Delin ◽  
Liu Guijun ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Acupuncture Treatment ◽  
Spinal Cord Tissue ◽  
Autophagy Flux ◽  
Nissl Staining ◽  
Microscopy Imaging ◽  
Locomotor Function ◽  
Cord Injury

Jia-Ji electro-acupuncture (EA) has been widely applied in clinic to exhibit curative effects on spinal cord injury (SCI). However, its underlying mechanisms leading to improvement of motor function after SCI remain unclear. Allen’s method was made by NYU Impactor M-III equipment to create the SCI rats model. Rats were randomly divided into four groups: Sham (only laminectomy), Model (SCI group), EA (SCI + Jia-Ji EA treatment), EA + CQ (SCI + Jia-Ji EA treatment + inhibitor chloroquine). Basso-Beattie-Bresnahan assessment showed improvement of hind limb motor function after Jia-Ji electro-acupuncture treatment. Histological change of injured spinal cord tissue was alleviated after treatment, observed by hematoxylin-eosin and Nissl staining. The mRNA and protein expression levels of RIPK1, RIPK3 and MLKL were decreased in EA group. Besides, the increased expression of LC3 and reduced expression of P62 after treatment compared with Model group, confirmed that Jia-Ji electro-acupuncture could enhance the autophagy flux. Electron microscopy imaging showed increasing the number of lysosomes, autophagosomes, and autolysosomes after Jia-Ji electro-acupuncture treatment. Furthermore, inhibition of lysosome function with CQ led to partly eliminate the effect of EA on reducing necroptosis. These data make the case that Jia-Ji electro-acupuncture treatment may improve locomotor function by promoting autophagy flux and inhibiting necroptosis.

scholarly journals Intraspinal Injection of Platelet-Rich Plasma Promotes Regeneration of the Spinal Cord and Improves Locomotor Function by Modulating the Apoptosis and the Wnt Signaling Pathways

2021 ◽  
Author(s):  
Zahra Behroozi ◽  
Fatemeh Ramezani ◽  
farinaz Nasirinezhad
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Wnt Signaling ◽  
Motor Function ◽  
Platelet Rich Plasma ◽  
Wnt Signaling Pathway ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Locomotor Function ◽  
Cord Injury

Abstract Background: There are complex mechanisms for reducing intrinsic repair ability and neuronal regeneration following spinal cord injury (SCI). Platelet-rich plasma (PRP) is a rich source of growth factors and has been used to stimulate regeneration of peripheral nerves in degenerationtive diseases. However, only a few studies have investigated the effects of PRP on the SCI models. We examined whether PRP derived from human umbilical cord blood (HUCB-PRP) could recover motor function in animals with spinal cord injury. We also investigate the role of Wnt signaling pathway.Methods: Ault male Wistar rats were randomly divided into 6 groups (n=60) as control, sham, SCI, vehicle (SCI+platelet-poor plasma), PRP2day (SCI+injection 2 days after SCI) and PRP14day (SCI+injection 14 days after SCI). SCI was performed at the T12-T13 level. BBB tests were done weekly after injury for six weeks. caspase3 expression was determined using the Immunohistochemistry technique. The expression of GSK3β, Tau and MAG were determined using the Western blot technique. Data were analyzed by PRISM & SPSS software. Results: PRP injected animals showed a higher locomotor function recovery than those in the SCI group (p<0.0001). The level of caspase3, GSK3β and CSF- Tau reduced and MAG level in the spinal cord increased by injection of HUCB-PRP in animals with spinal cord injury. Conclusions: Injection of HUCB-PRP enhanced hind limb locomotor performance by modulation of caspase3, GSK3β, tau and MAG expression. Using HUCB-PRP could be a new therapeutic option for recovering the motor function and axonal regeneration after spinal cord injury.

Inhibition of x-irradiation–enhanced locomotor recovery after spinal cord injury by hyperbaric oxygen or the antioxidant nitroxide tempol

2007 ◽  
Vol 6 (4) ◽  
pp. 337-343 ◽  
Author(s):  
Virany H. Hillard ◽  
Hong Peng ◽  
Kaushik Das ◽  
Raj Murali ◽  
Chitti R. Moorthy ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Hyperbaric Oxygen ◽  
Spinal Cord Tissue ◽  
Irradiation Site ◽  
Injury Site ◽  
Locomotor Recovery ◽  
Locomotor Function ◽  
Cord Injury ◽  
X Irradiation

