MEK1/2 Inhibition Synergistically Enhances the Preventive Effects of Normobaric Oxygen on Spinal Cord Injury in Decompression Sickness Rats

A previous study from our team found that hyperbaric oxygen (HBO) pretreatment attenuated decompression sickness (DCS) spinal cord injury by upregulating heat shock protein 32 (HSP32) via the ROS/p38 MAPK pathway. Meanwhile, a MEK1/2-negative regulatory pathway was also activated to inhibit HSP32 overexpression. The purpose of this study was to determine if normobaric oxygen (NBO) might effectively induce HSP32 while concurrently inhibiting MEK1/2 and to observe any protective effects on spinal cord injury in DCS rats. The expression of HSP32 in spinal cord tissue was measured at 6, 12, 18, and 24 h following NBO and MEK1/2 inhibitor U0126 pretreatment. The peak time of HSP32 was observed at 12 h after simulated air diving. Subsequently, signs of DCS, hindlimb motor function, and spinal cord and serum injury biomarkers were recorded. NBO-U0126 pretreatment significantly decreased the incidence of DCS, improved motor function, and attenuated oxidative stress, inflammatory response, and apoptosis in both the spinal cord and serum. These results suggest that pretreatment with NBO and U0126 combined can effectively alleviate DCS spinal cord injury in rats by upregulating HSP32. This may lead to a more convenient approach for DCS injury control, using non-pressurized NBO instead of HBO.

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Rhein lysinate improves motor function in rats with spinal cord injury via inhibiting p38 MAPK pathway

The Kaohsiung Journal of Medical Sciences ◽

10.1002/kjm2.12123 ◽

2019 ◽

Vol 35 (12) ◽

pp. 765-771

Author(s):

Jian Hao ◽

Ping Wang ◽

Dai‐Ping Pei ◽

Bin Jia ◽

Qun‐Sheng Hu

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

P38 Mapk ◽

Motor Function ◽

Mapk Pathway ◽

P38 Mapk Pathway ◽

Cord Injury ◽

Rhein Lysinate

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

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.574041 ◽

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.

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

10.21203/rs.3.rs-111721/v1 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-021-01490-1 ◽

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.

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

Frontiers in Neuroscience ◽

10.3389/fnins.2020.616864 ◽

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.

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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

Cell & Bioscience ◽

10.1186/s13578-020-00526-9 ◽

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.

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

10.1101/2020.10.21.347807 ◽

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.

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A comparison of adenosine A2A agonism and methylprednisolone in attenuating neuronal damage and improving functional outcome after experimental traumatic spinal cord injury in rabbits

Journal of Neurosurgery Spine ◽

10.3171/spi.2006.4.1.64 ◽

2006 ◽

Vol 4 (1) ◽

pp. 64-70 ◽

Cited By ~ 16

Author(s):

David O. Okonkwo ◽

T. Brett Reece ◽

Jeffrey J. Laurent ◽

A. Stewart Hawkins ◽

Peter I. Ellman ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Function ◽

Receptor Activation ◽

Control Group ◽

Spinal Cord Tissue ◽

Neuronal Viability ◽

Time Points ◽

Cord Injury ◽

Better Than

Object Steroid agents remain the lone pharmacological treatment in widespread use for acute spinal cord injury (SCI), although their utility remains in dispute in the neurotrauma literature. Adenosine A2A receptor activation with ATL-146e, a selective A2A agonist, has shown potential benefit in treating SCI; however, it has not been compared with the gold standard, methylprednisolone. The authors of this study evaluated ATL-146e and methylprednisolone for their ability to preserve neuronal viability and motor function in experimental SCI. Methods New Zealand White rabbits sustained SCI or sham injury via the Allen weight-drop technique. Ten minutes postinjury, animals received ATL-146e (ATL group, 0.06 μg/kg/min intravenously for 3 hours), methylprednisolone (steroid group, 30 mg/kg intravenously), or saline (trauma control group). Hindlimb motor function was recorded every 12 hours using the Tarlov motor grading scale (0, paralysis–5, normal hop). At 48 hours, fixed spinal cord tissue was evaluated for neuronal viability. Hindlimb motor function in animals treated with ATL-146e was equivalent to that of sham-injured animals and was significantly better than that of trauma control animals at all time points and that of steroid-treated animals at 12 hours (p = 0.05). Motor function in steroid-treated animals was worse than in those given ATL-146e and better than that of trauma control animals at later time points, but was not statistically significant (both p > 0.05). Neuronal viability (measured in neurons/hpf) was significantly higher in both treatment groups compared with the trauma control group (12.1 ± 1.4 neurons/hpf for the ATL and 13.3 ± 1.4 neurons/hpf for the steroid group compared with 7.5 ± 1.5 neurons/hpf for the trauma control group; both p < 0.04). Neuronal viability did not differ among ATL-146e–treated, steroid-treated, and sham-injured groups. Conclusions The use of ATL-146e is at least as effective as methylprednisolone in preserving function and is equivalent to methylprednisolone in preserving the structure of spinal cord tissue after blunt SCI. Adenosine A2A receptor activation may be an effective treatment for acute SCI while avoiding the adverse effects of steroid agents.

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