Object Hyperbaric oxygen (HBO), the nitroxide antioxidant tempol, and x-irradiation have been used to promote locomotor recovery in experimental models of spinal cord injury. The authors used x-irradiation of the injury site together with either HBO or tempol to determine whether combined therapy offers greater benefit to rats. Methods Contusion injury was produced with a weight-drop device in rats at the T-10 level, and recovery was determined using the 21-point Basso-Beattie-Bresnahan (BBB) locomotor scale. Locomotor function recovered progressively during the 6-week postinjury observation period and was significantly greater after x-irradiation (20 Gy) of the injury site or treatment with tempol (275 mg/kg intraperitoneally) than in untreated rats (final BBB Scores 10.6 [x-irradiation treated] and 9.1 [tempol treated] compared with 6.4 [untreated], p < 0.05). Recovery was not significantly improved by HBO (2 atm for 1 hour [BBB Score 8.2, p > 0.05]). Interestingly, the improved recovery of locomotor function after x-irradiation, in contrast with antiproliferative radiotherapy for neoplasia, was inhibited when used together with either HBO or tempol (BBB Scores 8.2 and 8.3, respectively). The ability of tempol to block enhanced locomotor recovery by x-irradiation was accompanied by prevention of alopecia at the irradiation site. The extent of locomotor recovery following treatment with tempol, HBO, and x-irradiation correlated with measurements of spared spinal cord tissue at the contusion epicenter. Conclusions These results suggest that these treatments, when used alone, can activate neuroprotective mechanisms but, in combination, may result in neurotoxicity.

scholarly journals Rapamycin Preserves Neural Tissue, Promotes Schwann Cell Myelination and Reduces Glial Scar Formation After Hemi-Contusion Spinal Cord Injury in Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Junhao Liu ◽  
Ruoyao Li ◽  
Zucheng Huang ◽  
Junyu Lin ◽  
Wei Ji ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Schwann Cell ◽  
Motor Function ◽  
Neural Tissue ◽  
Glial Scar ◽  
Vehicle Group ◽  
Spinal Cord Tissue ◽  
Cord Injury

Protecting white matter is one of the key treatment strategies for spinal cord injury (SCI), including alleviation of myelin loss and promotion of remyelination. Rapamycin has been shown neuroprotective effects against SCI and cardiotoxic effects while enhancing autophagy. However, specific neuroprotection of rapamycin for the white matter after cervical SCI has not been reported. Therefore, we aim to evaluate the role of rapamycin in neuroprotection after hemi-contusion SCI in mice. Forty-six 8-week-old mice were randomly assigned into the rapamycin group (n = 16), vehicle group (n = 16), and sham group (n = 10). All mice of the rapamycin and vehicle groups received a unilateral contusion with 1.2-mm displacement at C5 followed by daily intraperitoneal injection of rapamycin or dimethyl sulfoxide solution (1.5 mg⋅kg–1⋅day–1). The behavioral assessment was conducted before the injury, 3 days and every 2 weeks post-injury (WPI). The autophagy-related proteins, the area of spared white matter, the number of oligodendrocytes (OLs) and axons were evaluated at 12 WPI, as well as the glial scar and the myelin sheaths formed by Schwann cells at the epicenter. The 1.2 mm contusion led to a consistent moderate–severe SCI in terms of motor function and tissue damage. Rapamycin administration promoted autophagy in spinal cord tissue after injury and reduced the glial scar at the epicenter. Additionally, rapamycin increased the number of OLs and improved motor function significantly than in the vehicle group. Furthermore, the rapamycin injection resulted in an increase of Schwann cell-mediated remyelination and weight loss. Our results suggest that rapamycin can enhance autophagy, promote Schwann cell myelination and motor function recovery by preserved neural tissue, and reduce glial scar after hemi-contusive cervical SCI, indicating a potential strategy for SCI treatment.

STEREOTACTIC RADIOSURGERY IMPROVES LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY IN RATS

Neurosurgery ◽  
2008 ◽  
Vol 63 (5) ◽  
pp. 981-988 ◽  
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 &lt; 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.

scholarly journals Mmu-miR-27a-5p Promotes the Polarization of Macrophages to the M2 Phenotype at the Site of Spinal Cord Injury in Mice

2021 ◽  
Author(s):  
Mingkun Yang ◽  
Xiaoqian Dang ◽  
Xu Zhang ◽  
Chuan Liu ◽  
Min He
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Macrophage Polarization ◽  
Spinal Cord Tissue ◽  
Injured Spinal Cord ◽  
Arginase 1 ◽  
Tnf Α ◽  
Cord Injury ◽  
M2 Phenotype

Abstract BackgroundTo investigate the effect of mmu-miR-27a-5p on macrophage polarization in the injured spinal cord and the recovery of motor function after spinal cord injury (SCI) in mice.MethodsA total of 160 specific-pathogen-free male mice were randomly divided into sham, model, mmu-miR-27a-5p, mmu-miR-27a-5p-negative control (NC) groups, with 40 mice in each group. Hindlimb motor function was assessed using the Basso Mouse scale (BMS) before injury and at 1, 3, 7, and 14 days after surgery. Spinal cord tissue samples were obtained at 1, 3, 7, and 14 days after surgery, and macrophage polarization types were detected by using western blot analysis, immunofluorescence, flow cytometry and RT-qPCR.ResultsThe BMS score in the mmu-miR-27a-5p group was significantly higher than that in the model and mmu-miR-27a-5p-NC groups at 7 and 14 days after SCI (X2=26.45-57.62, P<0.05). No significant changes in the expression of M1 markers IL-1β, TNF-α and M2 markers IL-10, Arginase-1 at each time point in the sham group (P=0.96). The expression of IL-1β and TNF-α was significantly lower, while the expression of IL-10 and Arginase-1 were significantly higher in the mmu-miR-27a-5p group as compared to the model and mmu-miR-27a-5p-NC groups at 7 and 14 days after SCI (P<0.05).ConclusionAdministration of mmu-miR-27a-5p can promote the polarization of macrophages to the M2 phenotype in the injured spinal cord, and improve motor function recovery within 14 days after SCI in mice.

scholarly journals Transplantation of rat cranial bone-derived mesenchymal stem cells promotes functional recovery in rats with spinal cord injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuyo Maeda ◽  
Takashi Otsuka ◽  
Masaaki Takeda ◽  
Takahito Okazaki ◽  
Kiyoharu Shimizu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Motor Function ◽  
Cranial Bone ◽  
Transcranial Electrical Stimulation ◽  
Spinal Cord Tissue ◽  
Cell Based Therapy ◽  
Cord Injury

AbstractCell-based therapy using mesenchymal stem cells (MSCs) is a novel treatment strategy for spinal cord injury (SCI). MSCs can be isolated from various tissues, and their characteristics vary based on the source. However, reports demonstrating the effect of transplanted rat cranial bone-derived MSCs (rcMSCs) on rat SCI models are lacking. In this study, we determined the effect of transplanting rcMSCs in rat SCI models. MSCs were established from collected bone marrow and cranial bones. SCI rats were established using the weight-drop method and transplanted intravenously with MSCs at 24 h post SCI. The recovery of motor function and hindlimb electrophysiology was evaluated 4 weeks post transplantation. Electrophysiological recovery was evaluated by recording the transcranial electrical stimulation motor-evoked potentials. Tissue repair after SCI was assessed by calculating the cavity ratio. The expression of genes involved in the inflammatory response and cell death in the spinal cord tissue was assessed by real-time polymerase chain reaction. The transplantation of rcMSCs improved motor function and electrophysiology recovery, and reduced cavity ratio. The expression of proinflammatory cytokines was suppressed in the spinal cord tissues of the rats that received rcMSCs. These results demonstrate the efficacy of rcMSCs as cell-based therapy for SCI.

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

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1822 ◽  
Author(s):  
Liam M. Koehn ◽  
Qing Dong ◽  
Sing-Yan Er ◽  
Lachlan D. Rash ◽  
Glenn F. King ◽  
...  
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.

scholarly journals Mettl14-mediated m6A modification modulates neuron apoptosis during the repair of spinal cord injury by regulating the transformation from pri‐mir‐375 to miR-375

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haoyu Wang ◽  
Jing Yuan ◽  
Xiaoqian Dang ◽  
Zhibin Shi ◽  
Wenrui Ban ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Critical Region ◽  
Cell Model ◽  
Spinal Cord Tissue ◽  
Spinal Cord Neurons ◽  
Cord Injury ◽  
Neuron Apoptosis

Abstract Background Spinal cord injury (SCI) is a disabling disorder, resulting in neurological impairments. This study investigated the mechanism of methyltransferase-like 14 (Mettl14) on apoptosis of spinal cord neurons during SCI repair by mediating pri-microRNA (miR) dependent N6-methyladenosine (m6A) methylation. Methods The m6A content in total RNA and Mettl14 levels in spinal cord tissues of SCI rats were detected. Mettl14 expression was intervened in SCI rats to examine motor function, neuron apoptosis, and recovery of neurites. The cell model of SCI was established and intervened with Mettl14. miR-375, related to SCI and positively related to Mettl14, was screened out. The expression of miR-375 and pri-miR-375 after Mettl14 intervention was detected. The expression of pri-miR-375 combined with DiGeorge critical region 8 (DGCR8) and that modified by m6A was detected. Furthermore, the possible downstream gene and pathway of miR-375 were analysed. SCI cell model with Mettl14 intervention was combined with Ras-related dexamethasone-induced 1 (RASD1)/miR-375 intervention to observe the apoptosis. Results Mettl14 level and m6A content in spinal cord tissue were significantly increased. After Mettl14 knockdown, the injured motor function was restored and neuron apoptosis was reduced. In vitro, Mettl14 silencing reduced the apoptosis of SCI cells; miR-375 was reduced and pri-miR-375 was increased; miR-375 targeted RASD1. Silencing Mettl14 inactivated the mTOR pathway. The apoptosis in cells treated with silencing Mettl14 + RASD1/miR-375 was inhibited. Conclusions Mettl14-mediated m6A modification inhibited RASD1 and induced the apoptosis of spinal cord neurons in SCI by promoting the transformation of pri-miR-375 to mature miR-375.

scholarly journals Plant Scaffolds Support Motor Recovery and Regeneration in Rats after Traumatic Spinal Cord Injury

2020 ◽  
Author(s):  
Daniel J. Modulevsky ◽  
Charles M. Cuerrier ◽  
Maxime Leblanc-Latour ◽  
Ryan J. Hickey ◽  
Ras-Jeevan K. Obhi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Neural Regeneration ◽  
Plant Tissues ◽  
Traumatic Spinal Cord Injury ◽  
Spinal Cord Tissue ◽  
Vascular Bundles ◽  
Axonal Regrowth ◽  
Cord Injury

ABSTRACTAs of yet, no standard of care incorporates the use of a biomaterial to treat traumatic spinal cord injury (SCI)1–5. However, intense development of biomaterials for treating SCI have focused on the fabrication of microscale channels to support the regrowth of axons while minimizing scar tissue formation6–10. We previously demonstrated that plant tissues can be decellularized and processed to form sterile, biocompatible and implantable biomaterials that support cell infiltration and vascularization in vivo11–13. Notably, the vascular bundles of plant tissues are also composed of microscale channels with geometries thought to be relevant for supporting neural tissue regeneration9,14. We hypothesized that decellularized vascular bundles would support neural regeneration and the recovery of motor function. Therefore, rats which received a complete T8-T9 spinal cord transection were implanted with plant-derived channeled scaffolds. Animals which received the scaffolds alone, with no therapeutic stem cells or other interventions, demonstrated a significant and stable improvement in motor function over six months compared to controls. Histological analysis reveals minimal scarring and axonal regrowth through the scaffolds, further confirmed with tracer studies. Taken together, our work defines a novel route for exploiting naturally occurring plant microarchitectures to support the repair of functional spinal cord tissue.

scholarly journals Trehalose Augments Neuron Survival and Improves Recovery from Spinal Cord Injury via mTOR-Independent Activation of Autophagy

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Kailiang Zhou ◽  
Huanwen Chen ◽  
Huazi Xu ◽  
Xiaofeng Jia
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Therapeutic Potential ◽  
Neurological Dysfunction ◽  
Tissue Loss ◽  
Compression Injury ◽  
Autophagy Flux ◽  
Nissl Staining ◽  
Cord Injury

Spinal cord injury (SCI) is a major cause of irreversible nerve injury and leads to serious tissue loss and neurological dysfunction. Thorough investigation of cellular mechanisms, such as autophagy, is crucial for developing novel and effective therapeutics. We administered trehalose, an mTOR-independent autophagy agonist, in SCI rats suffering from moderate compression injury to elucidate the relationship between autophagy and SCI and evaluate trehalose’s therapeutic potential. 60 rats were divided into 4 groups and were treated with either control vehicle, trehalose, chloroquine, or trehalose + chloroquine 2 weeks prior to administration of moderate spinal cord crush injury. 20 additional sham rats were treated with control vehicle. H&E staining, Nissl staining, western blot, and immunofluorescence studies were conducted to examine nerve morphology and quantify autophagy and mitochondrial-dependent apoptosis at various time points after surgery. Functional recovery was assessed over a period of 4 weeks after surgery. Trehalose promotes autophagosome recruitment via an mTOR-independent pathway, enhances autophagy flux in neurons, inhibits apoptosis via the intrinsic mitochondria-dependent pathway, reduces lesion cavity expansion, decreases neuron loss, and ultimately improves functional recovery following SCI (all p < 0.05 ). Furthermore, these effects were diminished upon administration of chloroquine, an autophagy flux inhibitor, indicating that trehalose’s beneficial effects were due largely to activation of autophagy. This study presents new evidence that autophagy plays a critical neuroprotective and neuroregenerative role in SCI, and that mTOR-independent activation of autophagy with trehalose leads to improved outcomes. Thus, trehalose has great translational potential as a novel therapeutic agent after SCI.

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